NHS R&D HTA Programme

Health Technology A

ssessment 2006;Vol. 10: N

o. 12A

decision analysis for sampling and treating infected diabetic foot ulcers

A series of systematic reviews toinform a decision analysis for samplingand treating infected diabetic footulcers

EA Nelson, S O’Meara, D Craig, C Iglesias, S Golder, J Dalton, K Claxton, SEM Bell-Syer, E Jude, C Dowson, R Gadsby, P O’Hareand J Powell

Health Technology Assessment 2006; Vol. 10: No. 12

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EA Nelson,1* S O’Meara,1 D Craig,2 C Iglesias,1

S Golder,2 J Dalton,1 K Claxton,3 SEM Bell-Syer,1

E Jude,4 C Dowson,5 R Gadsby,6 P O’Hare7

and J Powell8

1 Department of Health Sciences, University of York, UK2 Centre for Reviews and Dissemination, University of York, UK3 Department of Economics and Centre for Health Economics,

University of York, UK4 Tameside General Hospital, Ashton-under-Lyne, UK5 Department of Biological Sciences, University of Warwick, UK6 Warwick Diabetes Care, University of Warwick, UK7 Warwick Medical School, University of Warwick, UK8 Faculty of Medicine, Imperial College, London, UK

* Corresponding author

Declared competing interests of authors: none

Published April 2006

This report should be referenced as follows:

Nelson EA, O’Meara S, Craig D, Iglesias C, Golder S, Dalton J, et al. A series of systematicreviews to inform a decision analysis for sampling and treating infected diabetic foot ulcers.Health Technol Assess 2006;10(12).

Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE,Excerpta Medica/EMBASE and Science Citation Index Expanded (SciSearch®) and Current Contents®/Clinical Medicine.

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Objectives: To review systematically the evidence onthe performance of diagnostic tests used to identifyinfection in diabetic foot ulcers (DFUs) and ofinterventions to treat infected DFUs. To use estimatesderived from the systematic reviews to create adecision analytic model in order to identify the mosteffective method of diagnosing and treating infectionand to identify areas of research that would lead tolarge reductions in clinical uncertainty.Data sources: Electronic databases covering periodfrom inception of the database to November 2002.Review methods: Selected studies were assessedagainst validated criteria and described in a narrativereview. The structure of a decision analytic model wasderived for two groups of patients in whom diagnostictests were likely to be used.Results: Three studies that investigated theperformance of diagnostic tests for infection onpopulations including people with DFUs found thatthere was no evidence that single items on a clinicalexamination checklist were reliable in identifyinginfection in DFUs, that wound swabs perform poorlyagainst wound biopsies, and that semi-quantitativeanalysis of wound swabs may be a useful alternative toquantitative analysis. However, few people with DFUswere included, so it was not possible to tell whetherdiagnostic performance differs for DFUs relative towounds of other aetiologies. Twenty-three studiesinvestigated the effectiveness (n = 23) or cost-effectiveness (n = 2) of antimicrobial agents for DFUs.

Eight studied intravenous antibiotics, five oralantibiotics, four different topical agents such asdressings, four subcutaneous granulocyte colonystimulating factor (G-CSF), one evaluated oral andtopical Ayurvedic preparations and one comparedtopical sugar versus antibiotics versus standard care.The majority of trials were underpowered and weretoo dissimilar to be pooled. There was no strongevidence for recommending any particular antimicrobialagent for the prevention of amputation, resolution ofinfection or ulcer healing. Topical pexiganan cream maybe as effective as oral antibiotic treatment withofloxacin for the resolution of local infection. Ampicillinand sulbactam were less costly than imipenem andcilastatin, a growth factor (G-CSF) was less costly thanstandard care and cadexomer iodine dressings may beless costly than daily dressings. A decision analyticmodel was derived for two groups of people, those forwhom diagnostic testing would inform treatment –people with ulcers which do not appear infected butwhose ulcer is not progressing despite optimalconcurrent treatment – and those in whom a firstcourse of antibiotics (prescribed empirically) havefailed. There was insufficient information from thesystematic reviews or interviews with experts topopulate the model with transition probabilities for thesensitivity and specificity of diagnosis of infection inDFUs. Similarly, there was insufficient information onthe probabilities of healing, amputation or death in theintervention studies for the two populations of interest.


iii

© Queen’s Printer and Controller of HMSO 2006. All rights reserved.

Abstract

A series of systematic reviews to inform a decision analysis forsampling and treating infected diabetic foot ulcers

EA Nelson,1* S O’Meara,1 D Craig,2 C Iglesias,1 S Golder,2 J Dalton,1 K Claxton,3

SEM Bell-Syer,1 E Jude,4 C Dowson,5 R Gadsby,6 P O’Hare7 and J Powell8

1 Department of Health Sciences, University of York, UK2 Centre for Reviews and Dissemination, University of York, UK3 Department of Economics and Centre for Health Economics, University of York, UK4 Tameside General Hospital, Ashton-under-Lyne, UK5 Department of Biological Sciences, University of Warwick, UK6 Warwick Diabetes Care, University of Warwick, UK7 Warwick Medical School, University of Warwick, UK8 Faculty of Medicine, Imperial College, London, UK* Corresponding author

Therefore, we were unable to run the model to inform the most effective diagnostic and treatmentstrategy.Conclusions: The available evidence is too weak to beable to draw reliable implications for practice. Thismeans that, in terms of diagnosis, infection in DFUscannot be reliably identified using clinical assessment.This has implications for determining which patientsneed formal diagnostic testing for infection, on whetherempirical treatment with antibiotics (before the resultsof diagnostic tests are available) leads to betteroutcomes, and on identifying the optimal methods ofdiagnostic testing. With respect to treatment, it is notknown whether treatment with systemic or localantibiotics leads to better outcomes or whether any

particular agent is more effective. Limited evidencesuggests that both G-CSF and cadexomer iodinedressings may be less expensive than ‘standard’ care,that ampicillin/sulbactam may be less costly thanimipenem/cilastatin, and that an unlicensed cream(pexiganan) may be as effective as oral ofloxacin.Further research is needed to ascertain thecharacteristics of infection in people with DFUs thatinfluence healing and amputation outcomes, todetermine whether detecting infection prior totreatment offers any benefit over empirical therapy,and to establish the most effective and cost-effectivemethods for detecting infection, as well as the relativeeffectiveness and cost-effectiveness of antimicrobialinterventions for DFU infection.

Abstract

iv


v

List of abbreviations .................................. vii

Executive summary .................................... ix

1 Background ................................................ 1The impact of diabetic foot ulcers ............. 1Quality of life ............................................. 1General management of DFU ................... 2Wound infection and healing ..................... 2Management of infection in DFU .............. 3Methods used in this project ...................... 5Initial representation of pathway of care ............................................................. 5

2 Research questions .................................... 9

3 Review methods ......................................... 11Search strategy ........................................... 11Study selection ........................................... 13Data extraction ........................................... 15Critical appraisal of included studies ........ 15Data analysis ............................................... 17Decision analytic model ............................. 17

4 Results ........................................................ 19Literature search results ............................. 19Studies included in the diagnostic review ... 19Results of diagnostic review ....................... 19Effectiveness studies ................................... 26Overall summary ........................................ 47Decision analytic modelling ....................... 48

5 Discussion ................................................... 61Diagnostic studies ...................................... 61Effectiveness studies ................................... 64

Strengths and weaknesses of the review .... 68Integration of this review with previous work ............................................................ 69Decision analytic model ............................. 69

6 Conclusions ................................................ 71Implications for clinical practice ............... 71Implications for research ........................... 71

Acknowledgements .................................... 73

References .................................................. 75

Appendix 1 Search strategies .................... 87

Appendix 2 Expert advisory panel ........... 113

Appendix 3 Data extraction forms ............ 115

Appendix 4 Data extraction tables ............ 125

Appendix 5 Quality assessment ................ 199

Appendix 6 Summary of excluded studies ......................................................... 203

Appendix 7 Experts’ views on definition and management of clinically infected diabetic foot ulcers ..................................... 211

Health Technology Assessment reportspublished to date ....................................... 223

Health Technology Assessment Programme ................................................ 235

Contents

A/C amoxycilin and clavulanate

A/S ampicillin and sulbactam

CCT controlled clinical trial

CFU colony-forming unit

CI confidence interval

CONSORT Consolidated Standards ofReporting Trials

CRD Centre for Reviews andDissemination

DFU diabetic foot ulcer

DNA deoxyribonucleic acid

DNPU diabetic neuropathic plantar ulcer

DPN diabetic peripheral neuropathy

EQ-5D EuroQol quality of lifequestionnaire

G-CSF granulocyte colony-stimulatingfactor

HEED Health Economics EvaluationDatabase

HRQoL health-related quality of life

I/C imipenem and cilastatin

LR likelihood ratio

+LR positive likelihood ratio

–LR negative likelihood ratio

MRSA methicillin-resistant Staphylococcusaureus

NHS EED National Health ServiceEconomic Evaluation Database

NICE National Institute for Health andClinical Excellence

NPV negative predictive value

P/C piperacillin and clindamycin

P/T piperacillin and tazabacam

PCR polymerase chain reaction

PPV positive predictive value

QALY quality-adjusted life-year

QUADAS Quality Assessment of Studies ofDiagnostic Accuracy Included inSystematic Reviews

QUOROM Quality of Reporting of Meta-Analyses

RCT randomised controlled trial

rh-G-CSF recombinant human granulocytecolony-stimulating factor

rhPDGF recombinant human platelet-derived growth factor

ROC receiver operating characteristic

RR relative risk

RVP retrograde venous perfusion

SD standard deviation

SEK Swedish kroner

SPSS Statistics Package for SocialSciences

STARD Standards for Reporting ofDiagnostic Accuracy

T/C ticarcillin and clavulanate

VAS visual analogue scale


vii


List of abbreviations

All abbreviations that have been used in this report are listed here unless the abbreviation is well known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only in figures/tables/appendices in which case the abbreviation is defined in the figure legend or at the end of the table.


ix


BackgroundAround 6% of people with diabetes have a footulcer or have a history of one. Diabetic foot ulcers(DFUs) are associated with increased mortality,illness and reduced quality of life. Diagnosinginfection in DFU accurately and administeringantibiotics may be important as infection can leadto amputation. However, using antimicrobialagents inappropriately could be costly, and lead toincreased bacterial resistance. This reviewconcentrates on the diagnosis of infection and themanagement of DFUs with antimicrobial agents.

ObjectivesThe objectives of this study were:

� To review systematically the evidence on theperformance of diagnostic tests used to identifyinfection in DFUs and of interventions to treatinfected DFUs.

� To use estimates derived from the systematicreviews to create a decision analytic model inorder to identify the most effective method ofdiagnosing and treating infection and toidentify areas of research that would lead tolarge reductions in clinical uncertainty.

MethodsData sourcesElectronic searches were made of 19 databasescovering the period from inception of each databaseto November 2002. In addition, handsearches ofbook chapters, conference proceedings, a journaland bibliographies of retrieved studies were carriedout. Internet searches were also made.

Study selectionStudies that dealt with the following areas wereselected.

Diagnosis Studies of the diagnosis of infection in people withDFUs or venous leg ulceration where a referencestandard was compared with an alternativeassessment.

EffectivenessRandomised controlled trials (RCTs) or controlledclinical trials (CCTs) of the effect ofmicrobiological analysis or antimicrobial agents inpeople with DFUs.

Cost-effectivenessEconomic evaluations of eligible interventionsstudied in which costs and effectiveness weresynthesised.

ModellingEconomic or decision analytic models in which the progress of patients with DFUs was described in sufficient detail to allow replication of themodel.

Data extractionQuality checklists and data extraction forms foreach study design were completed by one reviewerand checked by a second. Interviews were heldwith experts to inform gaps in the evidence.

Data synthesisStudies were described in a narrative review. Thestructure of a decision analytic model was derivedfor two groups of patients in whom diagnostic testswere likely to be used.

ResultsDiagnosisThree studies investigated the performance ofdiagnostic tests for infection on populationsincluding people with diabetic foot ulcers. Onestudy investigated the performance of clinicalassessment, another investigated the performanceof punch biopsy versus wound swab andquantitative analysis and the third comparedquantitative and semi-quantitative wound swabs inpeople with chronic wounds, including DFUs, forthe identification of infection. These studies, all ofwhich looked at identifying infection in chronicwounds, found that:

� There was no evidence that single items on aclinical examination checklist were reliable inidentifying infection in DFUs.

� Wound swabs performed poorly against woundbiopsies.

Executive summary

x

� Semi-quantitative analysis of wound swabs maybe a useful alternative to quantitative analysis.

For the three diagnostic studies few people withDFUs were included, so it was not possible to tellwhether diagnostic performance differs for DFUsrelative to wounds of other aetiologies.

EffectivenessTwenty-three studies investigated the effectiveness(n = 23) or cost-effectiveness (n = 2) ofantimicrobial agents for DFU. Eight studiedintravenous antibiotics, five oral antibiotics, fourdifferent topical agents such as dressings, foursubcutaneous granulocyte colony stimulatingfactor (G-CSF), one evaluated oral and topicalAyurvedic preparations and one compared topicalsugar versus antibiotics versus standard care.

The majority of trials were underpowered andwere too dissimilar to be pooled. There was nostrong evidence for recommending any particularantimicrobial agent for the prevention ofamputation, resolution of infection or ulcerhealing. Topical pexiganan cream may be aseffective as oral antibiotic treatment with ofloxacinfor the resolution of local infection.

Ampicillin and sulbactam were less costly thanimipenem and cilastatin, a growth factor (G-CSF)was less costly than standard care and cadexomeriodine dressings may be less costly than dailydressings.

Decision analytic modelA decision analytic model was derived for twogroups of people, those for whom diagnostictesting would inform treatment – people withulcers which do not appear infected but whoseulcer is not progressing despite optimalconcurrent treatment – and those in whom a firstcourse of antibiotics (prescribed empirically) havefailed. There was insufficient information from thesystematic reviews or interviews with experts topopulate the model with transition probabilitiesfor the sensitivity and specificity of diagnosis ofinfection in DFUs. Similarly, there was insufficientinformation on the probabilities of healing,amputation or death in the intervention studies

for the two populations of interest. Therefore, wewere unable to run the model to inform the mosteffective diagnostic and treatment strategy.

ConclusionsImplications for healthcareThe available evidence was too weak to be able todraw reliable implications for practice. This meansthat, in terms of diagnosis, infection in DFUscannot be reliably identified using clinicalassessment. This also has implications fordetermining which patients need formaldiagnostic testing for infection, whether empiricaltreatment with antibiotics (before the results ofdiagnostic tests are available) leads to betteroutcomes, and identifying the optimal methods ofdiagnostic testing. With respect to treatment, wedo not know whether treatment with systemic orlocal antibiotics leads to better outcomes orwhether any particular agent is more effective.Limited evidence suggests that both G-CSF andcadexomer iodine dressings may be less expensivethan ‘standard’ care, that ampicillin/sulbactammay be less costly than imipenem/cilastatin, andalso that an unlicensed cream (pexiganan) may beas effective as oral ofloxacin.

Implications for researchQuestions to be answered are:

• What characteristics of infection in people withDFUs influence healing and amputationoutcomes?

• Does detecting infection prior to treatmentoffer any benefit over empirical therapy?

• If detecting infection offers clinical benefit, thenwhat are the most effective and cost-effectivemethods for detecting infection, e.g. clinicalassessment, wound swabbing or wound biopsyand microbiological analysis, or noveltechniques such as electronic nose/tongue andpolymerase chain reaction analysis?

• What are the relative effectiveness and cost-effectiveness of antimicrobial interventions forDFU infection, e.g. combinations of broad-spectrum antibiotics, larval therapy, growthfactors and topical agents/dressings?

Executive summary

The impact of diabetic foot ulcersDiabetic foot ulcers (DFUs) are costly andassociated with increased mortality, thedevelopment of morbidity and reduced quality oflife. It has been estimated that the proportion ofpeople with diabetes in the UK who have ever hadfoot ulceration is around 6%.1 Currie andcolleagues analysed routine inpatient data from ahospital in Cardiff, UK, and estimated that thecost per admission for DFU was £1451 and thatthe extrapolated annual national cost would be£17 million (price year 1994).2 A prognostic studyconducted in the USA showed that presence offoot ulceration was related to a higher risk ofshort-term mortality (mean follow-up 692 days) inpeople with diabetes.3

A large proportion of DFUs may fail to heal andare associated with the development of infection(including osteomyelitis) and/or gangrene and anincreased risk of lower extremity amputation.4,5

A review of European studies examining theincidence of amputations in diabetic patientsreported estimates ranging from 5.7 to 20.5 amputations per 100,000 total populationper year.1 Although the variation in estimates may be due to differences between thecharacteristics of the various populations studied,it is also likely to be explained by differences inthe ways in which amputation rates are recordedand expressed.1

Amputation can be performed at several differentlevels, including the following: toe excision; toeand ray excision (longitudinal amputation of a toeand its metatarsal); tarsometatarsal (Lisfranc)disarticulation (amputation of junction of tarsusand metatarsus); midtarsal (Chopart)disarticulation (amputation through thetalonavicular and calcaneocuboid joints, leavingonly the hindfoot); Syme ankle disarticulation;transtibial (below knee); knee disarticulation(through knee); and transfemoral (above knee).6,7

The excision must be proximal to the level ofdamaged tissue. Other considerations indetermining the level of amputation includedegree of tissue oxygen perfusion, predictedpatient adherence with after-care and lack ofprotective sensation.7

It has been suggested that amputation should notbe viewed as failure of management, but rather asa means of restoring a patient’s functional status.However, this may depend upon the level ofamputation performed. Partial foot excision isconsidered to have several advantages, includingpreservation of weight-bearing and proprioceptiveabilities, less alteration of body image and modestpostoperative requirements for footwearmodification or application of a small prosthesisor orthosis. Such devices may help restore near-normal ambulatory function.7 The term‘proprioceptive’ refers to the capability ofreceiving stimuli originating in muscles, tendonsand other internal tissues.8 However, the short-and long-term success of amputation can dependupon the underlying morbidity at the time ofsurgery and also future morbidity. A non-systematic review of mainly surgical case seriessuggested postoperative re-ulceration rates ofaround 25%.9 In addition, it has been noted that aproportion of patients undergo repeatedamputations of either a higher level of the samelimb or the contralateral limb.5,10,11

Quality of lifeStudies have shown that diabetic people with footulceration suffer from reduced quality of life interms of pain, restricted mobility, time lost fromwork and reduction in social activities, leading tosocial isolation and loneliness.12–14

A number of studies have attempted to assess theimpact of amputation on quality of life in diabeticpatients. Three studies reported the surprisingfinding that some amputees experienced a betterquality of life than those with a DFU, at least insome domains.15–17 In studies where informationwas given about the level of amputation, theincreased quality of life scores in amputees relativeto people with a foot ulcer were seen only in thosewith minor amputations (toe ortransmetatarsal).15,17 This finding may beexplained by the possibility that those with a DFUdevelop depression associated with theacknowledgement of a poorer state of health.18 Inaddition, reduced mobility has been shown to beassociated with reduced quality of life in diabetic


1


Chapter 1

Background

patients.13 Those with a DFU often have a regimenof reduced mobility imposed upon them, owing tothe requirement to reduce pressure on the affectedfoot, whereas amputees who have had a prosthesisfitted are normally encouraged to mobilise.18

General management of DFUThe management of the patient with a DFUrequires input from a multidisciplinary team whoprovide different aspects of care, as follows:

� patient education� optimisation of blood glucose control� correction (where possible) of arterial

insufficiency� reduction of pressure on the foot, for example,

through the use of pressure-relieving/redistributing orthoses such as totalcontact casts

� optimal skin care� optimal care of wounds, with respect to

cleansing and dressings� debridement of non-viable tissue� reduction of pain associated with ulceration

(particularly arteriopathic ulcers)� surgical intervention, including debridement,

drainage of pus, revascularisation oramputation, as considered necessary

� maintenance of mobility and independence� prevention of wound infection, where possible� early detection and treatment of wound

infection.

Care may take place in various settings, includingprimary care, specialist outpatient clinics, hospital(acute care) and rehabilitation centres. Currentrecommendations state that diabetic patientsshould be screened regularly and entered on to aregister. Those deemed to be at risk of footproblems should be referred to a diabetes footcare team consisting of a physician, a nursespecialist and a podiatrist.19,20 However, manyhospitals in the UK have yet to implement such ateam.21 A recent survey of consultantdiabetologists (79/160 usable questionnairesreturned) indicated that 67% of respondents hadaccess to a designated diabetic foot clinic.However, the staff members of the clinics were notdescribed.22

Wound infection and healingThe presence of a combination ofpathophysiological factors means that people with

diabetes are particularly susceptible to footinfection. These factors include impairedglycaemic control, neuropathy, altered footanatomy, lower extremity oedema, peripheralvascular disease, immunodeficiency, impairedwound healing, altered flora on unbroken skin andan increased incidence of skin disorders leading tobreaks in the skin.23,24 Foot ulceration may beviewed as one of a number of clinical signs thatcan alert the clinician to the development ofdiabetic foot infection, a broader clinical problemthan ulceration alone. Other indicative lesionsinclude cellulitis, abscess, osteomyelitis and aninflamed appearance of the soft tissue of the foot.Other local signs of diabetic foot infection includepain, swelling, sinus tract formation, crepitation(thought to suggest presence of soft tissue gas andnecrosis) and fluctuance (thought to indicateundrained suppuration). Systemic signs andsymptoms of infection (fever, rigors, vomiting,tachycardia, confusion, malaise) and metabolicdisturbances such as severe hyperglycaemia mayalso indicate a locally developing infection of thefoot.24,25 Although we recognise that diabetic footinfection may occur in conjunction withulceration, this project will focus on themanagement of foot ulceration with regard toinfection. Therefore, infections of the foot wherethere is no ulcer present will not be considered forthe purposes of this project.

Moist chronic skin ulcers are an ideal medium formicrobiological growth and the identified floracan include both aerobic and anaerobic bacteria,and fungi.24 Results from studies of microbiologicalcultures from DFUs have indicated that the mostfrequently identified isolates are as follows:

� Aerobes – Staphylococcus aureus, Staphylococcusepidermidis, coagulase-negative Staphylococcusspecies, group B Streptococcus, Enterococcus spp.,Escherichia coli, Pseudomonas aeruginosa, Proteusmirabilis and other Proteus species26–36

� Anaerobes – Bacteroides melaninogenicus,Bacteroides fragilis, Peptostreptococcus species andPeptococcus species27–29,32,33,35–37

� Fungi – Candida tropicalis and Candida albicans.27

Anaerobes are sometimes mentioned as importantcausative organisms in DFU infection.Microbiological surveys in DFUs show a widerange of anaerobe prevalence, expressed as aproportion of the total number of isolates found(5–58%).26–36 This variation may depend upon thesetting of the study, the methods used forcollecting, transporting and analysing specimensand patient or wound characteristics. It may also

Background

2

reflect the possible difficulties of culturinganaerobes from routine swabs and/or failure to useprolonged anaerobic culture methods.38

Some authors suggest that infection in DFUs maybe caused by the presence of more than oneisolate.30,39 In a Canadian study, the mean numberof organism types per lesion varied according tothe setting of treatment: 2.1 isolates for auniversity hospital, 2.3 for a community hospitaland 3.4 for a district hospital.30 In a smaller studybased in the UK and Ireland, the mean number ofisolates cultured from patients attending a diabeticclinic was 4.5 per wound.39

It is possible that different microorganisms thatare present in the same wound may interact withone another, for example aerobes and anaerobes.An emerging area of research interest is thepossible impact of biofilms on outcomes in chronicwounds. A biofilm has been defined as “a layeredculture of microorganisms growing on a surfacethat they have created themselves by secretingpolysaccharides and glycoproteins”.8 Thestructured communities of bacteria within abiofilm are thought to have increased resistance toantimicrobial agents compared with bacteria livingas planktonic forms (meaning free-living bacteriaas opposed to those contained within biofilmcommunities).40,41 Biofilms have been cultured inanimal models.41 In a case series of 15 patientswho had undergone vascular grafts, 13 hadbiofilms cultured from their graft sites duringfollow-up times ranging from 5 months to14 years.42 It has been proposed that the presenceof biofilms may have an adverse impact ondiabetic foot infections and that therapies otherthan antimicrobial agents may need to beconsidered such as enzymatic therapy or inhibitionof bacterial communication.40 However, furtherresearch is required in this area to establish theimpact of biofilms on outcomes in DFUs and todetermine the optimum methods of management.

The eradication of causative microorganisms hasbeen deemed to be an important outcome in themanagement of infection in DFUs, as reflected inthe literature and through expert opinion.43–47

However, wound healing has also been identifiedas an important outcome, and may be of greaterimportance to patients than outcomes such as theresolution of infection.13,48,49

The relationship between bacterial colonisation andhealing in chronic wounds is currently unclear.50–53

Although it has been proposed that higher bacterialcounts may be associated with failure to heal,51,54,55,

some sources suggest that the presence of bacteriais unimportant.50,52 However, other findingsindicate that the presence of four or more bacterialgroups may be associated with delayed healing.56

Results from some studies suggest that the presenceof specific microorganisms may be detrimental towound healing, including �-haemolytic streptococciand Staphylococcus aureus.51 However, most of thisliterature relates to venous leg ulcers. An earliersystematic review did not find any such data onDFUs.48

Management of infection in DFUGeneral treatment considerationsThe resolution of infection in DFUs requires abroad consideration of several aspects of clinicalmanagement, including optimisation of glycaemiccontrol, surgery (debridement, drainage andrevascularisation) and the treatment of associatedand concurrent deep soft tissue infection and/orosteomyelitis.

Prolonged, poorly controlled hyperglycaemia isassociated with progressive adverse changes invarious types of body tissue and abnormalities ofthe immune system. Impaired glycaemic control isthought to contribute to increased rates ofinfection, and to generate more serious infections.It is therefore generally recommended thatattention be given to optimising blood glucoselevels in any diabetic patient with an infected footor ulcer.57

Surgical procedures may also have a role inmanaging infected DFUs. Sharp or surgicaldebridement may help counter wound infectionthrough the removal of necrotic tissue, which canfoster microorganisms.24,25,58 Surgical drainage ofpus can be deemed necessary if the infected ulceris associated with a deeper soft tissue infection.24

The presence of vascular disease impairs thedelivery of antibiotics and oxygen to areas ofinfection.58 Vascular reconstruction surgery to treatperipheral arterial disease may help resolveinfection by improving the blood flow to the foot,thereby improving the supply of nutrients anddrugs to infected tissue.24,25,58

Long-term and refractory infection of DFUs maybe associated with the presence of underlyingosteomyelitis.58 Findings from a small, non-randomised study suggested that conservativesurgical treatment of osteomyelitis added tomedical treatment may produce an increasedhealing rate of foot ulcers compared with medical


3


treatment alone.59 The potential importance ofthe above therapies in treating infected DFUs isacknowledged. However, this project will focus onthe diagnosis of infection and use of antimicrobialagents in the management of DFUs.

Diagnosis of infection in DFUsDiagnostic aspects of infection in DFUs focus onthe identification of infection through clinicaljudgement and/or laboratory techniques. Theacquisition of microbiological specimens isrequired in order to culture potentially causativemicroorganisms and study their sensitivities toantibiotic therapy; however, when more than onebacterial species is identified it is difficult todetermine which is/are causing the infection.Acquisition techniques include the wound swab,curettage, tissue biopsy and fine-needleaspiration.24,60 Two more recently developed,potentially useful techniques are the electronicnose/tongue and polymerase chain reaction (PCR).The electronic nose/tongue is a type of electronicsensor used to detect the presence of bacteria. Ithas been used in rhinological research61 and for invitro studies.62 PCR is a system for the in vitroamplification of DNA, amplification in this contextbeing an increase in the number of copies of aspecific DNA fragment.8 This technique has beenused for detecting resistant staphylococcalinfection following cardiac surgery63 and in burnspatients.64 It may be useful in cases wheresuspected bacterial presence cannot easily bedetected using culture techniques,65 where thecultivation of a causative microorganism isconsidered to be risky66 or where a pathogen isknown to be slow-growing.67 Relevant evidencerelating to these newer techniques, and also themore established bacterial acquisition methods,will be sought and assessed in this review. Of thecurrently available techniques, it could be arguedthat wound swabs are the most important as theyare performed more frequently than the othermethods. There is an important related debateabout whether techniques and procedures used forswabbing and plating out (spreading a specimenonto a nutrient surface) are always optimal.56

The interactions between clinical assessment,microbiological sampling and antibiotic prescribingare of importance in the management of DFU.There is some debate in the literature as towhether it would be advisable to wait forbacteriology results prior to prescribing antibioticsin order to ensure that the correct agent isadministered, or whether to give antibiotics beforethe result has been reported. Early treatmentwithout the test result might be beneficial as it may

promote faster healing and help to reduceamputation rates. However, it could also mean thatthe wrong antibiotics are prescribed, which mayencourage bacterial resistance. Another approachis not to rely on cultures at all, but to treat thewound according to clinical judgement.24,25

Several different study designs may be consideredfor primary evaluations of diagnostic tests. It ispossible to combine diagnostic and treatmentcomponents of clinical management in a diagnosticrandomised controlled trial (RCT). Such studiescombine an evaluation of the performance ofdiagnostic tests and subsequent treatmentstrategies in a sequential design, capturing theeventual effect of diagnostic procedures on clinicaloutcomes. Just as in evaluations of the clinicaleffectiveness of a therapy, this design is consideredoptimal.68,69 Diagnostic RCTs have been conductedin areas such as acute appendicitis70–71 anddevelopmental hip dysplasia.72

Alternative designs in diagnostic research includecase–control and cohort studies. When comparedwith a diagnostic RCT, these study designs aremore prone to bias. Important types of bias indiagnostic research include the following:68,69

� Spectrum bias (occurs when the group recruitedto the study is not representative of thepopulation to which the test will be applied inclinical practice).

� Absent, inappropriate or imperfect referencestandard.

� Rapid developments in technology, meaningthat study findings rapidly become obsolete.

� Disease progression bias (patients may getbetter or worse over time owing to the time lagbetween the application of the index andreference tests).

� Partial verification bias (only some patientsreceive the reference test).

� Differential verification bias (inconsistentreference standards used).

� Incorporation bias (index test is part of thereference standard).

� Treatment paradox (improvement of conditiondue to treatment given, usually following theresults of the index test).

� Review bias (failure to blind to findings of indexand/or reference test).

� Clinical review bias (interpretation influencedby availability of clinical data).

� Inappropriate handling of unclear results in thedata analysis (i.e. failure to report them clearly).

� Arbitrary choice of threshold value (especially ifdetermined post hoc).

Background

4

Diagnostic cohort and case–control studies areseen more frequently in the literature thandiagnostic RCTs, and therefore evidence fromthese designs is likely to be of value, provided thatthe potential impact of important sources of biascan be taken into account.68,69

Systemic antimicrobial agentsSystemic treatments for infection in DFUs revolvearound the prescription of antibiotics. Systemicagents can be administered orally for mild tomoderate infections or intravenously for moreserious infections, and usually fall into thefollowing groups:73

1. penicillins, for example flucloxacillin andamoxicillin

2. cephalosporins, cephamycins and other �-lactams, for example cefalexin and cefazolin

3. tetracyclines (oral route only), for exampletetracycline

4. aminoglycosides (given by the intramuscular orintravenous route), for example gentamicinand netilmycin

5. macrolides, for example erythromycin andclarithromycin

6. quinolones, for example ciprofloxacin.

There are also several other drugs available,including clindamycin, metronidazole andtrimethoprim.73 A previously published systematicreview including only studies reporting objectivelyassessed wound healing outcomes found two smallRCTs of oral antibiotics used with DFUs. In termsof wound healing, oral amoxycillin combined withclavulanic acid proved to be no better thanplacebo,74 and no statistically significant differencewas observed between clindamycin andcephalexin.75 Despite this paucity of existingevidence, current recommendations for DFU careinclude systemic antibiotics as considerednecessary in conjunction with cleansing,debridement, wound dressings, pressure relief andgood glycaemic control.23,49,76–79

Topical antimicrobial agentsTopical preparations may be divided into twocategories, according to their function. One groupconsists of lotions with antimicrobial properties,used to irrigate or cleanse wounds. These usuallyhave only a brief contact time with the woundsurface, unless they are used as a pack or soak.They include the hypochlorites (e.g. Eusol),hexachlorophene (hexachlorophane) – a constituentof some soaps and other skin cleansers – andsubstances such as potassium permanganate andgentian violet (both used in solution).73

The second group consists of preparationsdesigned to stay in contact with the wound surfacefor a longer period of time, ideally until the nextdressing change. These include creams, ointmentsand impregnated dressings. Most topicalantibiotics come into this category, and includemupirocin, fusidic acid and neomycin sulfate.Other preparations include silver-based products,such as silver-sulfadiazine.73

Products that fall into both categories includepovidone-iodine, chlorhexidine and hydrogenperoxide.73

An emerging topical agent is pexiganan acetate, apeptide antibiotic.24

Methods used in this projectSystematic reviews may be based on evaluations ofdiagnostic tests and evaluations of clinicaleffectiveness. On occasions, a series of suchreviews may be required to answer a complexresearch question, as opposed to the single reviewsthat are often seen in the literature. Systematicreviews are most commonly used to addressindividual and focused research questions aboutthe effects of healthcare interventions.80 However,health professionals usually view patients in thecontext of a more complex sequence of decisionsand associated interventions. Decision analysis is atechnique that allows representation of this morecomplicated scenario.81

Clinical decision analysis is a modelling techniquethat represents the different pathways of care thatare possible for a given patient together with thecomplex sequence of decisions involved in thatcare. It is a useful technique for helping healthprofessionals to identify the optimum pathway ofcare under conditions of uncertainty.82 Some ofthe advantages of clinical decision analytic modelsinclude the option of being able to undertakesensitivity analyses if there is uncertainty aroundimportant model parameters, patient preferencescan be incorporated into the model and decisions,preferences and utilities can be made explicit.82

Initial representation of pathwayof careIn order to make the linkages between thediagnostic and effectiveness questions explicit, wewill describe a theoretical pathway of care,highlighting the decisions made by clinicians at


5


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various stages. Figure 1 is a simple representationof the decisions made in the treatment of apotentially infected DFU. This pathway wasconstructed at the start of the project to helprepresent the interdependence of the variousdecisions that can be made. It was amendedduring the project from the literature and the finalpathway is shown in Figure 8 (p. 59). This pathwayintegrates the methods of diagnosis of infection,the decision to treat immediately or await resultsof an antibiogram and the effectiveness and cost-effectiveness of individual antimicrobial agents (anantibiogram has been defined as an examinationthat measures the biological resistance ofsubstances causing disease, performed prior tochemotherapy so as to make it more efficient).83

This simplified pathway does not take into accountthe transitions of an ulcer from uninfected toinfected status or the pathway of care for thoseulcers that are unhealed at the end of this episode.It does serve, however, to illustrate thecombination of clinical questions and decisionsthat inform the care of a person with a diabeticfoot ulcer. At the very left of the pathway, at thepoint where a patient enters the system, a clinicalassessment is undertaken to assess for the presenceof infection. The clinical pathway followeddepends on the result of this assessment.

A person with an ulcer that appeared infectedwould follow the route A–B. At this point, theclinician decides whether to take a microbiologicalsample to inform therapy or to treat empirically. Aclinician makes this decision when they reach boxB, that is, do the advantages of waiting forbacteriology results outweigh the benefits ofimmediate, empirical treatment? The route F–Jrepresents empirical treatment, whereas the routeG–I–J represents taking a sample to inform choiceof antimicrobial agent.

If the decision is made to take a sample to informmicrobiological therapy, then the clinician makes achoice from a number of types of sampling

techniques, such as biopsy, swab or near-patienttesting techniques for bacteria such as theelectronic nose. The clinician makes the decisionabout choice of sample at box G. We need to knowwhether, for example, a wound swab is a validindicator of the presence of infection. Followingthe collection of a bacteriological sample, asubsequent decision may need to be maderegarding the sample processing, for example,qualitative culture and sensitivity, quantitative orsemi-quantitative culture or techniques using DNAreplication to expand and identify bacterialpopulations. The decision about the processingand analysis of the sample is made at box I.

A person with an ulcer that appeared uninfectedand yet failed to heal may also be offeredantimicrobial therapy as the clinician may suspectthat the wound is in fact infected withoutdisplaying signs and symptoms of infection. Thepathway A–C–D would represent this situation. Atpoint D in the pathway, the clinician decideswhether to treat empirically or to take amicrobiological sample to inform therapy.

A patient whose ulcer is not clinically infected andwhose ulcer is healing satisfactorily will not usuallybe offered antimicrobial agents and would followthe pathway A–C–E–K.

At each decision point, there is the potential forthe results of the systematic reviews of theperformance of diagnostic tests or the clinical andcost-effectiveness of antimicrobial therapy to guideclinical decisions/sampling policies. Patientpreferences may also be taken into account. Thepoints at which the review questions (1–5, seeTable 1) are addressed are also highlighted inFigure 1.


7


The aim of this research is to define theoptimum management strategies for infected

DFUs with reference to clinical examination,microbiological sampling of the wound andantimicrobial therapy.

This research had two objectives:

1. to undertake a series of systematic reviews ofthe evidence relating to the diagnosis andtreatment of infection in DFU

2. to use estimates derived from the systematicreviews to create a decision analytic model

Five linked systematic reviews were conducted,three concerning aspects of diagnosis, onefocusing on effectiveness of microbiologicalanalysis and the other on both clinical and cost-effectiveness of antimicrobial treatment. Theresearch questions and corresponding systematicreviews are outlined in Table 1.


9


Chapter 2

Research questions

TABLE 1 Research questions and corresponding systematic reviews

Question Systematic review of

1. How can clinicians determine whether a sample should … the sensitivity and specificity of clinical examination in be taken from a DFU? the identification of infection in DFUs

2. What sampling techniques are the most accurate for … the sensitivity and specificity of different sampling people with DFUs? techniques (wound swab, biopsy, wound lavage and/or

curettage, near-patient testing techniques) in theidentification of infection in DFUs

3. What laboratory techniques are the most accurate for … the sensitivity and specificity of techniques of analysing samples from DFUs? microbiological analysis (qualitative, quantitative, semi-

quantitative) in the identification of infection in DFUs

4. What impact does microbiological analysis have on … the effects of microbiological analysis on the treatment therapy? of infection, pain (in patients without neuropathy), exudate

associated with DFUs, the impact on healing, impact onHRQoL and the development of complications

5. What is the effectiveness and cost-effectiveness of … the clinical effectiveness and cost-effectiveness of management of infection in DFU? techniques for treating infection in DFUs including wound

healing and the transfer of drug-resistant organisms to staffand other patients

Search strategySearch strategies and bibliographicdatabases usedWe searched 19 electronic databases, two Internetsources of ongoing research, six conferenceproceedings, one journal and three books forprimary research or systematic reviews, and nineInternet sources for clinical practice guidelines orreviews. All sources were searched for diagnostic,effectiveness and modelling studies. For thediagnostic questions we searched for systematicreviews of diagnostic studies, primary diagnosticstudies, and economic evaluations of diagnosticstudies. For the effectiveness questions, we searchedfor systematic reviews of trials [RCTs and/orcontrolled clinical trials (CCTs)], primary studies(RCTs and/or CCTs) or economic evaluations ofintervention studies. For the modelling question wesearched for decision analytic or economic models.The sources are listed in Table 2.

The searches were carried out in three stages. Thefirst set of searches aimed to retrieve papers relatingto clinical effectiveness, the second papers relatingto economic effectiveness and the third to diagnostictesting. All three sets of retrieved records were thenimported into reference manager software(Endnote) and labelled as either ‘rct’, ‘econ’ or ‘diag’depending on the search strategy from which theywere retrieved. These records were then de-duplicated and any records that were retrieved frommore than one of the search types labelled as such.

Diagnostic searchesLiterature searches were carried out on samplingand microbiological techniques for the diagnosisof DFUs. Databases were searched from the dateof inception of each database to the most recentdate available.

Internet databases� Allied And Complementary Medicine (AMED)

(1985–2002 November).Searched: 23 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.

� British Nursing Index (BNI) (1994–2002September).Searched: 23 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.

� CINAHL (1982–2002 October, week 4).Searched: 23 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.

� EMBASE (1980–2002, week 46).Searched: 24 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.

� MEDLINE (1966 to 2002 October, week 5).Searched: 24 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.

� PREMEDLINE (up to 21 November 2002).Searched: 24 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.

HandsearchesSix conference proceedings, the Diabetic Footjournal and three books were handsearched.

Clinical effectiveness searchesThe following sources were searched for studiesrelating to the impact of microbiological analysison therapy and the effectiveness of differenttreatments. The literature searches were designedto retrieve systematic reviews and trials only.However, some databases cannot be reliablyrestricted by study type and in these cases thesearch was not limited by study design, and theresults of the searches were entered into anEndnote Library. A range of free text terms andsubject headings were used as appropriate. Detailsof the search strategies are contained inAppendix 1.

CRD internal administration databases (searched:12 November 2002 using CAIRS software)� Database of Abstracts of Reviews of Effectiveness

(DARE).� Health Technology Assessment Database (HTA).

Internet databases� Allied And Complementary Medicine (AMED)

(1985–2002 November).Searched: 12 November 2002 OvidWebGateway at http://gateway.ovid.com/athens.

� British Nursing Index (BNI) (1994–2002August).Searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.

� CINAHL (1982–2002 October, week 4).Searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.


11


Chapter 3

Review methods

� Cochrane Controlled Trials Register (CCTR)(2002: Issue 4).Searched: 12 November 2002 on InternetExplorer using the “new generation software” athttp://www.update-software.com/cochrane/.

� Cochrane Database of Systematic Reviews(CDSR) (2002: Issue 3).Searched: 12 November 2002 on InternetExplorer using the ‘new generation software’ athttp://www.update-software.com/cochrane/.

� EMBASE (1980–2002, week 44).Searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.

� MEDLINE (1966–2002 October, week 4).Searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.



No date or language restrictions were applied toany of the literature searches. The bibliographies

Review methods

12

TABLE 2 Sources for primary studies, reviews and guidelines

Electronic databasesAllied and Complementary Medicine Database (AMED)British Nursing Index (BNI)Cochrane Controlled Trials Register (CCTR)Cochrane Database of Systematic Reviews (CDSR)Cochrane Specialised Wounds RegisterCumulative Index to Nursing and Allied Health Literature (CINAHL)Database of Abstracts of Reviews of Effects (DARE)DH-DataEconLitEMBASEHealth Economic Evaluation Database (HEED)Health Management Information Service Database (HELMIS)Health Technology Assessment (HTA) databaseIndex to Scientific and Technical Proceedings (ISTP)King’s Fund DatabaseMEDLINEMEDLINE In Process NHS Economic Evaluation Database (NHS EED)System for Information on Grey Literature in Europe (SIGLE)

Additional sources to identify ongoing researchControlled Clinical Trials (http://controlled-trials.com)National Research Register (NRR) (http://www.nrr.nhs.uk/search.htm)

Handsearching conference proceedings3rd International Conference on the Diabetic Foot, Noordwijkerhout, The Netherlands, 1999Diabetic Foot Study Group meeting: Fiuggi, Italy, 2000; Crieff, Scotland, 2001; Balaton, Hungary, 20028th and 9th Malvern Diabetic Foot Conferences, 2000 and 2002

Handsearching journals and booksJournal: The Diabetic FootBooks: The Foot in Diabetes. Boulton AJM, Connor H and Cavanagh PR, editors. 3rd edition, Wiley, Chichester, 2000Levin and O’Neal’s The Diabetic Foot. Bowker JH and Pfeifer MA, editors. 6th edition, Mosby, St Louis, MO, 2001The Evidence Base for Diabetes Care. Williams R, Herman W, Kinmonth AL and Wareham NJ, editors. 2002

Internet searches to identify review/guideline documentsClinical Evidence (http://www.clinicalevidence.com/)Health Evidence Bulletins Wales (http://www.uwcm.ac.uk/uwcm/lb/pep)Health Services Technology Assessment Text (HSTAT) (http://text.nlm.nih.gov/)National Coordinating Centre for HTA (http://www.hta.nhsweb.nhs.uk)National Guideline Clearing House (http://www.ahcpr.gov/clinic/assess.htm)National Institute for Health and Clinical Excellence (NICE) web page (published appraisals)

(http://www.nice.org.uk/nice-web/)ScHARR Lock’s Guide to the Evidence (http://www.shef.ac.uk/uni/academic/R-Z/scharr/ir/scebm.html)Scottish Intercollegiate Guidelines Network (SIGN) (http://www.sign.ac.uk)Turning Research Into Practice (TRIP) (http://tripdatabase.com)

of all included studies were examined in order toidentify any additional relevant studies.

Cost-effectiveness and modelling searchesThose databases restricted by study design in theclinical effectiveness searches were searched againwith a search strategy designed to retrieve cost-effectiveness studies, decision models or economicmodels. Two specialist databases were alsosearched, the NHS Economic Evaluation Database(NHS EED) and the Health Economic EvaluationDatabase (HEED); no economic filter wasnecessary for these databases.

CRD internal administration databases� NHS EED (searched 13 November 2002 on

CAIRS software).

CD-ROM resources� EconLit (1969–2002 October)

Searched: 12 November 2002 on ARCSilverPlatter

� HEED (Issue: November 2002) Searched: 13 November 2002 on stand-aloneCD-ROM

Internet databases� Allied and Complementary Medicine Database

(AMED) (1985–2002 November).Searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.

� British Nursing Index (BNI) (1994–2002August).Searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.

� CINAHL (1982–2002 October week 4).Searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.

� EMBASE (1980–2002 week 44).Searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.

� MEDLINE (1966–2002 October, week 5).Searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens.



Generic searchesThere were a number of databases for which it wasnot practical to justify searching separately forclinical, cost-effectiveness and diagnosis studiesbecause the database was either too small to

warrant such a detailed search or the interfaces forthe database were too simplistic. A general searchfor papers on DFUs was therefore sufficient forthe following databases and the papers were thensifted for relevance.

Internet resources and databases (searched: 26 August 2002)� Health Evidence Bulletins Wales

http://www.uwcm.ac.uk/uwcm/1b/pep� Health Services Technology Assessment Text

(HSTAT) http://text.nlm.nih.gov/

� Index to Scientific and Technical Proceedings(ISTP) (1990 onwards)http://wos.mimas.ac.uk/

� National Coordinating Centre for HealthTechnology Assessmenthttp://www.hta.nhsweb.nhs.uk

� National Guideline Clearinghousehttp://www.ahcpr.gov/clinic/assess.htm

� National Institute for Health and ClinicalExcellence (NICE) (published appraisals)http://www.nice.org.uk/nice-web/

� Scottish Intercollegiate Guidelines Network(SIGN) Guidelineshttp://www.sign.ac.uk/

� Turning Research Into Practice (TRIP) Indexhttp://www.ceres.uwcm.ac.uk/framset.cfm?section=trip

CD-ROM resources� Health Management Information Consortium

(HMIC) Databases: HELMIS 1984–1998/DH-Data and King’s Fund Database1983–2002/King’s Fund Database 1979–2002.Searched: 09 November 2002 on ARCSilverPlatter).

� National Research Register (NRR) (2002,Issue 4).Searched: 13 November 2002 on stand-aloneCD-ROM.

� SIGLE (1967–2002 July, week 3).Searched: 06 November 2002 on ARCSilverPlatter.

Study selectionReferences identified from the search strategieswere de-duplicated and entered into abibliographic software package (ProCite Version 5for Windows). Titles and abstracts, where available,were examined by two reviewers. If either reviewerconsidered a reference to be potentially relevant,the full report was retrieved. Full reports werescreened for inclusion with close reference to the


13


inclusion criteria described below. At both stagesof study selection, two reviewers made decisionsindependently and met subsequently to discussdisagreements. Any disagreements were resolvedby discussion. No restrictions were applied interms of the date of publication or the language ofthe report.

Inclusion criteria for systematic reviewsof diagnosis (questions 1–3)1. The study must compare the results of an

independent gold standard (as defined in thestudy) with an alternative assessment.

2. The target population must comprise patientswith diabetes mellitus aged 18 years or olderwith a foot ulcer. Since it was expected that thebody of literature relating to diagnosis ofinfection in DFUs would be small, trialsrecruiting adults with venous leg ulcers werealso eligible for inclusion for questions 1–3. Itwas considered that although the focus of thisproject should remain the management ofpatients with infected DFUs, it is possible thatuseful information may be obtained from thevenous leg ulcer literature as techniques forobtaining and analysing samples are likely tobe similar, regardless of wound aetiology.

3. Sufficient data must be presented in the paperto enable completion of a 2 × 2 diagnostic table(true positives, false positives, true negatives,false negatives), thus allowing outcomes such assensitivity, specificity, predictive values andlikelihood ratios to be calculated.

Inclusion criteria for systematic reviewof impact of microbiological analysis ontherapy or outcomes (question 4)1. The study must be an RCT or a CCT of one or

more strategies of managing suspected infectionof DFUs, such as empirical therapy versusmicrobiological analysis and the use ofappropriate antimicrobial regimens. A CCT wasdefined as a prospective non-randomisedcomparative study with concurrent studygroups.

2. The target population must comprise patientswith diabetes mellitus aged 18 years or olderwith a foot ulcer. Studies recruiting solely peoplewith diabetic foot infection or osteomyelitiswithout ulceration were not included.

3. The study must compare policies of prescribingantimicrobial agents (i.e. wait for result ofmicrobiological analysis before administrationversus administration without test result).Evaluations of relevant strategies/policiesdelivered in any healthcare setting wereconsidered for inclusion in the review.

4. At least one of the following outcome measuresmust be reported: (a) mortality (all or related to amputation)(b) incidence and type of amputation(c) incidence of osteomyelitis(d) pain (in patients without neuropathy)(e) proportion of ulcers healing(f) time to complete healing(g) change in ulcer area (absolute or relative)(h) healing rate(i) change in ulcer depth or volume (absolute

or relative)(j) ulcer recurrence(k) number and duration of hospital

admissions for diabetic foot problems(l) bacterial profile of ulcer(m) acquisition of resistant organisms(n) relationship between ulcer healing and

bacteriology(o) change in mobility(p) change in level of

dependence/independence(q) impact on health-related quality of life.

The most important outcomes were considered tobe those relating to mortality, amputation andwound healing. However, evaluations reportingany of the outcomes described above wereconsidered for inclusion. In addition, data onadverse events and adherence were recorded,where available. Large cohort/population studieswould be needed to identify rare adverse events,such as the acquisition of resistance, and we didnot search for these as there are poorly developedmethods of searching for these study designs andthere was insufficient time within this project toundertake this.

Inclusion criteria for systematic reviewof clinical effectiveness (question 5: part 1)1. The study must be an RCT or a CCT of one or

more antimicrobial regimens (the comparatorcan include no intervention, placebo orstandard care). A CCT was defined as aprospective non-randomised comparative studywith concurrent study groups.

2. The target population must comprise patientswith diabetes mellitus aged 18 years or olderwith a foot ulcer. Studies recruiting solelypeople with diabetic foot infection orosteomyelitis without ulceration were excluded.

3. The study must evaluate an antimicrobial agentused with the primary intention of treatinginfection in DFUs. Evaluations of relevantinterventions delivered in any healthcare

Review methods

14

setting were considered for inclusion in thereview. Evaluations of interventions possiblyinfluencing healing that might be usedconcurrently with antimicrobial agents (e.g.pressure relief, optimisation of blood glucosecontrol, improvement of blood supply to thefoot) were excluded.

During the process of screening studies foreligibility, it was noted that several trials includedmixed populations, for example, people with softtissue infection who did not all necessarily havefoot ulceration or diabetes. Separate outcomes forthe patients with DFU were not always reported inthe papers and, in some cases, authors were notable to supply the stratified data. Recognising thatuseful evidence could still be gleaned from amixed population study where the majority ofpatients had a DFU, a post hoc decision was takento include such studies in the review on conditionthat it could be ascertained that at least 80% ofrecruited patients had a DFU.

4. At least one of the following outcome measuresmust be reported:(a) mortality (all or related to

amputation)(b) incidence and type of amputation(c) incidence of osteomyelitis(d) pain (in patients without neuropathy)(e) proportion of ulcers healing(f) time to complete healing(g) change in ulcer area (absolute or

relative)(h) healing rate(i) change in ulcer depth or volume (absolute

or relative)(j) ulcer recurrence(k) number and duration of hospital

admissions for diabetic foot problems(l) bacterial profile of ulcer(m) acquisition of resistant organisms(n) relationship between ulcer healing and

bacteriology(o) change in mobility(p) change in level of

dependence/independence(q) impact on health-related quality of life.

The most important outcomes were considered to be those relating to mortality, amputation and wound healing. However, evaluationsreporting any of the outcomes described abovewere considered for inclusion. In addition, data on adverse events and adherence with the treatment regimen were recorded, whereavailable.

Inclusion criteria for systematic reviewof economic evaluations (question 5:part 2)Economic evaluations were considered forinclusion if they focused on the diagnosis and/ortreatment of infected DFUs and if they reported asynthesis of associated costs and benefits.Evaluations of any diagnostic test or antimicrobialtreatment strategy in infected diabetic foot ulcerswere eligible. Any type of economic evaluation waseligible, including cost-effectiveness analysis,cost–benefit analysis, cost–utility analysis or cost-minimisation analysis.

Data extractionDetails of eligible studies were extracted andsummarised using a structured data extractiontable (see Appendix 3). If data were missing fromreports, then attempts were made to contact theauthors to obtain sufficient data to carry out dataextraction and critical appraisal. Multiplepublications of the same study were regarded as asingle report and all relevant details wererecorded. Two reviewers verified data extractionindependently. Disagreements were resolved bydiscussion.

Critical appraisal of includedstudiesThree separate checklists were used for diagnosticstudies, effectiveness studies and economicevaluations. Two reviewers performed criticalappraisal of each individual included studyindependently. Disagreements in judgementsabout methodological quality were resolvedthrough discussion.

Critical appraisal of diagnostic studiesA 12-item checklist known as QUADAS (QualityAssessment of Studies of Diagnostic AccuracyIncluded in Systematic Reviews)84 was used (Table 3). This was generated using evidence-basedmethods combined with a Delphi procedure. Thechecklist was accompanied by a guide forcompletion that aims to minimise subjectivejudgement.84 Where an item is scored as ‘unclear’,this refers to the quality of reporting within thepaper rather than the methodological quality ofthe diagnostic evaluation.

Critical appraisal of effectivenessstudiesThe methodological quality of all included RCTswas assessed using a validated five-point scale,85


15


and the allocation concealment criterion describedby Schulz,86 as follows:

1. Randomisation. Score: 0 or 1 or 2 One point was given if the study describedusing words such as random or randomisation.One extra point was given if the method ofrandomisation was described and wasappropriate. One point was deducted if themethod of randomisation was described andwas considered to be inappropriate.

2. Double-blinding. Score: 0 or 1 or 2One point was given if the study was describedas double-blind. One extra point was given ifthe method of double-blinding was describedand was appropriate. One point was taken awayif the method of double-blinding was describedand was inappropriate.

3. Withdrawals. Score: 0 or 1One point was given if the number and reasonsfor withdrawals in each group were stated.

4. Allocation concealment. Score: A or B or C(A) Adequate: if adequate measures were taken

to conceal allocation.(B) Unclear: if report of allocation

concealment was not reported or did notfit in category A or C.

(C) Inadequate: trials in which allocationconcealment was inadequate.

The critical appraisal of CCTs included the pointsabove, with the exception of the first(randomisation). In CCTs, the following additionalitems were assessed: method of allocation totreatment groups; degree of baselinecomparability between treatment groups; andappropriateness of adjustment during dataanalysis for observed imbalances betweentreatment groups.

Critical appraisal of economicevaluationsThe following checklist was used:87

1. Was a well-defined question posed inanswerable form?

2. Was a comprehensive description of thecompeting alternatives given?

3. Was the effectiveness of the programmes orservices established?

4. Were all the important and relevant costs andconsequences for each alternative identified?

5. Were costs and consequences measuredaccurately in appropriate physical units?

6. Were costs and consequences valued credibly?7. Were costs and consequences adjusted for

differential timing?8. Was an incremental analysis of costs and

consequences of alternatives performed?

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TABLE 3 Critical appraisal of diagnostic studies checklist – the QUADAS84 tool

Item Yes No Unclear

1. Was the spectrum of patients representative of the patients who will receive the test in practice?

2. Were selection criteria clearly described?3. Is the reference standard likely to correctly classify the target condition?4. Is the time period between reference standard and index test short enough

to be reasonably sure that the target condition did not change between the two tests?

5. Did the whole sample or a random selection of the sample, receive verification using a reference standard of diagnosis?

6. Did patients receive the same reference standard regardless of the index test result?

7. Was the reference standard independent of the index test (i.e. the index test did not form part of the reference standard)?

8a. Was the execution of the index test described in sufficient detail to permit replication of the test?

8b. Was the execution of the reference standard described in sufficient detail to permit its replication?

9a. Were the index test results interpreted without knowledge of the results of the reference standard?

9b. Were the reference standard results interpreted without knowledge of the results of the index test?

10. Were the same clinical data available when test results were interpreted as would be available when the test is used in practice?

11. Were uninterpretable/intermediate test results reported?12. Were withdrawals from the study explained?

9. Was allowance made for uncertainty in theestimates of costs and consequences?

10. Did the presentation and discussion of studyresults include all issues of concern to users?

Data analysisQuestions 1–3: diagnosisThe included studies were summarised using anarrative description. Meta-analysis wasconsidered where studies were considered to besufficiently similar with respect to patientcharacteristics and the index and reference testsused. In this case, standard methods forcombining primary studies were to be followed.88

Statistical analysis of the receiver operatingcharacteristic (ROC) curve was performed usingSPSS version 12.0.2 and the plot was generatedusing Excel 2000.

It was planned to analyse studies recruitingpatients with venous leg ulcers separately to thoseof DFU patients. Findings from venous leg ulcerstudies were interpreted with great caution whenconsidering any implications for DFUs. For DFUs,it was planned to group studies according to thetype of diabetes (type 1 and type 2) and type offoot ulcer (neuropathic and neuroischaemic).

Question 4: effect of microbiologicalanalysisThe included studies were summarised using anarrative description. Meta-analysis wasconsidered if studies were deemed to besufficiently similar with respect to patientcharacteristics, interventions and outcomes.

Question 5(1): clinical effectivenessThe included studies were summarised using anarrative description. Meta-analysis wasconsidered if studies were deemed to besufficiently similar with respect to patientcharacteristics, interventions and outcomes.

Methods of meta-analysis for questions4 and 5(1)The method of synthesising the studies woulddepend upon the quality, design andheterogeneity of studies identified. Clinicalheterogeneity would be explored by examiningfactors that may impact on outcomes such as caresetting and test, patient and ulcer characteristics.Statistical heterogeneity was assessed using a �2

test. In the absence of clinical heterogeneity andin the presence of statistical heterogeneity, a

random effects model was used for pooling. Thesummary statistic used depended on the event rateobserved. Where the event rate was over 30%, therelative risk (RR) was employed. When the eventrate was less than 30%, a summary odds ratio wascalculated. Where there was no clinical orstatistical heterogeneity, a fixed effects model wasapplied.

Question 5(2): cost-effectivenessEach included economic evaluation was describedin a narrative fashion. In addition, the use of asummary grading for each evaluation wasconsidered, according to the direction of cost-effectiveness estimates. A matrix was used (Box 1)in order to indicate when a clear decision may bemade on the basis of the evidence presented (i.e.better health outcomes with lower costs, or poorerhealth outcomes with higher costs, cells G and C,respectively). Situations where decisions were lessfavoured (either costs are lower or healthoutcomes are better) were represented by cells D,B, F and H. Cases where a financial or clinicaltrade-off was required are shown in cells A and I.Cell E represents a case where no differences wereobserved between the competing strategies. Theposition of each individual evaluation within thematrix has been shown.87,89 Although this methodgives a useful summary of results, and isparticularly helpful when the results of severaleconomic evaluations are presented, the findingsof each individual economic evaluation should beinterpreted in the light of methodological quality(see checklist above).

Decision analytic modelThe first step in the construction of the model wasto conduct a review of the literature to identify anymodels that described the natural history ofpatients with DFUs, and to identify studies thatcould inform the transitions within a decisionanalytic model. We searched for economic modelsor decision analytic models, that is, studies inwhich a mathematical structure had been used torepresent the health and/or economic outcomes ofpatients with a DFUs. Table 2 describes the sourcesused to identify research. The results of allsearches were scrutinised to identify potentiallyrelevant studies. We planned to model explore thecost-effectiveness of different strategies formanaging people with DFUs. The modelcombines information on the precision ofdiagnostic tests with clinical consequences ofundertaking those tests, for example, whichtreatment strategies are chosen (cost, amputation


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rates, healing times) to variations in the methodsof sampling, analysis and treatment regimens. Inthis way, the area of greatest uncertainty can beidentified and this can be used to identify priorityareas of future research. For example, it may bepossible to recognise whether the priority shouldbe to investigate the sensitivity and specificity ofmethods of sampling, or to assess the impact ofantibiotic therapy on the likelihood of healing.

Hence, the decision analysis combines informationon the precision of diagnostic tests with clinicalconsequences of undertaking those tests, forexample, which treatment strategies are chosen.

A full description of the methods for constructingthe decision analytic model and the outputs isgiven in the section ‘Decision analytic modelling’(p. 48).

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Incremental effectiveness+ 0 –

+ A B C

Incremental costs 0 D E F

– G H I

Decision strongly favoured Key: Effectiveness CostG = Accept treatment + Better HigherC = Reject treatment 0 Same Same

– Poorer LowerDecision less favouredD = Accept treatmentB = Reject treatmentF = Reject treatmentH = Accept treatment

No obvious decisionA = Is the added benefit worth the cost?I = Is the reduced effect acceptable given reduced costs?E = Neutral cost and effect. Other reasons to adopt treatment?

BOX 1 Permutation matrix for possible outcomes of economic evaluations for studies of intervention versus comparator87,89

Literature search resultsA total of 4225 studies were identified as beingpotentially relevant to the reviews in ourdiagnostic, effectiveness and economics searches,of which 14% were identified in more than onesearch (see Figure 2).

Diagnostic studies are summarised first, then theeffectiveness studies and cost-effectiveness studies.Finally, the decision analytic model results aredescribed. Data extraction sheets and summaryquality assessment tables are summarised inAppendix 5. Studies thought to be relevant fromtitle and/or abstract but excluded after scrutiny forthe diagnostic, effectiveness and economicsearches are summarised in the excluded studiestables in Appendix 6.

Studies included in the diagnosticreviewIn the diagnostic review search we identified 2762study citations, of which 219 were retrieved (threeincluded and 216 excluded). The reasons forexclusion were as follows:

Reasons for exclusion NPopulation not DFU 12 × 2 data not available 9Study of inter-observer variation 2No verification of infection 6Description of signs/symptoms 1Description of diagnostic techniques 1Osteomyelitis diagnosis 43Diabetic foot infection (not ulcer infection) 8Systematic review of osteomyelitis 2Prevalence studies/other reasons 163

Results of diagnostic reviewThree eligible diagnostic studies wereidentified.90–92 All three recruited patients with avariety of chronic wounds (including DFUs), andwere conducted in the USA. One study evaluatedthe diagnostic performance of clinical examinationusing tissue biopsy as the reference standard (relatesto review question 1),90 one study assessed woundswab against tissue biopsy as a method of specimenacquisition (relates to review question 2)91 and thethird focused on methods of laboratory analysis ofthe wound swab, namely semi-quantitative analysisversus quantitative analysis as the referencestandard (relates to review question 3).92


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Chapter 4

Results

Possiblediagnostic studies, n = 2762

Possibleeconomicstudies, n = 747

PossibleRCTs,n = 1310

878

2116153

422

168 2322

FIGURE 2 Results of search strategy: number of ‘possible’ RCTs, diagnostic studies and economic studies

Each of the studies was described individually, in anarrative fashion. All studies reported 2 × 2diagnostic data and we calculated additionaldiagnostic outcomes (sensitivity, specificity,predictive values, likelihood ratios) as required.Where cells in 2 × 2 tables contained zero, a valueof 0.5 was used in order to permit calculations. Aseach study addressed a different research question,data were not pooled. The numbers recruitedaccording to wound aetiology were reported in allthree studies (see Appendix 4, data extractiontables). A summary of the quality assessment ofthe diagnostic studies is given in Appendix 5. Inone study, separate outcome data were providedon venous leg ulcers (n = 7), but the very smallnumber of DFUs did not merit separate analysis(n = 2).90 For the other two studies, data werereported for the overall sample of wounds ofmixed aetiologies, without further breakdown. Interms of patient characteristics related to the DFU(type 1 or type 2 diabetes and presence ofneuropathy/ischaemia), insufficient data wereavailable from the papers to consider subgroupanalyses according to these factors. One studyreported the type of diabetes90 and none of thestudies reported numbers of patients with DFUwho had neuropathy and/or ischaemia.

Review question 1: What is thediagnostic performance of clinicalexamination in the identification ofinfection in DFU? Gardner andcolleagues (2001)90

In a cross-sectional study, people with chronicwounds of various aetiologies were recruited viafour centres: an acute care veterans’ facility, along-term care veterans’ facility, a mixed acutecare and long-term care veterans’ facility and achronic wound clinic at a university medicalcentre. At three of the four study sites, only peoplewith a white blood cell count of >1500 cells/mm3

or a total lymphocyte count of >800 cells/mm3,plus a platelet count of >125,000/mm wereeligible for inclusion. People with wounds ofarterial aetiology were excluded at all study sites.Of the overall sample of 36 participants, 19 hadpressure ulcers, seven had venous leg ulcers, sixhad wounds from a secondary incision and twoeach had non-healing traumatic wounds andDFUs. Punch biopsy was the reference test and theindex test consisted of the use of a clinical signsand symptoms checklist constructed from twoother checklists. One of these checklists containedsigns of infection that the study authors defined as‘classic’: pain, erythema, oedema, heat andpurulent exudate. The second checklist consistedof a list of signs and symptoms specific to

secondary wounds proposed by other authors:93

serous exudate plus concurrent inflammation,delayed healing, discoloration of granulationtissue, friable granulation tissue, pocketing of thewound base, foul odour and wound breakdown.The inter-rater reliability of the items on thechecklist was assessed using wound observationsmade independently by the principal investigatorand one of five specifically trained nurses,representing each study site (� range from 0.53 to1.00). The authors did not report outcomes forone clinical sign, pocketing of the wound base, asthere was no agreement owing to non-occurrenceof the sign within the study sample.90 At thechronic wounds clinic, the biopsy was performedwithin 8 hours of data collection for clinical signsand symptoms; the time interval between tests wasless than 1 hour for the other study sites (GardnerSE, University of Iowa School of Nursing: personalcommunication, 2003). Infection was defined asthe presence of at least 105 organisms per gram ofviable wound tissue, or wounds containing �-haemolytic Streptococcus at any level. Diagnosticmeasures were calculated for each individualclinical sign or symptom and verified againsttissue biopsy findings. The results that follow arefor the overall sample of wounds of variousaetiologies. Explanations for the diagnosticoutcomes used have been provided. Results areshown in Table 4 and in Appendix 4.

Sensitivity and specificity are properties of a testthat are concerned with the correct classification ofpeople according to their disease status. It isassumed that the result of the reference test iscorrect, and therefore that a positive result fromthe reference test equates to presence of thedisease and that a negative result denotes absenceof the disease. Sensitivity can be defined as theproportion of participants with the target diseasewho have a positive result for the disease from theindex test.94 In this study, the highest sensitivityvalues were seen for two separate clinical signs,presence of friable granulation and delayedhealing. They both correctly identified around80% of patients with a wound infection. However,the respective specificity values were 76% and64%, suggesting that the diagnostic performanceof these two signs may be less than optimal.Although increasing pain and wound breakdownboth had 100% specificity, they were associatedwith low sensitivity levels.

Predictive values are an estimate of the probabilityof disease, given the result of a test. They aredetermined by the prevalence of disease in thepopulation being tested. Positive predictive value

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(PPV) is defined as the probability of disease in apatient with a positive index test result.94 For thesymptom of increasing pain and the sign of woundbreakdown, the probability of patients with eitherof these clinical indicators having a woundinfection was 100%, whereas the probability forthose with purulent exudate was 18% (lowestvalue). Negative predictive value (NPV) is theprobability of not having the disease when the testresult is negative.94 In this study, the probability ofnot having a wound infection in the absence ofboth friable granulation and delayed healing wasaround 90% (highest values), around 80% forincreasing pain, oedema, serous exudate plusconcurrent inflammation or discolouration, withthe lowest value being 64% for purulent exudate.

Likelihood ratios (LRs) are another way ofexpressing the performance of a diagnostic test.Whereas sensitivity, specificity and predictivevalues use probability in their estimations, LRs arebased on the use of odds. They estimate howmany times more (or less) likely a test result is tobe found in diseased compared with non-diseasedparticipants.94

For this study, the range of values for positiveLR (+LR) included 1.14 for heat and 22.73 forwound breakdown, meaning that, for example,wound breakdown is almost 23 times more likelyto be observed in the presence of wound infectionthan in the absence of it. The +LR for increasingpain was around 18. The negative LR (–LRs)ranged from 0.97 for heat to 0.24 for friablegranulation. These values gives odds of around1:1.02 that absence of heat would occur in thepresence of an infection compared with absence ofinfection, and odds of around 1:4.2 that absence

of friable granulation would occur in the presenceof an infection compared with absence ofinfection. A proposed ‘rule of thumb’ suggests that +LRs greater than 10 or –LRs less than 0.1 give convincing diagnostic evidence, and that values above five and below 0.2, respectively,provide strong diagnostic evidence.88 Going by this, it seems that increasing pain and woundbreakdown may be useful individually asdiagnostic tests. However, these findings should be interpreted with caution owing to thesmall size of the study and the heterogeneity ofthe group recruited with respect to woundaetiology.

The LR values for one particular clinical sign,purulent exudate, merit special consideration (seedata extraction table in Appendix 4, pp. 126–30).The calculated values are the opposite to whatwould normally be expected, that is, the +LR inthis case is less than 1 (0.51), and the –LR isgreater than 1 (1.28). This may be explained asfollows. For the +LR, the ratio is derived from thevery low sensitivity rate for this test (18%) and therelatively high number of false positives expressedas a proportion of the total without disease asverified by the reference standard. For the –LR theratio is derived from the large proportion of falsenegatives relative to the total with disease and thespecificity of 64%. These findings are as would beexpected for a test that excludes disease asopposed to identifying it. The conclusion fromthese data is that purulent exudate is a particularlypoor test for identifying wound infection, and thatabsence of this clinical sign is more likely toindicate infection than its presence. The valuesobtained for related diagnostic outcomes supportthis conclusion. In terms of sensitivity, only 18% ofpatients with a wound infection were correctly


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TABLE 4 Diagnostic outcomes for individual clinical signs and symptoms90

Sign or symptom Se (%) Sp (%) PPV NPV +LR –LR

Increasing pain 36 100 100 78 18.18 0.64Erythema 55 68 43 77 1.71 0.67Oedema 64 72 50 82 2.27 0.50Heat 18 84 33 70 1.14 0.97Purulent exudate 18 64 18 64 0.51 1.28Serous exudate plus concurrent inflammation 55 72 46 78 1.95 0.63Delayed healing 81 64 50 89 2.27 0.28Discoloration 64 56 39 78 1.45 0.65Friable granulation 82 76 60 90 3.41 0.24Foul odour 36 88 57 76 3.03 0.72Wound breakdown 46 100 100 81 22.73 0.55

+/–LR, positive/negative likelihood ratio; NPV, negative predictive value; PPV, positive predictive value; Se, sensitivity; Sp, specificity.

identified with purulent exudate, and forspecificity, 64% without a wound infection hadabsence of this clinical sign. In addition, theprobability of patients with purulent exudatehaving a wound infection was 18% (PPV), and theprobability of not having an infection in theabsence of this sign was 64% (NPV). Anotherclinical sign that is noteworthy in this respect isthe presence of heat around the wound. Heat had+LR and –LR values that were very close to one,indicating limited diagnostic usefulness (+LR1.14, –LR 0.97). Other outcomes for heat were asfollows: sensitivity 18%; specificity 84%; PPV 33%;and NPV 70%. Again, the small size of this studymeans that findings should be viewed withcaution.

The author was contacted to request data stratifiedaccording to wound type. Data on sensitivity forclinical signs and symptoms for venous leg ulcerswere provided (n = 7).95 The values ranged from100% for oedema or delayed healing to 25% forincreasing pain, heat, serous exudate plusconcurrent inflammation, discoloration or foulodour (see data extraction tables for the full rangeof values). The sensitivity for purulent exudate was67%, somewhat higher than the value calculatedfor the overall sample.

A summary of the quality assessment of this studyis given in Appendix 5. The selection criteria forpatients were clearly described, all patientsreceived both index and reference tests, the indextest did not form part of the reference test,execution of both tests was described in sufficientdetail to permit replication and there did notappear to be any uninterpretable test results orstudy withdrawals. Owing to the general scarcity ofresearch in this area, it was unclear whether thereference test (tissue biopsy) would correctlyclassify wound infection. It was also unclear fromthe paper whether interpretation of test resultswas blind and whether the same clinical datawould be available when test results wereinterpreted as would be available when the test isused in clinical practice. Standard practice maynot involve examination of a gauze swab appliedto the wound for 1 hour as an assessment forpresence of exudate. For three of the four studysites, tissue biopsy was obtained less than 1 hourafter clinical assessment (Gardner SE, Universityof Iowa School of Nursing, personalcommunication, 2003), and this would seem to bea short enough time interval to be confident thatthe infection status of the wound would not havechanged between tests. However, the time lag waslonger in the fourth site (8 hours) and it is

possible that the infection status of the woundcould have changed during this time. In terms ofthe spectrum composition (patient characteristicsof the sample recruited for the study), theselection criteria used in three out of the fourstudy sites (white blood cell count>1500 cells/mm3 or total lymphocyte count>800 cells/mm3; platelet count >125,000 mm)may have meant that the group recruited were notrepresentative of the patients who would receivethe test in clinical practice.

SummaryA wide range of values was seen for sensitivity,specificity and predictive values for the individualsigns and symptoms. It is arguable that highsensitivity is most important in this context, inorder to rule out disease, due to the potentiallyserious consequences of DFU infection.Interpretation of the derived LRs suggests that thesigns and symptoms checklist is not a usefulmethod of identifying infection in chronic wounds, with the possible exceptions of increasing pain and wound breakdown. Thedifferent values observed for the small subgroup ofpatients with venous leg ulcers relative to thewhole sample may be due to chance or differentialperformance of the tool when used with specificwound types. Generalisability of findings ishindered owing to the participant eligibilitycriteria used and aspects of the method ofassessment. Interpretation of study findings isfurther impeded by possible sources of bias andthe current lack of information on an optimumreference standard.

Review question 2: What is thediagnostic performance of specimenacquisition techniques in theidentification of infection in DFU?Bill and colleagues (2001)91

Patients attending a university-based chronicwound centre were recruited to a cross-sectionalstudy if they had a cutaneous wound at any bodysite, present for at least 6 months. Of the overallsample of 38 participants, 18 had pressure ulcers,10 had DFUs and five each had venous leg ulcers and arterial ulcers. Punch biopsy taken from the centre of the wound was the referencetest and wound swab with quantitative analysis was the index test. Tissue biopsy was carried out immediately after the wound swab wasobtained. The authors defined soft tissue infectionas the presence of more than >105 colony-formingunits (CFUs) per gram of tissue for tissue biopsyand greater than >105 CFUs cm2 for swabculture.91

Results

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Although the authors did not calculate diagnosticoutcomes, they reported sufficient data topopulate a 2 × 2 diagnostic table for the overallsample. From these data, the sensitivity, specificity,PPV, NPV, +LR and –LR for wound swab withrespect to wound tissue biopsy as the referencestandard were calculated.

The estimated sensitivity for wound swab was 79%and specificity was 60%, as verified by tissuebiopsy. In terms of predictive values, PPV was 85%and NPV was 50%. The +LR was 1.96, meaningthat a positive wound swab result is almost twice as likely to occur in people with a woundinfection compared with those without aninfection. The –LR was 0.36, giving odds ofaround 1:2.8 that a negative wound swab wouldoccur in the presence of an infection comparedwith absence of infection. Going by the rule ofthumb described previously, it seems that thewound swab as used in this evaluation is not auseful diagnostic test.

The authors were contacted and requested toprovide 2 × 2 diagnostic data on the patients withDFUs, but data were unavailable.

The main issues around quality assessment (seeAppendix 5) were lack of evidence as to whethertissue biopsy is a valid reference standard, nodescription of blind test verification and lack ofclarity as to whether the same clinical data wereavailable when test results were interpreted aswould be available when the test is used inpractice. On a positive note, the selection criteriaand baseline characteristics of participants wereclearly described, the time lag between tests wasvery short, patients were sampled consecutivelyand all patients received the reference test. Theindex test did not form part of the referencestandard, and the execution of both tests wasdescribed in sufficient detail to permit replication.There did not appear to have been anyuninterpretable tests or withdrawals from thestudy.

SummaryThe sensitivity for wound swab was 79%, meaningthat the swab would fail to detect approximatelyone in five wound infections. The derived LRssuggest that the wound swab is not a usefulmethod of identifying infection in chronic wounds.Interpretation of study findings is impeded bypossible sources of bias and the current lack ofinformation on an optimum reference standardthat should be used to verify the diagnosticperformance of wound swab.

Review question 3: What is thediagnostic performance of differentlaboratory analysis techniques in theidentification of infection in DFU?Ratliff and Rodeheaver (2002)92

Patients attending a university-based wound careclinic were recruited if they had any type ofcutaneous wound present at any body site formore than 6 months. Of the overall sample of 124 participants, 44 had pressure ulcers, 27 hadulcers due to venous insufficiency, 29 hadneuropathic or diabetic ulcers, eight had lowerextremity ulcers due to arterial disease and 16 hadwounds due to other aetiologies (not described in the paper). The aim of this study was to assessthe diagnostic performance of semi-quantitativeanalysis of wound swab using quantitative analysis as the reference standard. All patients hadtwo wound swabs taken, using similar techniquesand materials (calcium alginate-tipped swabs).Quantitative techniques for analysing specimensobtained from wound swabs involve identifying thetype, and counting the numbers ofmicroorganisms present. Semi-quantitativetechniques entail classifying a level of bacterialgrowth by observing growth on four quadrants ofan agar plate where each quadrant has beenstreaked in sequence using a sterile loop for eachquadrant, thus making dilutions of the originalstreak on to each sequential quadrant. The greater the quantity of bacteria on the originalswab, the more quadrants will display bacterial growth. In this study, the swab forquantitative analysis was obtained after the swab for semi-quantitative analysis; however, thetime interval between acquisitions of the twospecimens was not stated. Soft tissue infection wasdefined as the presence of at least 105 CFUs cm2

for swab culture, derived from quantitativeanalysis.

The authors presented 2 × 2 diagnostic data fordifferent diagnostic thresholds of semi-quantitativeand quantitative analyses (quantitative range from102 to 107 CFUs cm2 for swab culture). In thepaper, sensitivity and specificity were reported fora reference standard level of 105 CFUs cm2. Wecalculated additional diagnostic outcomes(predictive values and LRs) and also generatedoutcomes for a range of possible diagnosticthresholds for the semi-quantitative analysis, ineach case using the stipulated reference standardlevel of 105 CFU cm2 for the quantitative analysis.Referring to the spread of bacterial growth acrossquadrants of an agar plate, the range of diagnosticthresholds for semi-quantitative analyses aredescribed and illustrated in Box 2.


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The outcomes for the different levels of semi-quantitative analysis are given in Table 5.

As may be expected, sensitivity was higher withless stringent definitions of infection, whereasspecificity decreased. As seen from Table 5,different values of sensitivity and specificity arederived when different diagnostic thresholds areused. When several different thresholds have beenproduced, these can be displayed on an ROC plotin order to help determine the optimumcombination of sensitivity and specificity (andtherefore the optimum diagnostic threshold touse). An ROC curve was generated for the fourdifferent levels of cut-off that were used for semi-quantitative analysis of wound swab (Figure 3). Thetrue positive rate (sensitivity) is plotted against thefalse positive rate (1 – specificity). Table 6 showsthe coordinates used to plot the ROC curve. Anuninformative test would be represented by a

diagonal line sloping upwards from left to rightacross the graph. Coordinates appearing closest tothe top left-hand corner of the graph indicate themost informative combination of sensitivity andspecificity values, and therefore indicate theoptimum diagnostic threshold to use.88 Accordingto these principles, it appears from this plot thatthreshold C is the most useful. However, asdiscussed in the original paper, it is necessary toconsider the clinical implications of different ratesof false positives and false negatives. For example,extrapolating from this study using the diagnosticthreshold C (Tables 5 and 6), 21% of patientswould have a false negative test result using semi-quantitative analysis and would experience a delayin receiving antimicrobial treatment. In addition,10% of patients would have false positive resultsand would receive antimicrobial therapyunnecessarily.92 Consideration of the effect of suchrates on clinical outcomes and costs may help

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A. Observed bacterial growth in any quadrant (QI, or Q1 + Q2, Q1 + Q2 + Q3, or Q1 + Q2 + Q3 + Q4: the least strict definition of infection)

B. Observed bacterial growth in at least 2 quadrants: Q1 + Q2, or Q1 + Q2 + Q3, or Q1 + Q2 + Q3 + Q4

C. Observed bacterial growth in at least three quadrants: Q1 + Q2 + Q3, or Q1 + Q2 + Q3 + Q4 (the definition of infection used by the study authors)

D. Observed bacterial growth in all four quadrants: i.e. Q1 + Q2 + Q3 + Q4 (most strict definition of infection)

BOX 2 Semi-quantitative descriptions of infection

TABLE 5 Diagnostic outcomes for semi-quantitative analysis of wound swab when different diagnostic thresholds (levels of growth) are used

Level of growtha Se (%) Sp (%) PPV (%) NPV (%) +LR –LR

A 100 37 54 100 1.58 0.026B 100 63 67 100 2.73 0.015C 79 90 86 85 8.04 0.23D 26 99 93 64 18.75 0.75

+/–LR, positive/negative likelihood ratio; NPV, negative predictive value; PPV, positive predictive value; Se, sensitivity; Sp, specificity.a A, observed bacterial growth in quadrant I, quadrants I and II, quadrants I, II and III or quadrants I, II, III and IV;

B, observed bacterial growth in quadrants I and II, quadrants I, II and III or quadrants I, II, III and IV; C, observed bacterialgrowth in quadrants I, II and III or quadrants I, II, III and IV; D, observed bacterial growth in quadrants I, II, III and IV.

clinicians to determine the optimum diagnosticthreshold to use.

ROC curve plots enable the area under the curveto be estimated. This value is the probability of thediagnostic test correctly classifying a patient withor without an infection. The greater the area, themore accurate is the test, with perfect performancerepresented by a value of 1.0. A value of 0.5represents an uninformative test.96,97 For semi-quantitative analysis of wound swabs, theestimated area under the ROC curve was 0.92[95% (CI) 0.87 to 0.97], meaning that theprobability that cases were correctly classified was 92%.

In terms of predictive values, PPVs increased withthe more strict criteria and NPVs decreased(Table 5). +LRs, an estimate of how many moretimes a positive test result is likely to be found indiseased people compared with non-diseasedpeople, increased with increasing stringency ofdiagnostic criteria. According to the rule of thumbmentioned earlier for interpretation of +LRs, thestrictest diagnostic criterion provided convincingdiagnostic evidence (threshold D), the secondstrictest criterion provided strong diagnosticevidence (threshold C), whereas the values derivedfrom the two least strict criteria were lessinformative (thresholds A and B). For –LRs,thresholds A and B (the less strict definitions of


25


0.0

Threshold C

0.0

0.2

0.4

0.6

0.8

1.0

0.2 0.4 0.6 0.8 1.0

Threshold D

Threshold B

Threshold A

Sens

itivi

ty (t

rue

poiti

ve r

ate)

1 – specificity (false positive rate)

FIGURE 3 ROC plot for detecting wound infection using semi-quantitative analysis of wound swab with reference to quantitativeanalysis of swab as the reference standard

TABLE 6 Coordinates used to plot the ROC curve

Level of growtha Sensitivity (true positive rate) 1 – Specificity (false positive rate)

A 1.000 0.634B 1.000 0.366C 0.792 0.099D 0.264 0.014

a See Table 5.

infection) showed convincing diagnostic evidence,whereas for the two stricter definitions of infection(thresholds C and D), the values derived were notinformative according to the rule of thumb.However, for diagnostic threshold C, the valueapproached usefulness (see Table 5).

A summary of the quality assessment for this studyis given in Appendix 5. The patient selectioncriteria were clearly described and the spectrum ofpatients recruited appeared to be representative ofthose who would receive the test in clinicalpractice. All patients received both tests, the indextest was not a component of the reference test,both tests were reported in sufficient detail topermit replication and there did not appear to beany uninterpretable results or study withdrawals.However, the time lag between tests was notstated. In addition, it was not clear whether thereference standard (quantitative analysis of woundswab) could correctly identify wound infection,whether blind interpretation of test results wasperformed or whether the same clinical data wereavailable when test results were interpreted aswould be likely to be available in clinical practice.

SummaryFindings suggest that semi-quantitative analysismay be a useful alternative to quantitative analysis,particularly for settings where the equipment andmaterials necessary for the latter are not available.Overall, threshold C gave the best diagnosticperformance (see Box 2). Interpretation of studyfindings is hindered by possible sources of biasand the current lack of information on anoptimum reference standard.

Effectiveness studiesOur searches identified 1903 citations, of which163 were potentially relevant to questions 4 and 5,namely effectiveness/cost-effectiveness ofmicrobiological analysis or antimicrobial agents.

Excluded studiesThe 140 effectiveness studies that were thought tobe potentially relevant to review questions 4 and 5,which were found to be ineligible after retrieval,are summarised in the excluded studies table inAppendix 6.

The reasons for exclusion were as follows: studynot an RCT or CCT of an antimicrobial, n = 98;study did not report data for diabetic foot ulcersseparately and <80% of patients had diabetic footulcers, n = 40. Two systematic reviews were

identified in the search and these werehandsearched for RCTs/CCTs.98,99

Review question 4: What impact doesmicrobiological analysis have ontherapy?Included studiesWe found no trials answering this question. Suchstudies would have compared a policy of taking amicrobiological sample (e.g. swab) or not at thepoint at which a patient was deemed to have aninfection and hence would have allowed us toevaluate the impact that microbiological analysishas on clinical outcomes.

Review question 5: What is theeffectiveness and cost-effectiveness ofmanagement of infection in DFU?Included studiesWe identified 23 trials (21 RCTs and two CCTs),including 25 comparisons, addressing thisquestion.

Quality of included studiesDetails of study quality assessment are given inAppendix 5. The methodological quality of allincluded RCTs was assessed using the criteriareported in the Jadad five-point scale85 and theallocation concealment criterion described bySchulz and colleagues.86

Results using the four assessment criteria are asfollows. Nine studies reported appropriatemethods of randomisation, 12 trials were simplydescribed as ‘randomised’ and two allowed thepatients to choose the groups to which they wereallocated. Two studies reported an appropriateprocedure for allocation concealment; in 17studies it was unclear if the person randomisingthe participants was aware of the allocation, in twostudies allocation was open and two studies wereCCTs, in which patients chose their treatment.Three trials described appropriatedouble–blinding, five described the trial asdouble-blind, in 13 trials there was no informationon double-blinding and in the two CCTs thepatients and clinicians were not blinded. Thirteenstudies reported the number and reason forwithdrawals, nine studies did not report reasonsfor withdrawal by group and one reported nowithdrawals.

Gough and colleagues100 and Peterson andcolleagues101 both described appropriate methodsfor allocation concealment, described appropriatemethods of generating the randomisationsequence, and both reported reasons and number

Results

26

of withdrawals by study group. In addition, bothstated they were double-blind, with the trial byGough and colleagues100describing how this wasachieved . Other trials may have been designed,performed and analysed to the highest standardsbut failed to report this in the study publication.Although these two trials were of high quality, theweight given to their findings is moderated by thefact that both are small (40 and 48 patients) andtherefore underpowered.

OutcomesThere was a wide variation across studies of theoutcome measures used. Twenty-one outcomeswere reported and no single outcome was reportedin all trials (Table 7). Adverse events, includingdeath, were reported in 16 trials. Amputation wasreported in 11 trials, clinical diagnosis of cure ofinfection in nine trials and proportion of ulcershealed in 11 trials. The large number of outcomesused and the lack of consistency in reportingoutcomes mean that the data on effectiveness aredifficult to synthesise.

The incidence of osteomyelitis, pain, ulcerrecurrence, mobility, level of independence,number of hospital admissions or health-relatedquality of life were not reported in any of theincluded studies. A large number of outcomes,which we had not specified in the review protocol,were reported in the studies and these are

identified in Table 7 as shaded columns. Clinicalcure of infection and the need for vascularreconstruction were not initially included in thereview outcomes. As these outcomes were reportedin nine and five trials, respectively, and we felt theymay report clinically important outcomes, wedecided, post hoc, to report these outcomes wherethey were available. If clinical assessments ofinfection status were found by the diagnosticreviews to be a valid indication of infection status(question 1), which was not the case, then thisoutcome would be a valid outcome measure.Vascular reconstruction may be seen as a procedureused to avert amputation, and therefore we felt thatit may also provide clinically relevant information.

PopulationThere was wide variation in the types of patientsrecruited to the trials and the ulcer characteristicsand settings are summarised in Table 8. There wasno information on the severity of ulceration in14 trials. One trial used its own ulcer gradingsystem and the remainder (eight trials) used theWagner classification system (Box 3)102 or theUniversity of Texas San Antonio Diabetic WoundClassification System (Box 4)103 The latterclassification system takes account of infection andischaemia in addition to ulcer depth. Three trialsstated that they included people with a grade1 ulcer, six included grade 2 ulcers, four grade3 ulcers and two grade 4 ulcers (as some trials


27


Grade Lesion0 No open lesions; may have deformity or cellulitis 1 Superficial diabetic ulcer (partial or full thickness) 2 Ulcer extension to ligament, tendon, joint capsule or deep fascia without abscess or osteomyelitis3 Deep ulcer with abscess, osteomyelitis or joint sepsis4 Gangrene localised to portion of forefoot or heel5 Extensive gangrenous involvement of the entire foota Source: Frykberg.104

BOX 3 Wagner ulcer classification systema

Stage Grade

0 1 2 3

A Pre- or postulcerative Superficial wound, not Wound penetrating to Wound penetrating tolesion completely involving tendon, capsule tendon or capsule bone or joint

or bone

B With infection With infection With infection With infection

C With ischaemia With ischaemia With ischaemia With ischaemia

D With infection and With infection and With infection and With infection and ischaemia ischaemia ischaemia ischaemia

BOX 4 University of Texas San Antonio Diabetic Wound Classification System

recruited patients with a range of ulcer severity,this total is greater than eight).

Four studies did not provide sufficient informationto allow us to determine whether the patients hadulcers with established infection. Twelve studies

stated that the ulcer was infected and sevenevaluated antimicrobial agents on apparentlyuninfected ulcers.

Three studies did not report information on thesite of treatment (inpatient or outpatient), 14 were

Results

28

TABLE 7 Outcome measures reporteda

Limb Infection outcomes Ulcer healing Organisationoutcomes outcomes outcomes

Study ID

Intravenous interventionsBouter (1996)106 × × ×Bradsher (1984)43 × × ×Erstad (1997)107 × × × × ×Grayson (1994)44 × × × × × × ×Lipsky (2004)109 × × ×Seidel (1991)110 × × × × × ×Seidel (1993,1994)111,112 × ×Tan (1993)108 × × ×

Oral interventionsChantelau (1996)74 × × ×Lipsky (1990)75 × × × ×Lipsky A114 × × × × ×Lipsky B114 × × × × ×Peterson (1989)101 × × ×

Subcutaneous interventionsGough (1997)100 × × × × × × × × ×Kastenbauer (2003)118 × × × × × ×de Lalla (2001)119 × × × × ×Yonem (2001)120 × ×

Topical interventions Apelqvist (1995)138 × × × × ×Marchina (1997)123 ×Markevich (2000)105 ×Rhaiem (1998)124 × × ×Vandeputte (1996)125 × × × × ×

Other interventionsDwivedi (2000)127 ×

a Shaded cells indicate outcomes listed in the protocol for this review as being relevant.

Am

puta

tion

Vas

cula

r re

cons

truc

tion

Req

uire

d su

rgic

al d

ebri

dem

ent

Clin

ical

cur

e of

infe

ctio

n

Dur

atio

n of

ant

ibio

tic

ther

apy

Erad

icat

ion

of p

atho

gens

Req

uire

d ad

diti

onal

ant

ibio

tics

Cur

e of

ost

eom

yelit

is

Bac

teri

olog

y

Tim

e to

res

olut

ion

of c

ellu

litis

Tim

e to

cle

ar s

wab

Pro

port

ion

wit

h re

solu

tion

of c

ellu

litis

Infe

ctio

n su

mm

ary

scor

e

Pro

port

ion

of u

lcer

s he

aled

Tim

e to

hea

ling

Are

a or

vol

ume

chan

ge

Cha

nge

in g

rade

Tim

e to

dis

char

ge

Cos

ts

Adv

erse

eve

nts

conducted on inpatients, five on outpatients andone on both inpatients and outpatients. The siteof treatment was related to the presence ofestablished infection (Table 8). Eleven studies ofestablished infection in ulcers were undertaken inhospital inpatients and only one treated peoplewith infected ulcers as outpatients.75 One studyapparently reported treatment of people withoutestablished infection as inpatients.105 There weretwo studies in which the setting was not clear andan additional four studies in which the status ofthe patient regarding ulcer infection was not clear.Therefore, it is not clear whether the relationshipbetween infection status and site of treatment isclear cut.

Interventions and comparisonsA number of intervention types were included inthis review: intravenous, oral, subcutaneous,topical and other methods. The ‘other’ groupincluded, for example, studies comparing oral andtopical administration methods with a topicalintervention, or where there were mixed methodsof administration.

Comparisons of methods of administrationincluded studies of intravenous versus intravenousadministration, oral versus oral, topical versustopical, oral versus topical and subcutaneousversus standard care or placebo. The variouscomparisons made are summarised in Table 9.

Owing to the heterogeneity in intervention andoutcomes, it was not possible to undertake anymeta-analyses.

Effectiveness of intravenousinterventionsEight studies are included in this group. Fourtrials made straight comparisons betweenintravenous regimens,44,106–108 one compared tworegimens in which therapy started as intravenousand was changed to oral as the patient’s conditionimproved,109 two trials (three reports) comparedtwo different methods of infusion of antibiotics(retrograde venous perfusion and regularintravenous infusion)110–112 and one compared anintravenous antibiotic with a comparator giveneither IV or intramuscularly.43


29


TABLE 8 Characteristics of study settings and patient characteristics

Study Setting Ulcer grade Infected

Bouter (1996)106 IP Wagner grade 2, 3 or 4 YBradsher (1984)43 IP No information Yde Lalla (2001)119 IP Wagner grades 3 and 4 YErstad (1997)107 IP Used own grading system – most were grade 2 and 3 – cellulitis Y

+ skin break or cellulitis + deep ulcer or cellulitis and puncture plus suspected osteomyelitis

Gough 1997100 IP No data on grade YGrayson (1994)44 IP No data on grade but did provide data on baseline coma YKastenbauer (2003)118 IP Wagner grade 2 or 3 YLipsky (2004)109 IP No data on grade YPeterson (1989)101 IP No data on grade YRhaiem (1998)124 IP No data on grade NSeidel (1991)110 (CCT) IP No data on grade, 12/40 had osteomyelitis UnclearSeidel (1993,1994)111,112 IP No data on grade, Unclear Tan (1993)108 IP No data on grade YYonem (2001)120 IP Wagner grade 2 or less YMarkevich (2000)105 IP Grade 2 and 3 NApelqvist (1996)122 OP Wagner grade 1 or 2 NDwivedi (2000)127 OP No data on grade Unclear Lipsky A114 OP No data on grade NLipsky B114 OP No data on grade NLipsky (1990)75 OP No data on grade YChantelau (1996)74 OP + IP Grade 1A to 2A (Texas) UnclearMarchina (1997)123 Unclear 1st or 2nd degree (not defined) NVandeputte (1996)125 Unclear No data on grade N

IP, inpatient; OP, outpatient; Y, yes; N, no.

We found no trials comparing an intravenousantibiotic with a placebo. We found no studiescomparing an intravenous antibiotic against anoral, topical or subcutaneous intervention.

All comparisons were unique and each featuredtwo active treatment groups. In seven trials morethan one antibiotic was used, for exampleampicillin and sulbactam (A/S) or imipenem andcilastatin (I/C); only Bradsher and Snow made asimple comparison of two single antibiotics,ceftriaxone versus cefazolin.43 A/S was acomparator in three trials,44,107,109 I/C was acomparator in two trials44,106 and linezolid,109

piperacillin and clindamycin (P/C),106 piperacillinand tazobactam108 and ticarcillin and clavulanate(T/C)108 were each used in one trial. Onecomparison of two methods of infusion usedpiperacillin and gentamicin110 and the other usedpiperacillin and netilmycin.111,112

The trial results are summarised in Table 10.Further details on each trial are provided in thedata extraction tables in Appendix 4.

Description of the studiesBouter and colleagues (1996)106

Bouter and colleagues106 compared I/C with P/Cadministered intravenously in 46 hospitalisedpatients (mean age 71.4 years) with DFUs whoseankle/brachial index was at least 0.45. Theantibiotic treatment period was a minimum of10 days and the mean duration of therapy was

23–24 days. All patients underwent bed rest andthrombolytic therapy. Foot infections wereidentified as polymicrobial in more than half ofthe cases. There was no statistically significantdifference in the numbers of people with clinical‘cure’ (defined as the disappearance of initialinfection) between the two groups: 4/22 (18%) withI/C and 6/24(25%) with P/C (RR 1.38, 95% CI 0.48to 4.11). There was no statistically significantdifference in the prevalence of ‘bacterialeradication’, 9/22 (41%) for I/C and 16/24 (67%)for P/C (RR 1.63, 95% CI 0.94 to 3.02). Theincidence of adverse events was statisticallysignificantly higher in the P/C group (50%) thanin the I/C group (19%) (RR 3.67, 95% CI 1.33 to11.13), with diarrhoea being the single mostfrequently reported event. The trial wasunderpowered, however, so it was unable to detectall but massive differences in effectiveness asstatistically significant.

Bradsher and Snow (1984)43

Bradsher and Snow compared cefazolin givenintravenously with ceftriaxone administered eitherintravenously or intramuscularly in 84 inpatientswith suspected skin and soft tissue infection, ofwhom 20 had suppurative DFUs.43 Baselineinformation on demographics and bacteriology ispresented for the whole study population,including people with cellulitis, abscess,thrombophlebitis, pressure ulceration and surgicalwound infection. Results for the people with DFUs

Results

30

TABLE 9 Comparisons made in included studies.

i.v Oral Topical Placebo Standard care

i.v. antibiotics 1. Bouter106

2. Erstad107

3. Grayson44

4. Lipsky109

5. Seidel110

6. Seidel111

7. Tan108

Oral antibiotics 1. Lipsky75 1. Lipsky A114 1. Chantelau74

2. Peterson101 2. Lipsky B114

Subcutaneous growth 1. Gough174 1. de Lalla119

factors 2. Kastenbauer118 2. Yonem120

Topical antimicrobial 1. Apelqvist122 1. Rhaiem124

2. Marchina123 (sugar vs standard 3. Markevich105 care)4. Vandeputte125

Other antimicrobial 1. Bradsher43 1. Rhaiem124 1. Dwivedi 127

agents (i.v. versus either (sugar vs i.v. or i.m.) antibiotics)


31


TA

BLE

10

Sum

mar

y of

com

paris

ons,

out

com

es a

nd re

sults

from

effe

ctive

ness

stu

dies

Stud

yC

ompa

riso

n A

Out

com

eD

ata

RR

, 95%

CI

Com

pari

son

B(d

icho

tom

ous

outc

omes

)M

ean d

iffe

rence,

95

% C

I

(conti

nuous

outc

om

es)

Intr

ave

nous

inte

rventi

ons

Bout

er (1

996)

106

Imip

enem

/cila

stat

in

Clin

ical

‘cur

e’ (d

isapp

eara

nce

of in

itial

infe

ctio

n)I/C

4/2

2 (1

8%)

RR 1

.38

Pipe

raci

llin/

clin

dam

ycin

P/C

6/2

4 (2

5%)

95%

CI 0

.48

to 4

.11

Imip

enem

/cila

stat

in‘B

acte

rial e

radi

catio

n’

I/C 9

/22

(41%

)RR

1.6

3Pi

pera

cilli

n/cl

inda

myc

inP/

C 1

6/24

(67%

) 95

% C

I 0.9

4 to

3.0

2Br

adsh

er (1

984)

43C

efaz

olin

‘In

fect

ion

elim

inat

ed’ a

t fo

llow

-up

I/C 4

/10

(40%

)RR

1.5

Cef

tria

xone

P/C

6/1

0 (4

0%)

95%

CI 0

.60

to 3

.74

Erst

ad (1

997)

107

Am

pici

llin/

sulb

acta

mA

ny a

mpu

tatio

nA

/S 8

/18

(44%

)RR

1.0

Cef

oxiti

nC

8/1

8 (4

4%)

95%

CI 0

.48

to 2

.09

Am

pici

llin/

sulb

acta

mC

linic

al ‘c

ure’

(res

olut

ion

of s

igns

and

sym

ptom

s A

/S 1

/18

(6%

)RR

0.1

4C

efox

itin

of in

fect

ion)

C 7

/18

(39%

)95

% C

I 0.0

2 to

0.7

6A

mpi

cilli

n/su

lbac

tam

Adv

erse

eve

nts

A/S

7/1

8 (3

9%)

RR 1

.17

Cef

oxiti

nC

6/1

8 (3

3%)

95%

CI 0

.5 t

o 2.

8

Gra

yson

(199

4)44

Am

pici

llin/

sulb

acta

mTo

tal n

umbe

r of

am

puta

tions

A/S

33/

48 (6

9%)

RR 0

.85

Imip

enem

/cila

stat

in

I/C 2

8/48

(58%

)95

% C

I 0.6

2 to

1.1

5A

mpi

cilli

n/su

lbac

tam

Clin

ical

‘cur

e’ (r

esol

utio

n of

sof

t tis

sue

infe

ctio

n)

A/S

28/

48 (5

8%)

RR 1

.04

Imip

enem

/cila

stat

inat

the

end

of t

reat

men

t I/C

gro

up 2

9/48

(60%

)95

% C

I 0.7

4 to

1.4

5A

mpi

cilli

n/su

lbac

tam

Clin

ical

‘cur

e of

infe

ctio

n’ r

ates

at

final

follo

w-u

pA

/S 2

7/48

(56%

)RR

1.2

2Im

ipen

em/c

ilast

atin

I/C

33/

48 (6

9%)

95%

CI 0

.89

to 1

.7A

mpi

cilli

n/su

lbac

tam

Adv

erse

eve

nts

A/S

16/

48 (3

3%)

Imip

enem

/cila

stat

in

I/C 1

7/48

(35%

)

Lips

ky (2

004)

109

Line

zolid

(i.v

. or

oral

)C

linic

al c

ure

rate

(res

olut

ion

of a

ll cl

inic

al s

igns

Li

nezo

lid 6

9% (1

31/1

90)

RR 0

.92

Am

pici

llin/

sulb

acta

m o

r an

d sy

mpt

oms

and

a he

alin

g w

ound

afte

r 5

days

A

S/A

C 6

3% (5

7/93

)95

% C

I 0.7

6 to

1.0

9am

oxic

illin

cla

vula

nate

of t

hera

py)

Line

zolid

(i.v

. or

oral

)A

mpi

cilli

n/su

lbac

tam

or

Mea

n to

tal d

urat

ion

of t

hera

py r

equi

red

Line

zolid

mea

n 17

.2da

ysD

iffer

ence

= –

0.7

days

amox

icill

in/c

lavu

lana

teA

S/A

C m

ean

16.5

days

95

% C

I –2.

66 t

o 1.

26Li

nezo

lid (I

V or

ora

l)D

urat

ion

of t

reat

men

t w

ith i.

v. a

ntib

iotic

s Li

nezo

lid m

ean

7.8

days

M

ean

diffe

renc

e 2.

6da

ysA

mpi

cilli

n/su

lbac

tam

or

AS/

AC

mea

n 10

.4da

ys95

% C

I 1.2

2 to

3.9

8am

oxic

illin

/cla

vula

nate

Line

zolid

(i.v

. or

oral

)W

ithdr

awin

g fr

om t

he s

tudy

due

to

an a

dver

se

Line

zolid

, n=

18

(7.5

%)

RR 2

.24

Am

pici

llin/

sulb

acta

m o

r ev

ent

AS/

AC

n =

4 (3

.3%

)95

% C

I 0.8

2 to

6.2

4am

oxic

illin

cla

vula

nate

cont

inue

d

Results

32 TA

BLE

10

Sum

mar

y of

com

paris

ons,

out

com

es a

nd re

sults

from

effe

ctive

ness

stu

dies

(co

nt’d

)

Stud

yC

ompa

riso

n A

Out

com

eD

ata

RR

, 95%

CI

Com

pari

son

B(d

icho

tom

ous

outc

omes

)M

ean d

iffe

rence,

95

% C

I

(conti

nuous

outc

om

es)

Seid

el (1

991)

110

i.v. a

ntib

iotic

sPe

ople

req

uirin

g am

puta

tion

due

to u

nder

lyin

g i.v

. 4/2

0RR

9 H

alda

ne a

ppro

xim

atio

nRV

P in

fusio

ns o

f ant

ibio

tics

oste

omye

litis

RVP

0/20

95%

CI 0

.52

to 1

57

i.v. a

ntib

iotic

sN

umbe

r of

ulc

ers

heal

edi.v

. 0/2

0RR

0.0

77 H

alda

ne

RVP

6/20

appr

oxim

atio

nRV

P in

fusio

ns o

f ant

ibio

tics

95%

CI 0

.005

to

1.28

i.v. a

ntib

iotic

s‘R

esol

ved’

ost

eom

yelit

isi.v

. 0/7

RR 0

.083

Hal

dane

RV

P in

fusio

ns o

f ant

ibio

tics

RVP

4/5

appr

oxim

atio

n95

% C

I 0.0

05 t

o 1.

27

Seid

el (1

993,

199

4)11

1,11

2i.v

. ant

ibio

tics

Am

puta

tion

rate

i.v. 4

/21;

19%

RR 1

.52

RVP

infu

sions

of a

ntib

iotic

sRV

P 3/

24; 1

2.5%

95%

CI 0

.42

to 5

.57

i.v. a

ntib

iotic

sU

lcer

s he

aled

i.v. 3

/21

(14%

)RR

0.4

3RV

P in

fusio

ns o

f ant

ibio

tics

RVP

8/24

(33%

)95

% C

I 0.1

3 to

1.2

8

Tan

(199

3)10

8Pi

pera

cilli

n/ta

zoba

ctam

(P/T

)C

linic

al ‘c

ure’

(def

ined

as

reco

very

from

infe

ctio

n)Pe

r pr

otoc

ol a

naly

sis (P

PA)

PPA

: RR

0.66

Tic

arci

llin/

clav

ulan

ate

P/T

56%

(9/1

6):

T/C

86%

(6/7

)95

% C

I 0.3

7 to

1.2

6 PP

AIn

tent

ion

to t

reat

ana

lysis

(IT

TA)

ITTA

: RR

0.87

P/T

29%

(9/3

1) T

/C 3

3% (6

/18)

95%

CI 0

.39

to 2

.07

if al

l miss

ing

data

ass

umed

to

equa

l ‘fa

iled

to a

chie

ve a

cure

’O

ral i

nter

vent

ions

Cha

ntel

au (1

996)

74A

mox

ycill

in+

clav

ulan

ic a

cid

Hea

ling

rate

s A

/C 6

/22

(27%

)RR

1.6

7(A

ugm

entin

®)

Plac

ebo

10/2

2 (4

5%)

95%

CI 0

.76

to 3

.83

Plac

ebo

Am

oxyc

illin

+cl

avul

anic

aci

d A

bsen

ce o

f mic

robe

s in

dee

p sw

ab w

ound

A

/C 7

/22,

32%

RR 0

.86

(Aug

men

tin®

)cu

lture

s ta

ken

at c

ompl

etio

n of

the

stu

dyPl

aceb

o 6/

22, 2

7%95

% C

I 0.3

5 to

2.0

9Pl

aceb

oLi

psky

(199

0)75

Clin

dam

ycin

hyd

roch

lorid

e In

fect

ion

‘cur

e’ r

ate

(sig

ns a

nd s

ympt

oms

reso

lved

) Pe

r pr

otoc

ol a

naly

sis (P

PA)

RR 0

.93

(Cle

ocin

) C

linda

myc

in 2

1/27

(78%

)95

% C

I 0.6

7 to

1.2

9C

epha

lexi

n (K

efle

x)

Cep

ahle

xin

21/2

9 (7

2%)

Clin

dam

ycin

hyd

roch

lorid

e U

lcer

s he

alin

gPe

r pr

otoc

ol a

naly

sisRR

0.8

3(C

leoc

in)

Clin

dam

ycin

10/

27 (3

7%)

95%

CI 0

.4 t

o 1.

73C

epha

lexi

n (K

efle

x)C

epha

lexi

n 9

/29

(31%

)

cont

inue

d


33


TA

BLE

10

Sum

mar

y of

com

paris

ons,

out

com

es a

nd re

sults

from

effe

ctive

ness

stu

dies

(co

nt’d

)

Stud

yC

ompa

riso

n A

Out

com

eD

ata

RR

, 95%

CI

Com

pari

son

B(d

icho

tom

ous

outc

omes

)M

ean d

iffe

rence,

95

% C

I

(conti

nuous

outc

om

es)

Clin

dam

ycin

hyd

roch

lorid

e Er

adic

atio

n of

bac

teria

l pat

hoge

nsPe

r pr

otoc

ol a

naly

sisRR

0.9

(Cle

ocin

) C

linda

myc

in 2

0/26

(77%

)95

% C

I 0.6

3 to

1.2

6C

epha

lexi

n (K

efle

x)C

epha

lexi

n 20

/29

(69%

)C

linda

myc

in h

ydro

chlo

ride

Adv

erse

eve

nts

Clin

dam

ycin

1RR

2.0

(Cle

ocin

) C

epha

lexi

n 2

95%

CI 0

.28

to 1

4.8

Cep

hale

xin

(Kef

lex)

Lips

ky A

114

Pexi

gana

n cr

eam

Num

ber

of a

mpu

tatio

nsPe

xiga

nan

6/24

6 (2

.4%

)RR

1.5

Oflo

xaci

n O

floxa

cin

4/24

7 (1

.6%

) 95

% C

I 0.4

6 to

4.9

2Pe

xiga

nan

crea

mC

linic

al ‘c

ure’

rat

es (n

o fu

rthe

r sig

ns o

r sy

mpt

oms

Pexi

gana

n 63

/243

(26%

)RR

1.0

8O

floxa

cin

of in

fect

ion)

at

day

10

Oflo

xaci

n 67

/240

(28%

) 95

% C

I 0.8

1 to

1.4

5Pe

xiga

nan

crea

m‘M

icro

biol

ogic

ally

res

olve

d in

fect

ion’

at

final

Pe

xiga

nan

75/1

85 (4

0%)

RR 1

.07

Oflo

xaci

nfo

llow

-up

Oflo

xaci

n 84

/193

(44%

)95

% C

I 0.8

5 to

1.3

6Pe

xiga

nan

crea

mA

dver

se e

vent

s le

adin

g to

pat

ient

with

draw

alPe

xiga

nan

28/2

47 (1

1%)

RR 0

.82

Oflo

xaci

nO

floxa

cin

23/2

46 (9

%)

95%

CI 0

.49

to 1

.38

Pexi

gana

n cr

eam

Serio

us a

dver

se e

vent

sPe

xiga

nan

28/2

47 (1

1.3%

)RR

0.7

2O

floxa

cin

Oflo

xaci

n 20

/246

(8.1

%)

95%

CI 0

.42

to 1

.23

Lips

ky B

114

Pexi

gana

n cr

eam

Clin

ical

‘cur

e’ r

ates

(def

ined

abo

ve) a

t da

y 10

Pexi

gana

n 34

/171

RR 1

.0O

floxa

cin

Oflo

xaci

n 34

/171

95%

CI

Pexi

gana

n cr

eam

Infe

ctio

n ‘re

solv

ed’

Pexi

gana

n 44

(26%

)RR

0.6

8O

floxa

cin

Oflo

xaci

n 30

(18%

)95

% C

I 0.4

5 to

1.0

2IT

T p

rinci

ple:

ass

ume

sam

ple

size

= 1

71 fo

r ea

chgr

oup

and

all m

issin

gpa

tient

s no

t cu

red

Pexi

gana

n cr

eam

Adv

erse

eve

nts

lead

ing

to p

atie

nt w

ithdr

awal

Pexi

gana

n 16

/171

(9%

)RR

0.9

4O

floxa

cin

Oflo

xaci

n 15

/171

(9%

) 95

% C

I 0.4

8 to

1.8

1

Pete

rson

(198

9)10

175

0 m

g N

umbe

r of

am

puta

tions

750

mg,

n=

4/24

(17%

)RR

1.5

1000

mg

twic

e da

ily c

ipro

floxa

cin

1000

mg,

n=

6/2

4 (2

5%)

95%

CI 0

.51

to 4

.49

750

mg

Adv

erse

eve

nts

whi

ch r

esul

ted

in d

iscon

tinua

tion

2 in

100

0 m

g gr

oup

RR 5

Hal

dane

10

00 m

g tw

ice

daily

cip

roflo

xaci

nof

the

dru

g ap

prox

imat

ion

95%

CI 0

.25

to 9

9

cont

inue

d

Results

34 TA

BLE

10

Sum

mar

y of

com

paris

ons,

out

com

es a

nd re

sults

from

effe

ctive

ness

stu

dies

(co

nt’d

)

Stud

yC

ompa

riso

n A

Out

com

eD

ata

RR

, 95%

CI

Com

pari

son

B(d

icho

tom

ous

outc

omes

)M

ean d

iffe

rence,

95

% C

I

(conti

nuous

outc

om

es)

Sub-

cuta

neou

s in

terv

enti

ons

Gou

gh (1

997)

100

G-C

SFTo

e am

puta

tion

G-C

SF 0

/20

RR 5

Hal

dane

Pl

aceb

o (s

alin

e)Pl

aceb

o 2/

20

appr

oxim

atio

n 95

% C

I 0.3

to

98G

-CSF

Ulc

er h

eale

dG

-CSF

4/2

0 (2

0%)

RR 9

Hal

dane

Pl

aceb

o (s

alin

e)

Plac

ebo,

0/2

0ap

prox

imat

ion

95%

CI 0

.5 t

o 15

7

Kast

enba

uer

(200

3)11

8G

-CSF

Hea

led

at d

ay 1

0 G

-CSF

0/2

0RR

5 H

alda

ne

Plac

ebo

(sal

ine)

Con

trol

2/2

0 (1

0%)

appr

oxim

atio

n95

% C

I 0.3

to

98

de L

alla

(200

1)11

9G

-CSF

Am

puta

tion

rate

G-C

SF g

roup

3/2

0 (1

5%)

RR 0

.33

Stan

dard

car

eSt

anda

rd c

are

9/20

(45%

) 95

% C

I 0.1

1 to

0.9

5G

-CSF

‘Cur

ed’ o

r ha

d a

stab

le u

lcer

at

6 m

onth

sG

-CSF

13/

16RR

0.9

2St

anda

rd c

are

Stan

dard

car

e 15

/20

95%

CI 0

.63

to 1

.38

Yone

m (2

001)

120

G-C

SFPr

opor

tion

of p

atie

nts

requ

iring

am

puta

tion

G-C

SF 2

/15

(13%

)RR

0.6

7St

anda

rd c

are

Stan

dard

car

e 3/

15 (2

0%)

95%

CI 0

.15

to 2

.95

Topi

cal i

nter

vent

ions

Ape

lqvi

st (1

995)

138

Cad

exom

er io

dine

oin

tmen

t N

umbe

r of

pat

ient

s w

ho r

equi

red

surg

ical

St

anda

rd t

reat

men

t 5/

18 (2

8%)

RR fo

r su

rger

y 0.

64G

enta

mic

in o

r st

rept

odor

nase

/in

terv

entio

nC

adex

omer

iodi

ne 3

/17

(18%

)95

% C

I 0.1

9 to

2.0

7st

rept

okin

ase

or d

ry s

alin

e ga

uze

Cad

exom

er io

dine

oin

tmen

t U

lcer

hea

led

Cad

exom

er io

dine

5/1

7 (2

9%)

RR 2

.65

Gen

tam

icin

or

stre

ptod

orna

se/

Stan

dard

car

e 2/

18 (1

1%)

95%

CI 0

.68

to 1

0.89

stre

ptok

inas

e or

dry

sal

ine

gauz

e

Mar

chin

a (1

997)

123

Ant

isept

ic s

pray

(con

tent

not

C

ompl

etel

y he

aled

at

15 d

ays

Ant

isept

ic s

pray

50%

NA

desc

ribed

) Eo

sin/c

hlor

oxyl

enol

82%

2% e

osin

and

0.3

% c

hlor

oxyl

enol

sp

ray

Mar

kevi

ch (2

000)

105

Larv

aeU

lcer

hea

ling

Larv

al t

hera

py 5

/70

(7.1

%)

RR 2

.5H

ydro

gel

Hyd

roge

l 2/7

0 (2

.9%

)95

% C

I 0.5

8 to

10.

9 cont

inue

d


35


TA

BLE

10

Sum

mar

y of

com

paris

ons,

out

com

es a

nd re

sults

from

effe

ctive

ness

stu

dies

(co

nt’d

)

Stud

yC

ompa

riso

n A

Out

com

eD

ata

RR

, 95%

CI

Com

pari

son

B(d

icho

tom

ous

outc

omes

)M

ean d

iffe

rence,

95

% C

I

(conti

nuous

outc

om

es)

Rhai

em (1

998)

124

Syst

emic

ant

ibio

tics

Hea

ling

rate

Syst

emic

ant

ibio

tics

16/4

0 (4

0%)

RR 1

.25

Suga

rSu

gar

8/16

(50%

)95

% C

I 0.6

4 to

2.2

3Su

gar

dres

sings

Suga

r dr

essin

gs 1

1/24

(46%

)RR

0.8

7St

anda

rd d

ress

ings

Stan

dard

dre

ssin

gs 1

6/40

(40%

)95

% C

I 0.5

to

1.59

Use

d w

ith s

yste

mic

ant

ibio

tics

Syst

emic

ant

ibio

tics

Ulc

er h

ealin

gSy

stem

ic a

ntib

iotic

s 11

/24

RR 1

.09

No

antib

iotic

s N

o an

tibio

tics

8/16

95%

CI 0

.55

to 2

.07

Also

sug

ar d

ress

ings

Vand

eput

te (1

996)

125

Hyd

roge

l dre

ssin

g N

eces

sity

for

ampu

tatio

n (o

ne o

r m

ore

toes

) H

ydro

gel 1

/15

(7%

)RR

5.4

Gau

ze a

nd c

hlor

hexi

dine

Chl

orhe

xidi

ne 5

/14

(36%

) 95

% C

I 0.9

8 to

32.

7H

ydro

gel d

ress

ing

Ulc

ers

heal

edH

ydro

gel 1

4/15

(93%

)RR

2.6

1G

auze

and

chl

orhe

xidi

neC

hlor

hexi

dine

5/1

4 (3

6%)

95%

CI 1

.45

to 5

.76

Hyd

roge

l dre

ssin

g In

cide

nce

of in

fect

ion

Hyd

roge

l gro

up 1

/15

(7%

)RR

7.5

Gau

ze a

nd c

hlor

hexi

dine

Chl

orhe

xidi

ne 7

/14

(50%

)95

% C

I 1.4

7 to

44.

1H

ydro

gel d

ress

ing

Syst

emic

/loca

l ant

ibio

tics/

requ

ired

Hyd

roge

l 1/1

5 (7

%)

RR 0

.067

Gau

ze a

nd c

hlor

hexi

dine

Chl

orhe

xidi

ne 1

4/14

(100

%)

95%

CI 0

.01

to 0

.31

Oth

er in

terv

enti

ons

Dw

ived

i (20

00)12

7A

yurv

edic

med

icin

e vs

Requ

ired

surg

ery

Act

ive

16%

NA

stan

dard

car

eSt

anda

rd c

are

30%

NA

, not

ava

ilabl

e.

are reported as ‘bacteriological response’. Sixpeople in the ceftriaxone group and four in thecefazolin group were described as having their‘infection eliminated’ at follow-up (RR 1.5, 95% CI0.60 to 3.74). The study reported the outcomes ofamputation, the need for other surgicalprocedures (such as incision and drainage ordebridement) and adverse events for all patientscombined (not stratified by patient type), hence itis difficult to determine whether these could begeneralised to the DFU population.

Erstad and colleagues (1997)107

Erstad and colleagues compared A/S versuscefoxitin, both administered intravenously, in adouble-blind RCT.107 Thirty-six hospitalisedpatients with at least a Wagner grade 1 diabeticfoot infection were treated for a minimumof 5 days, with initial follow-up at 2 weeks post-hospital discharge and again at 1 year. Thirty-three of the 36 (92%) had open ulcers. Followingtreatment, similar proportions of patients had hadamputations in each study group, i.e. 8/18 (44%).The RR for any amputation was 1.0 (95% CI 0.48to 2.09). There was also no statistically significantdifference between the levels of amputation in thetwo groups, i.e. number of either toe amputationsor toe and ray amputations. Some 33% (6/18) ofpeople allocated to cefoxitin had a toeamputation, whereas of those receiving A/S, 17%(3/18) had a toe amputation, RR for toeamputation 0.5 (95% CI 0.15 to 1.55). In thecefoxitin group, the proportion of people withcombined toe and ray amputations was 5.5%(1/18), in the A/S group it was 22% (4/18) (RR 4.0,95% CI 0.68 to 25.4). There was no statisticallysignificant difference in the rate ofrevascularisation in the cefoxitin (4/18; 22%) orA/S groups (2/18; 11%) (RR 0.5, 95% CI 0.12 to2.06). More people in the cefoxitin group (7/18;39%) were reported as having a clinical ‘cure’(defined as complete resolution of presentingsigns and symptoms of infection) than in the A/Sgroup (1/18; 6%) (RR 0.14, 95% CI 0.02 to 0.76).

The report also describes an outcome in which‘cure’ and ‘improved’ patients were pooled(without stating why this outcome was used), andfound no statistically significant difference in theproportions with this outcome (15/18; 83% A/S;16/18; 89% cefoxitin). A per protocol analysis ofthe rate of eradication of bacterial pathogensfound no statistically significant differencebetween groups: 8/11 (73%) in the cefoxitin groupand 6/6 (100%) in the A/S group (RR 1.38, 95% CI0.7 to 2.17). An intention-to-treat analysis foreradication of bacterial pathogens also found no

statistically significant difference between groups:8/18 (44%) in the cefoxitin group and 6/18 (33%)in the A/S group (RR 0.75, 95% CI 0.32 to 1.69).Adverse events, all described as gastrointestinal innature, were reported in 6/18 (33%) of thecefoxitin group and 7/18 (39%) of the A/S group(RR 1.17, 95% CI 0.5 to 2.8). The trial wasunderpowered (for all outcomes) in terms of itsability to detect clinically important differencesthat were statistically significant.

Grayson and colleagues (1994)44

A double-blind RCT with 93 patients (96 infections)compared the intravenous administration of A/Swith I/C in hospital inpatients with diabetes whohad a limb-threatening infection of the feet orlegs, of whom 92% (88) had a foot ulcer.44 A ‘limb-threatening infection of the feet or legs’ wasdefined as (as least) the presence of cellulitis, withor without ulceration or purulent discharge. Thetreatment period averaged 14 days and follow-upwas at 1 year. All patients had bed rest, surgicaldrainage and debridement of infected ulcers andnecrotic tissue. There were no statisticallysignificant differences between the A/S and the I/Cgroups for the total number of amputations [33/48(69%) A/S versus 28/48 (58%) I/C; RR 0.85, 95%CI 0.62 to 1.15; NB the denominator is number ofinfections rather than patients]. There was nostatistically significant difference in the number ofinfections requiring vascular reconstruction in theA/S (7/48; 15%) or I/C (15/48; 31%) groups (RR2.14, 95% CI 0.99 to 4.76). There was nostatistically significant difference in the rate ofclinical ‘cure’ (defined as the resolution of softtissue infection) at the end of treatment in the A/Sgroup (28/48, 58%) or I/C group (29/48, 60%) (RR1.04, 95% CI 0.74 to 1.45). Similarly, at finalfollow-up, clinical ‘cure of infection’ rates in thetwo groups were not statistically significantlydifferent: 27/48 in A/S (56%) and 33/48 (69%) inI/C (RR 1.22, 95% CI 0.89 to 1.7).

The authors reported that there was no statisticallysignificant difference in the number of doses orduration of antibiotic therapy; however, there wereinsufficient data provided in the paper to allow usto calculate the mean differences or CIs. They alsoreported no statistically significant difference inthe eradication of bacterial pathogens at day 5[17/48 (35%) in A/S versus 20/48 (42%) in I/C] andat end of therapy (32/48 in A/S versus 36/48 inI/C) (RR 1.125, 95% CI 0.87 to 1.46). Theproportion of patients with any adverse events was33% (16/48) in A/S versus 35% (17/48) in I/C, withhalf of these described as ‘significant’ (forexample, diarrhoea, rash, nausea or seizure).

Results

36

The trial was underpowered in terms of its abilityto detect clinically important differences asstatistically different for all reported outcomes. Asthere were no statistically significant clinicaldifferences between study groups, the concurrenteconomic analysis compared only the costs ofprimary, secondary treatment and hospital bedcosts using 1994 US dollar prices.113 The resultsrevealed that the mean total treatment cost waslower (by $3000 per patient; $14,000 versus$17,000) with A/S. Sensitivity analysis showed thatthe I/C treatment regimen would need to be 30%more effective than A/S in order to reach thecriteria for cost-effectiveness as defined in thisstudy (i.e. absolute risk difference for probabilityof success of around 30%). For the outcomesamputation, cure of infection at end of treatmentand cure of infection at final follow-up, andvascular reconstruction the difference in eventrates excludes the value where I/C would be 30%more effective than A/S, but larger trials areneeded to increase the precision of the estimatesof effectiveness and cost-effectiveness.

Using a matrix of cost-effectiveness87,89 in whichcosts and effectiveness outcomes are integrated,then A/S is preferred over I/C as there is noevidence of difference in effectiveness with reducedcosts, corresponding to cell H of the table in Box 1.

Lipsky and colleagues (2004)109

An open-label, multi-centre RCT comparedlinezolid (intravenously or orally administered)versus A/S (intravenously) or amoxicillin andclavulanate (A/C) (orally) in 361 patients withdiabetic foot infections, of whom 78% had footulcers.109 This study was identified by contact withexperts and was published in 2004. The methodof administration was switched (from intravenousto oral) at the investigators’ discretion and therapywas continued on both an inpatient and outpatientbasis for at least 7 days, but no more than 28 days.Data on 283 people with DFUs were presentedseparately. Vancomycin was added to the A/S orA/C regimen where necessary for the treatment ofmethicillin-resistant Staphylococcus aureus (MRSA)and all patients received wound dressings, but nottopical antimicrobial treatments. Investigatorscould administer aztreonam 1–2 g intravenously,every 8–12 hours, if required for the treatment ofGram-negative pathogens if the allocatedintervention was not effective against them.Wounds with callus or necrotic material weresharply debrided.

There was no statistically significant difference inthe overall clinical cure rate (resolution of all

clinical signs and symptoms and a healing woundafter 5 days of therapy) for those with infectedulcers, 69% (131/190) in linezolid and 61% (57/93)in A/S or A/C (RR 0.92, 95% CI 0.76 to 1.09).There was no statistically significant differencebetween groups in the mean total duration oftherapy required [mean 17.2 days, standarddeviation (SD) 7.9 in linezolid versus mean16.5 days (SD 7.9), difference –0.7 days, 95% CI–2.66 to 1.26]. Patients were treated withintravenous antibiotics for longer in the A/S orA/C group [mean 10.4 days (SD 5.7)] than thelinezolid group [mean 7.8 days (SD 5.5); meandifference 2.6 days, 95% CI 1.22 to 3.98]. Anumber of adverse events were reported, includingdiarrhoea, nausea, anaemia, thrombocytopenia,vomiting, decreased appetite and dyspepsia.Adverse events were reported for the whole studypopulation (of whom 78% had ulcers). There were64 events in 241 people with linezolid, of whom18 patients (7.5%) discontinued therapy becauseof the event, and 12 events in 120 people in theA/S or A/C group, of whom four (3.3%)discontinued therapy. As patients could experiencemore than one adverse event, and the study doesnot report the number of people in each groupwho experienced any event, we have calculated theRR of withdrawing from the study due to anadverse event (RR 2.24, 95% CI 0.82 to 6.24).

Seidel and colleagues (1991)110

Seidel and colleagues conducted two CCTs inwhich male inpatients with diabetic neuropathicplantar ulcers chose either conventionalintravenous or retrograde venous perfusion (RVP),that is, injection into a dorsal vein during arterialocclusion. In the first study, the RVP group hadone RVP infusion daily of gentamicin, buflomedil,dexamethasone, heparin and lignocaine inisotonic saline. This group also had anintramuscular injection of gentamicin, a long-acting buflomedil tablet and three intravenousinfusions of piperacillin.110 The standard infusiontechnique group had three infusions per day ofpiperacillin, gentamicin, buflomedil and heparinin dextran. Both groups received the sameregimen of local antibacterial therapy. Resultsincluded the number of people requiringamputation due to underlying osteomyelitis [0/20in the the RVP and 4/20 in the intravenous group;RR 9 (Haldane approximation used to avoid errorin the �2 tests if cell contains 0; it involves adding0.5 to all of the cells of contingency table), 95% CI0.52 to 157], although there were 10% more casesof osteomyelitis in this group at baseline, and thenumber of ulcers healed (6/20 in RVP and 0/20intravenous; RR 0.077, 95% CI 0.005 to 1.28).


37


They also reported mean reduction in ulcer size(55% in RVP, 7.5% in intravenous), but the reportdoes not specify whether the accompanyingfigures (±8 and ±3.6) represent the standarderror, SD or range and therefore the CI for thedifference cannot be calculated. Of those withosteomyelitis, 4/5 in the RVP group and 0/7 in theintravenous group had ‘resolved’ [RR 0.083(Haldane approximation), 95% CI 0.005 to 1.27].Note that none of the outcomes were assessedblind to the study group. The authors state thatbacterial analysis was amongst the outcomemeasures, but no data were presented. A numberof adverse events were noted in the RVP group,including petechiae (tiny broken blood vessels:6/20), pain from arterial occlusion (5/20),haemorrhage (4/20) and stasis dermatitis (3/20).

Seidel and colleagues (1993)111 and (1994)112

In a later study, the same group comparedintravenous and RVP administration of antibioticsin 45 male inpatients with diabetic neuropathicplantar ulcers (DNPUs) over a 10-dayperiod.111,112 People in the intravenous group hadthree infusions per day of netilmycin, buflomedil,heparin, rheomacrodex and dexamethasone, plustwice daily piperacillin (intravenous). The RVPgroup had once daily infusions of netilmycin,buflomedil, dexamethasone, lidocaine andheparin, plus an evening injection (intravascular)of netilmycin, a buflomedil tablet, and twice dailypiperacillin (intravenous). All patients receivedsimilar wound cleansing and dressing, along withdietary and medical interventions for diabetes.There was no statistically significant difference inthe amputation rate in the two groups [3/24(12.5%) in RVP versus 4/21 (19%) in intravenous:RR 1.52, 95% CI 0.42 to 5.57]. The number ofulcers healed was not statistically significantlydifferent in the two groups: 8/24 (33%) RVP and3/21 (14%) intravenous (RR 0.43, 95% CI 0.13 to1.28). The study was underpowered to detectclinically important differences in amputation rateor healing as statistically significant.

Tan and colleagues (1993)108

Tan and colleagues reported a double-blind multi-centre RCT in 251 patients of whom 49 had footulcers.108 Results for people with DFUs werereported separately. They compared piperacillinand tazobactam (P/T) with T/C over a minimum of5 days in hospitalised patients with complicatedskin/skin structure infections. Treatment continuedfor at least 48 hours following the resolution ofsigns and symptoms, followed by early(24–72 hours) and late monitoring (10–14 days)after treatment completion. The number of

evaluable patients with foot ulcers (of whom themajority were diabetic; the exact proportion wasnot reported in the paper) was 16/31 (52%)receiving P/T and 7/18 (39%) receiving T/C.Reasons for non-evaluability are only available forthe complete treatment group, but these werefailure to meet diagnostic criteria for infection10%, no baseline pathogen 10%, inadequateclinical follow-up 9%, prestudy antibiotic 7%,concomitant infection 6%, resistant pathogen atbaseline 4% and ‘other reasons’ 11%; 55% of thoserecruited were therefore non-evaluable. Allpatients underwent surgical debridement ordrainage as part of their managementprogramme. The mean duration of therapy was8–9 days. Results for those evaluable patients withfoot ulcers showed no significant difference in therate of achieving a clinical ‘cure’ (defined asrecovery from infection) between the T/C and P/Tgroups. A per protocol analysis reported that the‘cure of infection’ rate with T/C was 86% (6/7) and56% (9/16) with P/T (RR 0.66, 95% CI 0.37 to1.26). An intention-to-treat analysis of ‘cure ofinfection’ rates found that 33% (6/18) with T/Cand 29% (9/31) with P/T had this outcome (if allpersons in whom data are missing are assumed tohave failed to achieve a cure of infection) (RR0.87, 95% CI 0.39 to 2.07). The high proportionof missing data from ulcer patients means thatthese results must be treated with caution.

The trial was underpowered in terms of its abilityto detect clinically important differences inoutcomes amongst people with foot ulcers asstatistically significant. The proportion of patientsexperiencing at least one adverse event wasreported for all patients in the trial (of whom 20%had an ulcer) and was 42% in both groups, withgastrointestinal events (diarrhoea) being afrequent cause (11% of people in each group hada gastrointestinal adverse event).

SummaryThe eight trials of intravenous antibiotics do notprovide robust evidence of the superiority of anyparticular antibiotic regimen over any other, orwhether retrograde perfusion is superior tostandard infusion techniques. Erstad colleaguesfound that cefoxitin was better than A/S for anoutcome of clinical cure (in a trial described asdouble-blind), but there was insufficient evidenceregarding differences for outcomes of amputation,revascularisation, bacterial eradication or adverseevents.107 Bouter and colleagues found that I/C wasassociated with fewer adverse events probablyrelated to the trial drug than P/C, although therewas insufficient evidence of any differences in

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effectiveness outcomes of bacterial eradication ofpathogens or clinical cure.106 Lipsky and colleaguesreported that the length of treatment with A/S orA/C was greater than that with linezolid, althoughthere was insufficient evidence regarding anydifferences in clinical cure of infection rates oradverse events.109 None of the six RCTs in thisgroup reported that their method of allocation wasmasked so that the person performing therandomisation was unaware of the schedule, butthree of them described themselves as doubleblind.44,107,108 Four of the six RCTs describedappropriate methods of randomisation.43,44,106,108

Only the study by Tan and colleagues108 reportedthat it was double-blind and reported anappropriate method to generate the allocationsequence.

The two CCTs by Seidel and colleagues allowedpatients to choose their mode of therapy –conventional intravenous or RVP therapy.Insufficient information is presented on thecharacteristics to allow one to examine anydifferences in patient selection at the outset.110–112

Even if the two groups were well matched at theoutset for characteristics known to be prognostic,the groups may not be comparable for unknownprognostic variables. In addition, those patientswho chose the novel treatment may differ fromthose who chose conventional therapy.

Effectiveness of oral interventionsFive studies are included in this group. One studycompared oral antibiotics with placebo,74 twocompared different orally administeredantibiotics75 ,101 and two studies compared atopical intervention with oral antibiotics (reportedin one document).114 We found no studies thatcompared an oral intervention with an intravenousor subcutaneous intervention.

Description of the studiesChantelau and colleagues (1996)74

Chantelau and colleagues74 compared oral A/C(Augmentin®) with an identical placebo over a 20-day period in a double-blind RCT involving 44patients with foot lesions graded 1A to 2A usingthe Texas classification system (Box 4).115 Allpatients received mechanical debridement, woundcleansing, dressing and pressure relief. Theauthors state that there was no statisticallysignificant difference in mean reduction in ulcersize, but insufficient data were reported to allowcalculation of effect size or CIs. There was nostatistically significant difference between healingrates [6/22 (27%) in A/C and 10/22 (45%) inplacebo; RR 1.67, 95% CI 0.76 to 3.83]. In

addition, there was no difference in the numbersof people whose deep swab wound cultures takenat completion of the study showed absence ofmicrobes [7/22, (32%) in A/C versus 6/22 (27%) inplacebo; RR 0.86, 95% CI 0.35 to 2.09] or isolates[4/22 (18%) in A/C versus 1/22 (5%) in placebo;RR 0.25, 95% CI 0.04 to 1.51] at the end of thestudy. Diarrhoea occurred in only one patient(active intervention group) and this was resolvedwithout withdrawal from the study. Five otherpatients were withdrawn at the beginning of thetrial owing to non-compliance or bacteriaunresponsive to the antibiotic. It was not clearwhether these patients were included in theanalysis. The trial was underpowered in terms ofits ability to detect clinically important differencesas statistically significant.

Lipsky and colleagues (1990)75

Lipsky and colleagues compared orallyadministered clindamycin hydrochloride (Cleocin)with cephalexin (Keflex) in an RCT amongst 60male outpatients with diabetes (data reported on56 people).75 Treatment was over 2 weeks, with3 months of follow-up. Patients with clinicallyinfected lower extremity lesions were included inthe study, with 89% and 93% in the respectivestudy groups having an ulcer. All patients hadlesions cleansed and debrided at the initialevaluation and this was followed by instructionsfor self-care. There was no statistically significantdifference in the infection ‘cure’ rate (where allsigns and symptoms resolved), in a per protocolanalysis, between clindamycin and cephalexingroup [21/27 (78%) in clindamycin versus 21/29(72%) in cepahlexin; RR 0.93, 95% CI 0.67 to1.29]. There was no statistically significantdifference in the proportion of ulcers healing in aper protocol analysis between clindamycin, 10/27(37%) and cephalexin, 9/29 (31%) (RR 0.83, 95%CI 0.4 to 1.73). Results for the eradication ofbacterial pathogens, using per protocol results,showed a similar cure rate in each of the studygroups [20/26 (77%) for clindamycin and 20/29(69%) for cephalexin; RR 0.9, 95% CI 0.63 to1.26]. Adverse events were noted in only threepatients (one in the clindamycin group and two inthe cephalexin group; RR 2.0, 95% CI 0.28 to14.8), presenting as mild diarrhoea and nausea.The trial was underpowered in terms of its abilityto detect clinically important differences asstatistically significant.

Lipsky and colleagues (unpublished) A114 and B114

Two trials by Lipsky and colleagues compared anoral and a topical intervention. These wereidentified by contact with experts. The comparison


39


was of topically applied pexiganan cream(Locilex®) with ofloxacin (orally) over a 14–28-dayperiod with follow-up at 2 weeks after treatmenthad ended.114,116 The authors describe pexiganan cream as a broad-spectrumantimicrobial agent, structurally related to frogskin peptides. This product has not been licensedfor use.117 These double-blind RCTs recruitedoutpatients with a DFU in whom there were nosigns of extensive cellulitis, exposure ofbone/tendon or fever. All patients were offereddebridement and standard dressings. The authorspresent results at three time points (day 10, end oftreatment and follow-up), in 10 populations(including intention-to-treat, per protocol,intention-to-treat microbiology and per protocolmicrobiology). The primary outcome was ‘clinicaloutcome at day 10 in an evaluable population’.Other outcomes included clinical outcome at threetime points, microbiological outcome at three timepoints, therapeutic response at three time points,wound score, wound infection score, wound depth,absolute and relative wound area reduction (meanand median) and eradication of pathogens presentat baseline. The large number of outcomes (whichmay have been necessary for the submission to theFederal Drug Administration committee) may haveled to a Type I error, that is, concluding that thereis a statistically significant difference when noneexists.

Lipsky and colleagues (unpublished) A114

Results from the first of these studies (493participants) revealed no statistically significantdifference between the number of amputations inthe pexiganan group [4/247 (1.6%)] and theofloxacin group [6/246 (2.4%)] (RR 1.5, 95% CI0.46 to 4.92).

There was no statistically significant differencebetween the clinical ‘cure’ rates (defined as nofurther signs or symptoms of infection) at day 10[63/243 (26%) in pexiganan and 67/240 (28%) inofloxacin (RR 1.08, 95% CI 0.81 to 1.45], at endof treatment, [133/247 (54%) pexiganan and150/246 (61%) in ofloxacin (RR 1.13, 95% CI 0.97to 1.32] and at final follow-up [136/243 (56%) inpexiganan and 156/240 (65%) in ofloxacin (RR1.16, 95% CI 1.00 to 1.34)]. The mean reductionin wound area was similar in the two groups,namely 93.4 mm2 area reduction in pexiganan and96 mm2 area reduction in ofloxacin, butinsufficient data were provided to allow thecalculation of CIs. At final follow-up, the numbersof people with an outcome described as‘microbiologically resolved infection’ were 75/185 (40%) in pexiganan and 84/193 (44%) in

ofloxacin (RR 1.07, 95% CI 0.85 to 1.36). Therewere a similar number of adverse events leading to patient withdrawal from the study inpexiganan [28/247 (11%)] and ofloxacin [23/246(9%)] (RR 0.82, 95% CI 0.49 to 1.38), the mostfrequent causes being diarrhoea, nausea and pain. The incidence of serious adverse events such as cellulitis, infection or osteomyelitis was not statistically significantly different inpexiganan [28/247 (11.3%)] from ofloxacin[20/246 (8.1%)] (RR 0.72, 95% CI 0.42 to 1.23).

Lipsky and colleagues (unpublished) B114

The second study compared pexiganan andofloxacin in 342 patients. There was no statisticallysignificant difference in the number of people whohad an amputation: 7/171 (4%) in the pexiganangroup and 3/171 (2%) in the ofloxacin group (RR0.43, 95% CI 0.12 to 1.49). Clinical ‘cure’ rates(defined above) were not statistically significantlydifferent at day 10 (34/171 in pexiganan and34/171; RR 1.0, 95% CI 0.65 to 1.53) or at end oftreatment (84/171 in pexiganan and 80/171; RR 1.05, 95% CI 0.84 to 1.31). The mean reductionin wound area was 129 mm2 in pexiganan and142.6 mm2 in ofloxacin, but insufficient data wereprovided to allow the calculation of CIs.Microbiological response at 10 days was analysedboth per protocol and intention-to-treat. Forty-four patients (26%) had an outcome of ‘resolved’in pexiganan and 30 (18%) were ‘resolved’ inofloxacin. If one assumes that the sample size forthis analysis is 171 for each group and that noneof the patients for whom data are missing had amicrobiological ‘cure’, the RR of ‘resolved’ is 0.68(95% CI 0.45 to 1.02) using an intention-to-treatprinciple. This result is sensitive to the assumptionthat all missing data represented failures as theauthors present the microbiological cure asoccurring in 44/138 (32%) pexiganan and 30/140(21%) ofloxacin (RR 0.67, 95% CI 0.45 to 0.99).There was no statistically significant difference inthe proportion of patients classified as ‘resolved’in the two groups at end of treatment, that is,53/171 (31%) in pexiganan and 59/171 (34%) inofloxacin (RR 1.11, 95% CI 0.82 to 1.51) orfollow-up, 50/171 (29%) in pexiganan and 61/171(36%) in ofloxacin (RR 1.22, 95% CI 0.89 to 1.66).Adverse events leading to patient withdrawal inthis study involved similar proportions of patientsin each group: 16/171 (9%) from the pexiganangroup and 15/171 (9%) from the ofloxacin group(RR 0.94, 95% CI 0.48 to 1.81). The causes ofadverse events were the same as in the largerLipsky pexiganan study (described above). Seriousadverse events were observed in 22/171 (13%)

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pexiganan and 19/171 (11%) ofloxacin (RR forserious adverse events 0.86, 95% CI 0.49 to 1.52).

We did not pool the data from the Lipsky studiesas there was differential drop-out from the twoarms (ofloxacin and pexiganan) and we felt thatthis may have been misleading to use theper protocol data available. Given that thistreatment is not licensed for use currently, we didnot pursue acquiring the data from the studysponsors.

Peterson and colleagues (1989)101

Peterson and colleagues compared theeffectiveness of orally administered ciprofloxacinin an RCT in which 48 inpatients with lowerextremity DFUs were given different doses (750 or1000 mg twice daily) of ciprofloxacin, with follow-up at 12 months.101 Patients with osteomyelitiswere treated for 3 months and those with cellulitisfor 3 weeks. All patients received local wound care,comprising debridement, wound cleansing,dressing and pressure relief. Data were availableon 45 patients. There was no statistically significantdifference in the number of amputations betweenthe 750 and 1000 mg dose groups: 4/24 (17%) inthe 750 mg and 6/24 (25%) in the 1000 mg group(RR 1.5, 95% CI 0.51 to 4.49). A number ofadverse events occurred, of which two resulted indiscontinuation of the drug [both in the high-dosage group; RR 5 (Haldane approximation),95% CI 0.25 to 99]. Six patients in the high-dosegroup and two in the low-dose groups experiencednon-serious adverse events such as chemicalabnormalities (increased blood urea nitrogen orserum creatinine levels) thought to be associatedwith the treatment (RR 0.33, 95% CI 0.08 to 1.28).The trial was underpowered.

SummaryFive studies compared oral interventions, with onlythe two unpublished studies by Lipsky (reported inthe same document) comparing the sameinterventions (topical pexiganan and oralofloxacin) more than once.114 There is insufficientevidence from the studies to recommend anyparticular oral antimicrobial: none of the studiesreported significant difference on any outcomes,although trials by Chantelau and colleagues,74

Lipsky and colleagues75 and Peterson andcolleagues101 were so small that they were unlikelyto detect clinically important differences inoutcomes as statistically significant. The two large(unpublished) trials by Lipsky with 835 patients, inwhich an oral antibiotic was compared with anantimicrobial cream, found no difference inoutcomes in per protocol analyses.114

Peterson and colleagues described allocationconcealment, an appropriate method ofrandomisation (by the pharmacy).101 The otherfour trials did not make it clear whether allocationwas concealed. Both trials of pexiganan andofloxacin were described as double-blind.114

Effectiveness of subcutaneousinterventionsFour included studies evaluated subcutaneousadministration of recombinant humangranulocyte-colony stimulating factor (rhG-CSF,also known as filgrastim; Neupogen®) in additionto standard care versus placebo plus standardcare,100,118 or standard care alone.119,120

Granulocyte colony-stimulating factor (G-CSF) isan endogenous haemopoietic growth factor thatinduces terminal differentiation and release ofneutrophils from the bone marrow. There were nostudies comparing any subcutaneous interventionswith an intravenous, oral or topical treatment.

Description of the studiesGough and colleagues (1997)100

The double-blind RCT by Gough and colleaguescompared a subcutaneous injection of G-CSF witha placebo (saline solution) in 40 inpatients with aDFU with extensive cellulitis (the majorityoccurring in the forefoot) over a 7-day period.100

G-CSF dosage was initially 5 µg/kg/day (daily for2 days), and was then titrated against the patient’sneutrophil count, reduced to 2.5 µg/kg/day (dailyfor 2 days), and then given on alternate days (upto 7 days). All patients received an intravenouscombination of four antibiotics (ceftazidime,amoxycillin, flucloxacillin and metronidazole),appropriate glycaemic control, foam dressings andpodiatric treatment. Two patients in the placebogroup underwent toe amputation compared withnone in the G-CSF group [RR for amputation 5(Haldane approximation), 95% CI 0.3 to 98]. Twopatients in the placebo group required extensivedebridement under anaesthesia, compared withnone in the G-CSF group [RR for debridement 5(Haldane approximation), 95% CI 0.3 to 98]. The study is underpowered to detect clinicallyimportant differences in debridement oramputation outcomes as statistically significant.The median time to resolution of cellulitis was7 days in the G-CSF group (range 5–20) and12 days in the placebo group (range 5–93). Themedian time to negative swab was 4 days in the G-CSF group (range 4–10) versus 8 days in theplacebo group (range 5–93), and although therewere insufficient data available to allow us tocalculate the CIs for the difference in time, theauthors stated that the difference was statistically


41


significant. There was no statistically significantdifference in the number of people whose ulcerhealed in the two groups; 4/20 (20%) patients inthe G-CSF group healed their ulcer, whereas nopatients in the placebo group had a healed ulcer,but this difference was not statistically significant[RR 9 (Haldane approximation), 95% CI 0.5 to157]. People in the G-CSF group were more likelyto have resolution of cellulitis at day 7 than theplacebo group [11/20 (55%) versus 4/20 (20%), RR2.75, 95% CI 1.1 to 7.3]. The median time tohospital discharge was reportedly lower in the G-CSF group than the placebo group [10 days(range 7–31) versus 17.5 1 days (range 9–100)] butinsufficient data were provided to calculate the CIfor the difference. The authors state that thisdifference is statistically significant at theconventional 95% level. There was leucocytosisamongst some G-CSF patients (at day 7 thepatients receiving G-CSF had higher counts oflymphocytes and monocytes than patients in thecontrol group). The median dose of G-CSFrequired over the study period was 302 µg/day(range 200–440).

It is noteworthy that the median duration of ulcersprior to trial entry in the G-CSF group was21 days (range 2–1278) compared with 39.5 days(range 2–1825) in the placebo group, indicatingthat the G-CSF group was more likely to heal frombaseline as the randomisation of a small numberof participants had failed to distribute ulcers oflong duration equally between the two groups. Aneconomic analysis of G-CSF versus placebo wasundertaken by Edmonds and colleagues,121 usingthe resource use data from the first 28 patients (of40), in the Gough trial,100 from a hospital ratherthan a societal perspective. A decision tree modelwas built to estimate the mean treatment cost foreach group. They estimated that the mean costsavings associated with G-CSF over placebo were£2666. Sensitivity analysis was undertaken toexamine the effect of changing assumptions aboutthe patient type, probability distribution, unit costand duration of hospital stay on cost-effectiveness.They identified that the savings ranged from £155to £3129 when patients with vascular problemsand/or tissue necrosis were excluded from thestudy. The authors pointed out that the results ofthe economic analysis should be interpreted withcaution as the two groups were treated differentlyafter randomisation; more patients in the placebogroup had a vascular problem than in the G-CSFgroup (seven versus four) and these required more costly diagnostic tests and interventions. The results therefore need to be confirmed in alarge RCT.

Given that there is no clear evidence of differencein effectiveness, but lower costs associated with G-CSF, then in an economic analysis G-CSF ispreferred – corresponding to cell H of the cost-effectiveness matrix in Box 1.87,89

Kastenbauer and colleagues (2003)118

A second study in this group118 was a single(patient)-blinded RCT that compared the samedose of G-CSF as Gough and Colleagues100 with aplacebo (sterile saline solution). Thirty-sevenhospital inpatients with a DFU (Wagner grade 2 or3) were treated over a 10-day period.102 Allpatients maintained bed rest and received the samestandard wound care, including debridement.Intravenous antibiotics (clindamycin andciprofloxacin) were administered, followed by oralantibiotics where necessary. Daily clinicalobservations were supplemented by the calculationof an Infection Summary Score (no informationwas provided on validation of this scale). Healingdata were presented as changes in Wagner grade,reduction in volume, resolution of cellulitis andcomplete ulcer healing. All five of the grade 3ulcers from the GCSF group and all three of thegrade 3 ulcers in the placebo group progressed tograde 2 ulcers by day 10. There were similarreductions in ulcer volume in the control group(125 µl) and the G-CSF group (120 µl), but therewas no data on the variance to allow the calculationof CIs of the change. Furthermore, the groups werenot comparable at baseline for ulcer volumes (203versus 358 µl) and this may have biased the result.The proportion of patients with unresolvedcellulitis at day 10 showed a greater number in theactive intervention group (approximately 27%versus 17%, data derived from graph). There wasno statistically significant difference in theproportion of patients achieving complete healingat day 10: 10% (2/20) in the control group versusnone in the G-CSF group [RR 5 (Haldaneapproximation), 95% CI 0.3 to 98]. Adverse eventsof worsened liver function and skin efflorescencewere noted in two patients in the G-CSF group.The trial was underpowered to detect clinicallyimportant differences as statistically significant.

de Lalla and colleagues (2001)119

An RCT by de Lalla and colleagues comparedconventional treatment (local treatment plussystemic antibiotic therapy) and additionalsubcutaneously administered G-CSF withconventional treatment alone in 40 hospitalisedpatients with a DFU over 21 days.119 Follow-up wascarried out at 9 weeks and 6 months. All patientshad either Wagner grade 3 or 4 ulcer (describedas limb threatening) and all received local

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treatment and empirical antibiotic therapy(intravenous or oral ciprofloxacin andclindamycin) where necessary. The amputationrate was statistically significantly higher in theconventional treatment group at the end oftreatment [9/20 (45%)] compared with the G-CSFgroup [3/20 (15%)] (RR 0.33, 95% CI 0.11 to0.95). There was no statistically significantdifference in the number of major amputationsperformed in the conventional treatment group[2/20 (10%) conventionally treated versus 0/20(0%) in the G-CSF group] [RR 0.2 (Haldaneapproximation) 95% CI 0.01 to 3.9]. There was noreported difference between groups in theproportion of ulcers ‘cured’ (complete closure ofthe ulcer without signs of underlying boneinfection) at 21 days (none healed in both groups)or 9 weeks, as 7/20 (35%) healed in both groups(RR 1.0, 95% CI 0.43 to 2.3). At 6 months 13/16people in the GCSF group were either ‘cured’ orhad a stable ulcer (four lost to follow-up)compared with 15/20 in the control group (RR0.92, 95% CI 0.63 to 1.38).

There was no statistically significant difference inthe mean/median duration of antibiotic therapy inthe G-CSF group (58.7 days, SD 23.7) or thestandard care group (68.9 days, SD 29.2), meandifference 10.2 days (95% CI –6.3 to 26.7 days). Inaddition, there were no statistically significantdifferences between groups in terms of theproportion of patients requiring oral/antibiotictherapy during the trial period [11/20 (55%)versus 13/20 (65%), RR for oral therapy requiredin standard care 1.18, 95% CI 0.7 to 2.04]. Therewas no statistically significant difference betweengroups in terms of proportion of patients

requiring adjustments to empirical therapy [9/20(45%) in standard care versus. 7/20 (35%) in G-CSF, RR 0.78, 95% CI 0.36 to 1.65]. Theauthors reported that there were no adverse eventsassociated with G-CSF but two patients in thisgroup required a reduced dose of G-CSF owing toan elevated neutrophil count.

Yonem and colleagues (2001)120

Yonem and colleagues evaluated subcutaneous G-CSF against ‘standard’ local wound care in 30people; all patients received intravenousciprofloxacin and metronidazole.120 The settingand length of treatment were not reported. Allparticipants had either pedal cellulitis or a footlesion (Wagner grade 2 or less) secondary todiabetes mellitus and were placed on a dailymultiple-dose injection of short-acting insulin.There was no statistically significant difference inthe proportion of patients requiring amputation[3/15 (20%) in standard care versus 2/15 (13%) inthe G-CSF group; RR 0.67, 95% CI 0.15 to 2.95].The number of days to resolution of infection was22.3 in standard care (SD 1.7) and 23.6 in G-CSF(SD 1.8) (mean difference 1.3 days; 95% CI 0.05 to2.55). This trial was underpowered to detectclinically important outcomes such as amputationas statistically significant. Adverse events were notreported.

Three of the four G-CSF studies reported the rateof compete ulcer healing, and Figure 4 summarisesthe results for the three studies.

Three of the four G-CSF studies reportedamputation rates, and Figure 5 summarises theresults for these three studies.


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Review: G-CSF – DFUComparison: 01 G-CSF versus placebo or standard careOutcome: 01 Healed

Studyor subcategory

G-CSFn/N

Controln/N

RR (random)95% CI

RR (random) 95% CI

01 placebo studies Gough100 4/20 0/20 Kastenbauer118 0/17 2/20

02 standard care studies de Lalla119 7/20 7/20

9.00 (0.52 to 156.91)0.23 (0.01 to 4.55)

1.00 (0.43 to 2.33)

0.001 0.01 0.1 1 10 100 1000

Favours control Favours G-CSF

FIGURE 4 Forest plot of GCSF versus placebo or standard care for ulcer healing

Given that one study by Yonem and colleagues120

did not report ulcer healing outcomes and thepotential methodological and clinicalheterogeneity, we decided not to combine thehealing results in a meta-analysis. A similarapproach was used for the amputation results asone study (Kastenbauer and colleagues118) did notreport amputation rates.

SummaryThere is no reliable evidence that G-CSF isassociated with reduced amputation rates orincreased ulcer healing but the trials are too small(total of 147 participants) to exclude the possibilitythat there is a clinically important effect. A cost study121 of one of the trials100 suggestedlower treatment costs associated with G-CSF butthe authors stated that this finding should betreated with caution as it was based on aretrospective analysis of 28 patients from the 40 inthe original trial, and the two groups receiveddifferent concurrent treatments such as surgerypost-randomisation.

Effectiveness of topical interventionsFive eligible studies compared different topicalpreparations105,122–125

Description of the studiesApelqvist and colleagues (1996)122,126

An open RCT by Apelqvist and colleagues wasconducted in Sweden with 41 outpatients (withWagner grade 1 or 2 diabetic foot ulcer) over a 12-week period.122,126 The study comparedtopically applied cadexomer iodine ointment(Iodosorb) with a standard topical treatmentconsisting of gentamicin (Garamycin),streptodornase/streptokinase (Varidase) or dry

saline gauze (Mesalt). The authors describedcadexomer iodine ointment as a highly fluid-absorbing, antibacterial agent. All patients wereoffered oral antibiotics (ciprofloxacin,cephalosporin, metronidazole, clindamycin) ifnecessary, along with saline dressing, a paraffingauze and special footwear where appropriate.Outcomes are given on 35 patients as no data arepresented on five patients from the cadexomeriodine group and one from the standard caregroup. There was no statistically significantdifference in the number of patients who requiredsurgical intervention in the standard treatment[(5/18 28%)] or the chlorhexidine group [3/1718%)] (RR for surgery 0.64, 95% CI 0.19 to 2.07).There was no statistically significant differencebetween the proportions of patients whose ulcerwas completely healed, 2/18 (11%) in standardcare and 5/17 (29%) in cadexomer iodine (RR2.65, 95% CI 0.68 to 10.89). In addition, there wasno statistically significant difference in theoutcome of ‘wound area reduction of at least 50%or improvement in Wagner grade’ between the twogroups [12/17 (71%) in Iodosorb and 13/18 (72%)in standard care; RR 0.98, 95% CI 0.64 to 1.49].No adverse events were documented. Six patientswithdrew from the study owing to violation ofinclusion criteria, hospitalisation, non-adherenceto treatment and insufficient data on resource use.

Since there were no significant differences inclinical effectiveness between the two study groups,a cost-minimisation analysis was performed by thesame authors using the 1993 exchange rate for theSwedish Kroner (SEK).122,126 The analysis focusedupon resource use in terms of dressing changes,drug prescription, materials consumption andtime involved. Costs were estimated for dressing

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Review: G-CSF – DFUComparison: 02 G-CSF versus placebo or standard careOutcome: 01 Amputation

Studyor subcategory

G-CSFn/N

Controln/N

RR (random)95% CI

RR (random) 95% CI

01 placebo studies Gough100 4/20 0/20

02 standard care studies de Lalla119 3/20 9/20 Yonem120 2/15 3/15

0.20 (0.01 to 3.92)

0.33 (0.11 to 1.05)0.67 (0.13 to 3.44)

0.001 0.01 0.1 1 10 100 1000

Favours controlFavours G-CSF

FIGURE 5 Forest plot of G-CSF versus placebo or standard care for amputation

materials, drugs, staff, transport and othersrelating to secondary complications. There were ahigher (mean) number of dressing changes perweek in the standard care group (9.9, range3.12–13.9) compared with the cadexomer iodinegroup (4.7, range 3.2–6.9). The authors did notprovide sufficient data for the CIs for thedifference in the number of dressings changes perweek to be calculated. More dressings wereperformed by nurses and auxiliary nurses, ratherthan patient or spouse, in the standard caregroup. The authors reported the time for eachdressing change, 13 minutes (range 8–24) forcadexomer iodine, 11 minutes (range 5–23) forstandard care, and the mean number of weeks oftreatment needed, 10 (range 1–12) in cadexomeriodine, 11 (range 5–12) for standard care. Theystated that these were similar between the twogroups, although statistical significance was notreported. Mean staff costs were reported assignificantly higher in the standard care group(884 SEK, range 315–1492) than the cadexomeriodine group (380 SEK, range 96–570) (authorsstate p < 0.001), but insufficient data wereprovided to calculate CIs for the difference. Meanweekly transport costs were reported assignificantly higher in the standard care group(243 SEK, range 76–341) than the cadexomeriodine group (100 SEK, range 29–156) (authorsstate p < 0.001), but insufficient data wereprovided to calculate CIs for the difference. As thestaff costs and transport costs were both higher inthe standard care group, the mean total weeklycosts were also higher. Costs of materials anddrugs were lower in the standard care group (294 SEK, range 37–981) compared with thecadexomer iodine group (423 SEK, range166–1113). The authors state that this differenceis not statistically significant but insufficient datawere provided to allow calculation of the CIs forthe difference. Following a synthesis of costs andbenefits, the weekly cost per patient healed washigher in the standard care group (12,790 SEK)than the cadexomer iodine group (3070 SEK).The authors state that this difference is notstatistically significant but insufficient data wereprovided to allow calculation of the CIs for thedifference. Sensitivity analysis was carried out totest whether the findings were affected byvariations in assumptions about travel distanceand costs, the number of home-based dressingchanges, different staff categories beingresponsible for care, adherence to regimen andadverse reactions relating to treatment. Reducingthe costs of staff travel (from 10 to 5 km) reducedthe cost of standard care by 31% and ofcadexomer iodine treatment by 20%. Changing

the grade of staff changing the dressing so that anauxiliary performed all reduced the cost ofstandard care by 9% and of cadexomer iodinetreatment by 7%.

Assuming that a patient or their carer performed50% of dressing changes, rather than a paidhealth professional, reduced the cost of standardcare by 40% and of cadexomer iodine treatmentby 27%.

Assuming that the dressings were changed as perphysician’s instructions at all times (e.g. daily)meant that the cost of standard care reduced to1914 SEK and that of cadexomer iodine to 836SEK. When the sensitivity analysis included onepatient in the cadexomer iodine group who hadexperienced an adverse event and had beenhospitalised, then the cost of cadexomer iodineincreased to 1040 SEK and standard care costswere lower, at 903 SEK. Hence the economicanalysis is sensitive to inclusion or exclusion of thepatient with an adverse event.

Using the matrix of cost-effectiveness,87,89 and theauthors findings that Iodosorb was less costly thanstandard care, then we find that Iodosorb ispreferred, appearing in cell H of the cost-effectiveness matrix in Box 1, but this should beinterpreted with caution as the costs are sensitiveto the inclusion of costs of adverse events, andtherefore Iodosorb may be more expensive and nomore effective (cell B of the matrix in Box 1) thanstandard care.

Marchina and Renzi (1997)123

Marchina and Renzi compared an antiseptic spray(content not described) with a 2% eosin and 0.3%chloroxylenol spray in 40 people, of whom 21 hadDFUs, over 15 days.123 Data were reported for theDFU group. Ulcers were dressed with gauze andchanged 2–3 times per day. No otherantimicrobial agents, analgesics or anti-inflammatory agents were used during the study.At 15 days, 82% of the people in theeosin/chloroxylenol group were completely healed,compared with 50% in the antiseptic spray group.The actual number of ulcers healed was not givenfor the two groups and was only available from agraph in the trial report, therefore we cannotcalculate the RR of healing or the CIs. This trialwas too small to detect clinically importantdifference in healing rates.

Markevich and colleagues (2000)105

Markevich and colleagues reported an RCT oflarval therapy versus a hydrogel for DFUs (of


45


neuropathic origin) in 140 inpatients.105 Larvaltherapy uses sterile maggots of the green bottle fly(Lucilia sericata) to remove dead tissue withinwounds, and during this process the larvae ingestbacteria, which are destroyed in the larval gut, andare reputed to have an antibacterial effect.Hydrogel dressings rehydrate dead tissue withinwounds and allow the cells within the wound toremove it. The follow-up period was for up to10 days (after three applications of larvaltherapy/hydrogel). Complete healing was reportedin 5/70 (7.1%) patients in the larval therapy groupand 2/70 (2.9%) in the hydrogel group (RR 2.5,95% CI 0.58 to 10.9). The authors also reportoutcomes of ‘at least 50% reduction in area’ and‘granulation tissue covering at least 50% of thewound’, but the clinical relevance of theseoutcomes is not known. For example, it is not clearif halving ulcer area is a reliable interim outcomemeasure for complete healing, or if quickerprogression to a granulated wound bed necessarilyleads to quicker healing.

Rhaiem and colleagues (1998)124

Rhaiem and colleagues studied 80 hospitalisedpatients with cutaneous wounds [of whom 65(81%) had foot wounds].124 Participants wererandomised into three groups: local wound careplus sugar applied into the wound cavity (changeddaily), local wound care plus sugar plus systemicantibiotics, and local wound care plus systemicantibiotics. The method of administration of theantibiotics was not stated (intravenous,intramuscular or oral). All participants receivedstandard care comprising debridement, cleansingand drying.

The authors cited other studies that have usedsugar as a topical antimicrobial and gave detailson the physiological mechanisms to support theirclaim. The study period was not clear and detailswere not given with regard to any treatmentreceived by patients between hospital dischargeand follow-up. This three-arm study of topicalsugar versus systemic antibiotics versus sugar +antibiotics addresses three comparisons:

� systemic antibiotics versus topical sugar � sugar versus standard wound dressing (when

added to systemic antibiotics)� systemic antibiotic versus no treatment (when

added to topical sugar).

There was no statistically significant difference inthe healing rates between systemic antibiotics[16/40 (40%)] and sugar [8/16 (50%)] (RR 1.25,95% CI 0.64 to 2.23).

There was no statistically significant difference inthe healing rates between sugar dressings [11/24(46%)] and standard dressings [16/40 (40%)] whenused in the presence of systemic antibiotics (RR0.87, 95% CI 0.5 to 1.59).

There was no statistically significant difference inthe healing rates between systemic antibiotics[11/24 (46%)] and no antibiotics [8/16 (50%)] whenadded to a local treatment regimen of sugardressings (RR 1.09, 95% CI 0.55 to 2.07).

This study is too small to be able to detect asstatistically significant, clinically importantdifferences.

The usefulness of further data presented onhealing rates was limited, given that it was for all wounds (foot, leg and ‘other wounds’). Adverse effects were not assessed. Some economicanalysis was presented by the authors, whoclaimed that the average cost of treating the studypatients with sugar could be markedly reduced(when compared with hospitalisation) as themajority of care could be home-based, but therewas no concurrent collection of economic data or aformal economic analysis. The authors alsoreported that there was some difficulty in theapplication of sugar.

Vandeputte and Gryson (1996)125

Vandeputte and Gryson compared a hydrogeldressing with dry gauze dressing irrigated withchlorhexidine in an RCT including 29 people withDFUs (setting not stated) over a 3-monthperiod.125 Hydrogel dressings are said to providepressure relieving, moisturising and bacteriostaticproperties. Chlorhexidine is an antimicrobialagent. Systemic antibiotics and topicaltreatments/antiseptics were available to all patientsif required. The necessity for amputation (one ormore toes) was slightly higher in the chlorhexidinegroup [5/14 (36%) versus (1/15 (7%), RR foramputation 5.4, 95% CI 0.98 to 32.7], but thisdifference was not statistically significant.Complete healing data (verified by photographicmeasure) at the end of treatment showed fewerulcers healed in the chlorhexidine, group [5/14(36%)], than the hydrogel group [14/15 (93%)](RR 2.61, 95% CI 1.45 to 5.76). There was a lowerincidence of infection amongst patients in thehydrogel group [1/15 (7%)] than the chlorhexidinegroup [7/14 (50%)] (RR 7.5, 95% CI 1.47 to 44.1).They also reported a reduced requirement forsystemic/local antibiotics/topical treatment [14/14(100%) in chlorhexidine and 1/15 (7%) in thehydrogel group, RR 0.067, 95% CI 0.01 to 0.31].

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Two patients died in the chlorhexidine studygroup during the trial period compared with nonein the hydrogel group. Other adverse events werenot reported.

The trial was sufficiently powered on the completehealing outcome and infection incidence outcometo detect clinically important differences asstatistically significant, but was underpowered todetect other differences in outcomes as statisticallysignificant.

SummaryThe five studies of topical interventions, in whichthere were eight comparisons, found no robustevidence for a statistically significant difference inclinical outcomes associated with any particulartopical antimicrobial. Apelqvist andcolleagues122,126 reported lower treatment costsassociated with cadexomer iodine ointment versusstandard care dressings, but this was not robust tosensitivity analyses. Vandeputte and Gryson125

reported more ulcer healing with a hydrogel thanwith a topical antimicrobial (chlorhexidine ongauze), although it is not clear whether anintention-to-treat analysis was performed, whetherany assessments were blinded and howcomparable the ulcers were at baseline forduration, area and depth.

Effectiveness of other interventionsOne study compared a topical and oralintervention with a standard care regimen.127

Description of the studyDwivedi and colleagues (2000)127

This 5-year clinic-based RCT was conducted on100 people. Dwivedi and colleagues compared atherapy (a decoction of plant extracts) based onAyurvedic principles, administered as both an oraland a topical treatment against standard care – acombination of systemic antibiotics plusmetronidazole, local antiseptics and a peripheralvascular dilator.127 The oral treatment beingevaluated was a water-soluble solid extract of Rubiacordifolia (Manjishtha) and of Withania somnifera(Ashvagandha), each 500 mg, oral, three times perday. Patients were also required to soak theaffected part in a luke-warm water decoction ofthe plants for 30 minutes daily. The authors justifythe potential effectiveness of the Manjishtha plantextract on the basis of its ability to removemicroangiopathic and atherosclerotic changesinside the arteries/capillaries surrounding thewound area, thus facilitating blood supply andsubsequent removal of microbes. The additionalproperties of Ashvagandha, they believe, improve

the immunological status of patients. Patients withnon-healing DFUs of 6–12 months’ duration wereincluded. Both study groups received regularsurgical intervention, e.g. incision or debridement,as required. Some 30% of patients in the standardcare group required surgery, compared with 16%in the active intervention group (Ayurvedicmedicine). The authors do not report the exactnumbers for each group and therefore the CIs andRR cannot be calculated with certainty. However, ifthe data given represent an intention-to-treatanalysis, then the RR of healing with the standardtreatment would be 0.53 (95% CI 0.25 to 1.11).Adverse effects were not reported. This trial wasunderpowered to detect clinically importantoutcomes as statistically significant.

SummaryThere is no reliable evidence of the impact of thiscombination of interventions on non-healingDFUs with respect to the need for amputation.

Overall summaryThe quality of the trials identified was poor andthe sample sizes in the majority of trials wereinsufficient to identify clinically importantdifferences in effectiveness as statisticallysignificant. There was wide variation in theoutcomes reported and the possibility thatunfavourable outcomes were not reported whereasequivocal or positive ones were, cannot beexcluded, as trials rarely specified primaryoutcomes measures a priori.

Twenty-three trials made 19 unique comparisonsbetween interventions. Three comparisons werereplicated: oral ofloxacin versus topical pexigananin two trials, G-CSF growth factor versus placeboin two trials and G-CSF growth factor versusstandard care in two trials, and one trial had threearms, comparing sugar, standard care andantibiotics. None of the trials used a CONSORTchecklist for reporting, but some predate itspublication. Our criticisms of study quality mayreflect poor reporting rather than poor trialdesign, but without sufficient information thereader cannot determine whether sources of biasand error were minimised or not.

There is no strong evidence for recommendingany particular antimicrobial agents for theprevention of amputation, resolution of infectionor ulcer healing. Results suggest that growth factor(G-CSF) was less costly than standard care,cadexomer iodine dressings may be less costly


47


than standard care (daily dressings) and A/S wasless costly than A/C. These results are from small,single trials and need replication. Topicalpexiganan cream may be as effective as oralantibiotic treatment with ofloxacin.

Decision analytic modellingThis section of the results describes the structureof the decision analytic model constructed toinvestigate the clinical effectiveness and cost-effectiveness of different diagnostic tests for theidentification of infection in patients with a DFU.The first step in the construction of the model wasto conduct a review of the literature to identify anymodels that described the natural history ofpatients with DFUs, and to identify studies thatcould inform the transitions within a decisionanalytic model. We searched for economic modelsor decision analytic models, i.e. studies in which amathematical structure had been used to representthe health and/or economic outcomes of patientswith a DFU. Table 2 describes the sources used toidentify research. The results of all searches werescrutinised to identify potentially relevant studies.

We report the results of a review of the literatureand then describe the general structure of thenatural history of one DFU model selected for theinvestigation of the potential impact on healthand economic outcomes of using differentdiagnostic tests to identify infection in patientswith DFUs. Next, we describe the initialassumptions regarding the volume of healthcareresources required for the treatment of patientswith DFUs and the way in which the use ofdiagnostic test would influence and/or modify thenatural history, that is, prognosis and treatment ofpatients with DFUs. The information requirementsto inform this new model are then listed. Finally,we discuss the alternatives to using data fromresearch studies as a method of populating thedecision analytic model.

Review of previous models describingthe natural history of diabetic footulcers The literature review of models describing the‘natural history of individuals with diabetic footulcers’ [natural history of disease: the temporalcourse of disease from onset (inception) toresolution] identified five different decisionanalytic models (decision analytic model: theapplication of explicit, quantitative methods thatquantify prognoses, treatment effects and patientvalues in order to analyse a decision under

conditions of uncertainty) investigating a numberof treatment and preventative strategies fordiabetic patients at risk of or who have alreadydeveloped a foot ulcer.15,121,128–130 Among the fivedifferent models identified, there was only onewhich provided a comprehensive description ofthe natural history of patients with diabetic footulcers;130 however, for completeness, a briefdescription of the structure of the identifiedmodels is provided below.

Tennvall and Apelqvist (2001)128

Tennvall and Apelqvist report the findings of amodel that evaluated the cost-effectiveness of twocompeting alternatives for the prevention ofdiabetes-related foot ulcers and amputations.128

The economic evaluation took the form of acost–utility study in which the health benefitsassociated with the two alternative preventivestrategies were measured in terms of quality-adjusted life-years (QALYs). Mean estimates ofcosts and health benefits associated with eachalternative were derived using a decision analyticMarkov model. Transition probabilities for themodel were obtained from a survey of 1677diabetic Swedish patients aged 24 years and over,mean age 66 years. Estimates of the treatmentcosts were retrieved from a previously publishedstudy that reported an analysis of the long-termcosts for foot ulcers in diabetic patients within amultidisciplinary setting.131 Similarly, utilityweights associated with the eight health statesconsidered in this model were based on thefindings of a previously published study in whichthe health-related quality of life (HRQoL) ofpatients with diabetes mellitus and foot ulcers wasinvestigated using the EuroQol questionnaire.132

The main objective in this analysis was to explorethe cost-effectiveness of prevention in four groupsof diabetic patients at different risks of developingfoot ulcers and/or experiencing amputation.Consequently, the description of the naturalhistory of DFUs was mainly focused in thosehealth states more likely to result in amputation.Although a ‘deep foot infection’ health state in thepresence of an open ulcer was included in themodel, no attempt was made to identify footinfections at an earlier stage, the time point atwhich the contribution of formal diagnostic testmay be most valuable.

York Health Economics Consortium (YHEC)(1997)129

YHEC conducted a cost-effectiveness analysis oftissue engineered human dermal replacementcompared to conventional therapy in the treatmentof DFUs in the UK.129 A model-based economic

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evaluation analysis was conducted using a decisionanalytic Markov model. Health benefits weremeasured in terms of ulcer-free weeks. Transitionprobabilities used in the model were derived fromthe results of an RCT of bioengineered humandermal replacement.133 Resource use was estimatedfrom the experience at four major UK NHSdiabetic centres. The unit costs were retrieved froma variety of sources. Although the structure of thismodel did distinguish between health statesaccording to varying degrees of infection, themodel was not described in sufficient detail to beuseful in facilitating the construction of acomprehensive natural history model.

Edmonds and colleagues (1999)121

Edmonds and colleagues report on the results of aretrospective cost analysis of rhG-CSF versusplacebo in the treatment of hospitalised diabeticpatients with infected foot ulcers and extensivefoot cellulitis, of whom 39/40 had an ulcer.121 Adecision tree was constructed to estimate meanexpected costs for both alternatives. Transitionprobabilities and total volume of resource use werederived from a randomised double-blind placebo-controlled study.100 This analysis only consideredthe cost implications associated with the treatmentof diabetic patients with an acute spreading ofinfection, presumably the patient group for whichrhG-CSF is indicated. However, it does notprovide information regarding patients with alesser degree of infection and as such it was notuseful for this project.

Eckman and colleagues (1995)15

Eckman and colleagues report the findings of acost-effectiveness analysis of different alternativesfor the diagnosis and treatment of patients withtype 2 diabetes mellitus, an infected DFU, andsuspected osteomyelitis.15 A Markov statetransition model was constructed to estimate meanlife expectancy and cost. This model consideredthree treatment strategies: (1) a short course ofantibiotics; (2) empirical treatment of osteomyelitiswith a long course of antibiotics; and (3) testingvarious combinations of roentgenography,technetium-99m bone scanning, white blood cellscanning and magnetic resonance imaging. Lifeexpectancy was adjusted for changes in quality oflife. In the base case analysis, quality-adjustedscores were based on expert physicians’judgments. Although this model directly evaluateddifferent diagnosis strategies for infection inpatients with DFUs, there were three main factorsthat prevented us from following this structure inour evaluation. First, a detailed description of themodel structure was not provided in the report.

Second, the study focused only on patients with asevere degree of infection, who were suspected ofsuffering from osteomyelitis. Third, the diagnostictest(s) under evaluation is (are) used to detectosteomyelitis rather than soft tissue infectionassociated with diabetic foot ulcers.

Persson and colleagues (2000)130

Persson and colleagues developed a Markov modelto evaluate the cost-effectiveness of treatingdiabetic lower extremity ulcers with recombinanthuman platelet-derived growth factor (rhPDGF-BB: becaplermin gel, Regranex®) in fourEuropean countries: France, Sweden, Switzerlandand the UK.130 Model results have been reportedin the literature on a single-country basis and alsoin an encompassing multi-country analysis. Thestructure of the model described in this analysiswas not only sufficiently detailed and transparent,but importantly, it provided a comprehensivedescription of the natural history of patients withDFUs. Consequently, it was decided to utilise thismodel as the basic structure for the analysis. Theauthors of the UK analysis were contacted andkindly agreed to provide us with an electroniccopy of their model.134

A model to describe the natural historyof diabetic foot ulcersModel structurePersson and colleagues’ Markov model wasadapted and used to describe the natural historyof DFUs.130 This type of model was used as itallows the simulation of disease prognosisincorporating the complications and reoccurrencesassociated with DFUs over a lifetime. The modeldescribing the natural history of DFUs consistedof nine discrete health states, although in thePersson model there were only six. The states inthe adapted model comprised uninfected ulcer,infected ulcer, healed ulcer, gangrene, gangrenehistory of amputation, healed history ofamputation, uninfected history of amputation,infected history of amputation and death. Thesestates represent what appear to be clinically andeconomically important events in the diseaseprocess being modelled. All of the states aremutually exclusive, since one of the requirementsof a Markov model is that a patient cannot be inmore than one state at a time. By attachingestimates of both resource use and health outcomeconsequence to the states and transitionsthroughout the model and then running themodel for a specified number of cycles, it ispossible to estimate the long-term costs andoutcomes associated with the disease andintervention being modelled.135 Amputation was


49


considered to be a treatment that aided healingand as such was not considered a health state.

Transition probabilitiesMovement between the states is determined bytransition probabilities, and takes place after apredetermined length of time known as a cycle.Cycle length should be determined according to thefrequency with which patients are likely to changestates in real life. In this model, patients wereallowed to transit between states at monthly cycles.

In Persson’s natural history of the disease model,some transitions between states were disallowed,for example, a person could not develop an ulcerafter having an amputation (see Figure 6). ThePersson model was based on a patient populationwho were suffering from deep, ischaemia-free,diabetic neuropathic lower extremity ulcers.130

Consequently, it was necessary for the modelstructure to be modified to allow transitions thathad previously been ruled out, thus allowing themodel to reflect the clinical pathways of patientswith different underlying causes for DFUs, such asneuropathy and/or ischaemia. These conditionscover the largest proportion of patients withdiabetic foot ulcers.

The achievable transitions allow the patient tomove from the uninfected state to the healed,infected, gangrene or deceased state; from theinfected state a patient can make the transition tothe uninfected, gangrene, healed history of

amputation, infected history of amputation ordeceased state; and from the gangrene health statea patient can make transitions to the infected,gangrene history of amputation, healed history ofamputation or deceased state; from the healedhistory of amputation state a patient can onlymake the transition to deceased. The deceasedhealth state is an absorbing state from which notransitions can be made. An adaptation of theoriginal model is the transition from uninfected togangrene. Originally disallowed, this transitionwas incorporated into our model to allow for amore diverse study population that includedischaemic patients.

The transition probabilities used in Persson’smodel were derived from a cost of illness studyconducted in the USA. The study samplecomprised 183 US patients with either type-1 ortype-2 diabetes.136 The transition probabilitieswere derived directly from the study data (seeTable 11). Additionally, to ascertain the transitionsthat rely on information about the rates ofsuccessful or unsuccessful amputation, the studydata were augmented by Persson and colleaguesusing estimates based on the literature or expertclinical opinion.137,138 The transition cycles of themodel are monthly and the simulation is run untilall patients are healed or deceased.

Model assumptionsPersson and colleagues made a number of modelassumptions, which were necessary to facilitate

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Uninfectedulcer

Infectedulcer

Healedulcer amp.

Death

Amputationamp.

Healedulcer

Gangrene

Infectedhistory amp.

Gangrenehistory amp.

Uninfectedhistory amp.

FIGURE 6 Natural history of diabetic foot ulcers (Markov model)

completing the natural history model. Theassumptions were made both to simplify themodelling process and to supplement the lack ofavailable evidence to inform a different modellingsolution. First, it was assumed that after receivingan amputation that resulted in healing, it was notpossible for a patient to have a recurrence. Also, itwas assumed that amputation did not increase therisk of mortality and that a gangrene ulcer had thesame mortality rate as an infected ulcer. Finally, itwas assumed that infected ulcers are the cause ofapproximately 80–85% of all ulcer-relatedamputations and that gangrene is the cause of theremaining 15–20%.130

Elicitation of utility valuesIt was expected that the main outcome measure ofthe model would be cost per QALY. Identificationof studies reporting utility and HRQoL scores fordiabetic patients with and without DFUs was partof the main electronic searches for the project.Two suitable studies were identified.

Sullivan and colleagues (2002)139

Sullivan and colleagues elicited patientpreferences using both a rating scale and astandard gamble technique.139 The rating scaletechnique involves a scale from 0.0 to 1.0 whichrepresent the worst and best conceivable healthstates, respectively. The individual is then asked toplace health state descriptions on the scale. Theratings given to each health state descriptionsubsequently represent the individual’s rating scalevalues.

The standard gamble technique involves theindividual being given two options and asked tomake a choice as to which option they prefer. Theoptions are varied slightly and re-administered tothe individual in an attempt to reach the point atwhich the individual is indifferent between thechoices with which they are faced. When this pointhas been reached, it is possible to ascertain theindividual’s standard gamble value for the healthstate selected. The standard gamble technique isconsidered by many health economists to be thegold standard approach to eliciting cardinal healthstate values. This is because the technique isgrounded in expected utility theory, the dominanteconomic theory of risk.140

The patient population comprised adults with type1 and type 2 diabetes aged between 18 and80 years. Patients were excluded if they had anysymptoms of diabetic peripheral neuropathy(DPN) such as numbness, tingling or pain in theirextremities or any history of lower extremitycomplication such as a foot ulcer or anamputation. A total of 52 patients were enrolled inthe study. Patients were given detailed descriptionsof seven health states which fully described thestages of disease severity in DPN. The patientsthen completed the preference assessmentinterview for DPN-related health states. The studyfound that patients’ preferences for health statesdecreased as a function of increasing diseaseseverity in DPN regardless of the methods used tomeasure preferences. The results of the study arepresented in Table 12.


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TABLE 11 Model transition probabilities

Transition Probability Reference

Uninfected to healed 0.0787 136Uninfected to infected 0.0473 136Uninfected to dead 0.004 136Healed to uninfected 0.0393 136Healed to dead 0.004 136Infected to uninfected 0.1397 136Infected to gangrene 0.0075 136 Infected to healed (amputation) 0.045 131, 137Infected to infected (amputation) 0.0037 131, 137Infected to dead 0.0098 136 Gangrene to healed (amputation) 0.3082 131, 137Gangrene to gangrene (amputation) 0.1818 131, 137Gangrene to dead 0.0098 136Healed (amputation) to dead 0.004 136Uninfected to gangrenea

a No information regarding this transition probability was identified in the literature. However, for completeness thistransition was allowed in the model since this is a transition patients with arterial insufficiency can make.

When eliciting values for health states, thepopulation chosen can or cannot suffer from thedisease in question. Arguments against and infavour of either approach are a subject of debatefor many economic experts. For some thepreferred method would be to elicit preferencesfrom patients who are currently experiencing thehealth state; however, others will argue thatindividuals who are not experiencing such healthcondition are more likely to make an objectivevaluation. It is highly likely that Sullivan andcolleagues chose to exclude patients sufferingfrom DPN to allow an adequate recruitmentsample to the study.

Tennvall and Apelqvist (2000)141

Tennvall and Apelqvist (HRQoL) used the EuroQol quality of life questionnaire (EQ-5D),which included a visual analogue scale (VAS).141

The questionnaire was distributed by postal surveyat the end of a 3-year period to type 1 and 2diabetic patients who had been treated for footulcers during the 3-year study period. A total of440 patients participated in the study and weresent questionnaires. The study had a 70%response rate.

The study protocol defined four mutuallyexclusive groups dependent on their foot ulcerand amputation status at the time of thequestionnaire. The four groups were current footulcer with no previous amputation, primaryhealed with no current amputation, maximalminor amputation and maximal majoramputation. The study presents values for both EQ-5D and the VAS; the results of the studyare presented in Table 13. The study findings show that patients under current foot ulcertreatment value their HRQoL lower than thosewho have healed primarily without amputation. Inaddition, quality of life is reduced after majoramputations.

Utility values used in the modelThe health states which patients were asked tovalue in these two studies did not directly matchthose considered in this model. To facilitate theiruse, the differing health states were matchedwhere possible using both the Wagner scale,142

which is a widely used classification tool in theclinical field, and the health state descriptions aspresented by the individual papers (see Table 12).Where necessary, the project team usedassumptions and previous experience to ensurethe best possible match was achieved (seeTable 13).

Given that the standard gamble is considered tobe the ‘gold standard’ approach, it wasdetermined that the scores obtained using thistechnique would be used in the base-case model.Further, the other scores would be used tofacilitate sensitivity analysis in an attempt to assessthe robustness of the model results obtained.

Healthcare resource use requirementsThe perspective adopted for the economic analysisis that of the UK NHS and Personal SocialServices and as such only direct costs are included.Resource utilisation for the UK corresponds tothat reported by Ghatnekar and colleagues.143

Unit costs were derived from a number of sourcesincluding the BNF, NHS 2000 reference costs andpreviously published studies.

The unit costing and resource use used in thebase-case model are presented in Tables 14 and 15.

The prices are expressed in 2000 values. Themodel applies a discount rate of 6% to costs and1.5% to benefits according to NICE guidance foreconomic evaluation analysis.144

Based on Ghatnekar and colleagues’ assumptionsregarding volume of healthcare resources used,

Results

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TABLE 12 Health-related quality of life states

Model health state Tennvall health states141 Sullivan health state139

Healed Primary healed, no amputation Severe neuropathyUninfected Current foot ulcer, no amputation Minor ulcerInfected Severe ulcerGangrene Severe ulcerUninfected (amputation) Severe ulcerInfected (amputation) Maximal major amputation Major amputationHealed (amputation) Maximal minor amputation Minor amputationGangrene (amputation) Maximal major amputation Major amputation

the total monthly recurring and non-recurringcosts per patient for each health state wereestimated to be for the uninfected state £1248.47, for the infected state £1237.44, for the gangrene state £2220.95 and for the healedstate £14.01.

Incorporation of diagnostic test in the modelstructure of the natural history of diabetic footulcersThe use of a diagnostic test can facilitate earlydetection of infection and allow a treatmentpackage to be tailored to meet the requirements ofthe individual patient. Consequently, theincorporation of a diagnostic test to the modelallowed the patients to be split into two groups,those with a positive test result and those with anegative test result, with each group following adifferent treatment pattern.

The two groups then enter into two differenttrajectory paths within the model. Those with apositive test result enter their model in theinfected state (Figure 7a). Transitions through themodel follow the same structure as the naturalhistory model, although the rate at which eachtransition is made will vary. Those patients whohave a negative test result enter their model in theuninfected state and will follow the same structureas the natural history model, (Figure 7b). Although,as with the patients who had a positive test, thetransition probabilities will vary from those in thenatural history model.

Target populationThe identification of the target population, that is,those patients with DFU most likely to benefitfrom the use of diagnostic tests to inform their

treatment, was made based on the findings fromthe systematic reviews conducted within thisproject and consultation with clinical experts.Applying a diagnostic test for infection to allpatients with a DFU irrespective of the conditionof their ulcers might be an inefficient use ofalready scarce UK NHS resources, hence therelevance to identify the groups of patients whoare more likely to benefit. Initially, the researchteam identified clinically infected patients as thetarget population for diagnostic testing. Theliterature was then used to characterise this targetpopulation fully.

The review of the literature found no consensuson a definition of what it means to be clinicallyinfected. Owing to the lack of clarity surroundingan appropriate definition of ‘a clinically infectedulcer’, current clinical procedure, the relevance ofour target population, and data for the model, itwas decided to construct a questionnaire to beadministered to what was deemed a relevantaudience in an attempt first to derive a definitionfor clinically infected foot ulcers from clinicalexperts and to estimate relevant parameters forthe decision model using clinical judgement. Aquestionnaire was designed and personalinterviews conducted at the 13th Conference ofthe European Wound Management Association,Pisa, Italy, 22–24 May 2003. The target audienceat the conference was expert wound careresearchers and clinicians. Personal interviewswere conducted in an attempt to ascertain aconsensual definition of ‘clinical infection’ whichcould help us to characterise fully the populationof interest (see Appendix 7). This in turn wouldlead to clarification of the relevant economicquestion.


53


TABLE 13 Health-related quality of life scoresa

Health state Standard gamble Rating scale EQ-5D VASMean (SE) Mean (SE) Mean MeanRange (0.0 –1.0)139 Range (0.0–1.0)139 Range (–0.594 to 1)141 Range (0–100)141

Uninfected 0.76 (0.23) 0.57 (0.16) 0.44 52Healed 0.84 (0.19) 0.70 (0.15) 0.6 63Infected 0.62 (0.30) 0.41 (0.17)Gangrene 0.62 (0.30)a

Uninfected (amputation) 0.62 (0.30)a

Healed (amputation) 0.74 (0.24) 0.45 (0.19) 0.61 64Infected (amputation) 0.61 (0.29) 0.27 (0.19) 0.31 54Gangrene (amputation) 0.62 (0.30)b

a Higher scores indicate better health status.b Assumption.

The results of the interviews revealed that inpractice in the UK any patient showing any signsof an infection would receive a first course ofantibiotics when they first presented to a clinician.The only patients whose treatment would beinformed by diagnostic tests are those who showno signs of infection but whose ulcer is not healingand those in whom a first course of antibiotics was

not successful. These two groups of patients thenbecame our new target populations.

Model information requirementsIn order to operationalise the model, estimates ofall the parameters within it, such as transitionprobabilities, sensitivity of different diagnostictests, among others, and the uncertainty

Results

54

TABLE 14 Healthcare resource use requirements associated with the treatment of diabetic foot ulcers (Ghatnekar’s assumptions)143

Quantity Unit cost (£)

Topical treatment per visit (outpatient)� Patients were assumed to require 6 visits per week8-Ply gauze swab 1 0.0338Conforming bandage 0.5 0.435Nursing cost 1 22.00

Infected patients treated as outpatients� 14 days of treatment� After 14 days 20% required hospital treatmentAmoxicillin 1500 mg 0.15Flucloxacillin 2000 mg 0.498

Infected patients treated as inpatient� Treatment continued for 14 daysI.v. Ceftazidime 4000 mg 39.60Metronidazole 1500 mg 10.23

Antibiotics – daily treatment (gangrene)� 14 days of treatment � After 14 days 50% of patients require hospitalisationAnd 50% are treated as outpatients and require metronidazole

Gangrene treatment as outpatients� Treatment continued for 14 daysCiproxacillin 1000 mg 2.84Amoxicillin 1000 mg 0.15Flucloxacillin 2000 mg 0.498Metronidazole (50% require) 1200 mg 0.649

Gangrene treatment as inpatients� 50% require inpatient treatment for 14 daysI.v. Ceftazidime 4000 mg 39.60Metronidazole 1500 mg 10.23

Other outpatient costs (infected and uninfected)Podiatrist visit 4 per month 16.00Diabetologist 1 per month 73.00

Other outpatient costs (gangrene)Surgical consultation 1 per year 89.00

Inpatient careLength of stay 14 daysAmputation Major 7224.00

Minor 3052.00Prostheses 1 NA

Orthopaedic appliances� A percentage of patients are assumed to require orthopaedic appliancesAir cast (30%) 1 100.00Healing shoes (Neoprene) (70%) 1 pair 27.50Custom shoes (30% of healed) 1 pair 375.00Orthopaedic stock shoes (70% of healed) 1 pair 100.00

NA, not available.


55


TABLE 15 Clinical and diagnostic tests assumed to be required by diabetic patients with an open foot ulcera

Test Frequency Unit cost Uninfected Infected Gangrene(monthly) (monthly) (monthly)

Blood glucose 4 times/month 1.10 4.40 4.40 4.40X-ray 1 time/year 40.0 3.33 3.33 3.33Full blood count 2 times/year 3.73 0.62 0.62 0.62U + E 1 time/year 4.00 0.33 0.33 0.33Blood culture 1 time/year 8.05 0.67 0.67 0.67Chest X-ray 1 time/year 13.77 1.15 1.15 1.15HbA1c 1 time/3 months 1.10 0.37 0.37 0.37

Diagnostic tests Quantities Unit costs

Wound swabs 1 7.9 (5.61–9.33)Wound biopsy 1 7.9 (5.61–9.33)Wound lavage and analysis of the fluid 1 7.9 (5.61–9.33)

a As testing does not take place in the healed and dead state, no testing costs are incurred for these states.

Amputationamp.

Uninfectedulcer

Healedulcer

Infectedulcer (test +)

Gangrene




Healedulcer amp.

Death(a)

Amputationamp.

Infectedulcer

Healedulcer

Uninfectedulcer (test –)

Gangrene




Healedulcer amp.

Death

(b)

FIGURE 7 Model structure

associated with them are required. The modelinformation requirements are described inTables 16–19. It is worth noting that these datashould be specific to the two groups of patientswith DFUs in which diagnostic tests are routinelyused in the UK, namely:

� Patients with DFUs who do not show anyclinical symptoms of infection but whose ulcer isnot healing.

� Patients with diabetic foot ulcers in whom a firstcourse of antibiotics was not successful.

Results

56

TABLE 17 Effectiveness information requirements to run model

Impact on treatment Information required

Wound swabs Expected changes in antibiotic treatment effectiveness (i.e. changes in proportion ofpatients whose infection resolves) due to prompt detection of infection using thistest

Wound biopsy Expected changes in antibiotic treatment effectiveness due to prompt detection ofinfection using this test

Wound lavage and analysis of the Expected changes in antibiotic treatment effectiveness due to prompt detection of fluid infection using this test

TABLE 16 Diagnostic information requirements to run model

Diagnostic test Information required

Wound swabs Sensitivity and specificityWound biopsy Sensitivity and specificityWound lavage and analysis of the fluid Sensitivity and specificity

TABLE 18 Outcome information requirements to run model

Transition probabilities Information required

Uninfected to healed Proportion of patients with an uninfected ulcer who healUninfected to infected Proportion of patients with an uninfected ulcer who are later diagnosed as infectedUninfected to dead Proportion of patients with an uninfected ulcer who dieHealed to uninfected Proportion of healed patients who have an ulcer recurrenceHealed to dead Proportion of healed patients who dieInfected to uninfected Proportion of people diagnosed as infected whose infection resolves after a first

course of antibioticsInfected to gangrene Proportion of people with an infected ulcer who are later diagnosed as having

gangreneInfected to healed (amputation) Proportion of infected people who undergo amputation

Proportion of people with an amputation who healInfected to infected (amputation) Proportion of infected people who undergo amputation

Proportion of people with an amputation who are later diagnosed as infectedwithout having healed

Infected to dead Proportion of infected people who dieGangrene to healed (amputation) Proportion of people with an infected ulcer who are later diagnosed as having

gangreneProportion of people with gangrene who undergo amputationProportion of people with gangrene who heal after amputation

Gangrene to gangrene (amputation) Proportion of people with an infected ulcer who are later diagnosed as havinggangreneProportion of people with gangrene who undergo amputationProportion of people with gangrene whose gangrene reoccurs after amputation

Gangrene to dead Proportion of people with gangrene who dieHealed (amputation) to dead Proportion of people undergoing amputation who heal

Proportion of healed people after amputation who dieUninfected to gangrene Proportion of uninfected people who are later diagnosed with gangrene without a

prior diagnosis of infection


57


TABLE 19 Treatment information requirements to run model

(a) Topical treatment per visitCurrent assumptions in the model regarding topical treatment Does this assumption apply to Quantity

target groups in UK?6 visits per week8-Ply gauze swabConforming bandageNursing time

(b) Treatment of infection (outpatients)Current assumptions in the model regarding outpatients’ Does this assumption apply to Daily dosagetreatment of infection target groups in UK?Treatment was to be continued for 14 days. After 14 days. 20% of these patients required hospital treatmentAmoxicillinFlucloxacillin

(c) Treatment of infection (inpatients)Current assumptions in the model regarding inpatients’ Does this assumption apply to Daily dosagetreatment of infection target groups in UK?Treatment was assumed to continue for 14 daysI.v. CeftazidimeMetronidazole

(d) Treatment of gangrene (outpatients)Current assumptions in the model regarding outpatients’ Does this assumption apply to Daily dosagetreatment of gangrene target groups in UK?Treatment continued for 14 days. After 14 days 50% of these patients will require hospitalisation and 50% will be treated as outpatients and require metronidazoleCiproxacillinAmoxicillinFlucloxacillinMetronidazole

(e) Treatment of gangrene (inpatients)Current assumptions in the model regarding inpatients’ Does this assumption apply to Daily dosagetreatment of gangrene target groups in UK?50% require inpatient treatment for 14 daysI.v. CeftazidimeMetronidazole

(f) Other outpatients’ costs (apply to infected and uninfected patients)Current assumptions in the model regarding other outpatients’ Does this assumption apply to Quantityservices target groups in UK?Podiatrist visitDiabetologist

(g) Other outpatient costs (apply to patients with gangrene)Current assumptions in the model regarding other services for Does this assumption apply to Quantitypatients with gangrene target groups in UK?Surgical consultation

(h) Inpatient careCurrent assumptions in the model regarding other services Does this assumption apply to Quantityfor inpatients target groups in UK?Length of stayMajor amputationMinor amputationProstheses

continued

According to the results obtained from thesystematic review of diagnostic studies, there is apaucity of research regarding the use andcontribution of diagnostic tests in themanagement of patients with DFUs. The reviewfound only three diagnostic studies that wereeligible for inclusion and none of them providedinformation about the sensitivity and specificity ofthe diagnostic tests for the two target populationgroups. Equally, the studies reporting on theclinical effectiveness of different antibiotictreatments for infection do not specifically refer tothe effectiveness of such treatments for either ofthe target populations; rather, they refer to arange of patients with an infected foot ulcer/leg.Consequently, the decision analytic modeldescribed above could not be informed for thepopulations of interest. In order to populate themodel, the data requirements outlined inTables 16–19 would be required. The model couldbe adapted to suit any patient population thatmatched the natural history outlined previouslyand for whom the data could be obtained. At thistime no data for our target populations wereavailable. As a result, no estimates of healthbenefits or costs associated with the use ofdiagnostic test of infection in the relevant patientswith diabetic foot ulcers could be made.

Alternative options to populate the decisionanalytic modelGiven the lack of evidence identified in the reviewof the literature to populate the decision analyticmodel described above for the two populations ofinterest, it was necessary to pursue other avenuesthat may facilitate the data requirements. Hencethe research team decided to consult with clinicalexperts to explore the possibility of populating themodel using clinical judgments.

AimsAn interview schedule was designed with the aimof guiding semi-structured interviews with expertclinicians. The interviews sought to identify a

definition of clinical diagnosis of an infected footulcer and the clinical symptoms associated with it.Clinicians were then presented a number ofalternative courses of action to assess/treatindividuals with a DFU who had been clinicallydiagnosed as having an infected ulcer, and thosewith a non-healing but apparently uninfectedulcer. This included asking about the type ofmicrobiological sample taken and its role indetermining therapy. Finally, interviewees wereasked to give their views about a definition ofclinical diagnosis of infection in foot ulcers thathad been identified in the literature.

SampleOne interviewer approached six internationalexperts working with DFUs who were attending aconference on wound management. Theycomprised two podiatrists, one diabetologist, onevascular surgeon, one nurse specialist and onephysician with an interest in chronic wounds.Responses were recorded on an interview schedulerather than being recorded electronically. Replieswere tabulated to identify agreement anddisagreement between respondents.

Results The responses are reported in Appendix 7.

Definition of infection. Four experts reported thatswelling was indicative of infection (the other twocited cellulitis), four used pain as a potentialmarker of infection and four reported discharge orexudate as being important. The primacy of theclinical diagnosis of infection, as opposed to usingbacteriology to diagnose infection, is highlightedby the statement by respondent C: “We don’t useswabs to diagnose infection, the clinical impressionis the diagnosis, swabs simply confirm theorganism”. Other diagnostic clues for infectionincluded redness or erythema (three reports),smell (three reports), cellulitis (two reports), heat(one report), induration (one report), andundermining (one report).

Results

58

TABLE 19 Treatment information requirements to run model (cont’d)

(i) Orthopaedic appliancesCurrent assumptions in the model regarding orthopaedic appliances Does this assumption apply to Quantity

target groups in UK?Percentage of patients who are assumed to require orthopaedic appliancesAir cast (30%)Healing shoes (Neoprene) (70%)Custom shoes (30% of healed)Orthopaedic stock shoes (70% of healed)


59


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Empirical or bacteriology-guided therapy after diagnosisof infection. When asked whether a course ofantibiotics would be commenced following aclinical diagnosis of infection (and before a swabresult is available), three experts stated “all ofthem”, one stated “virtually all of them”, onestated “the majority” and one “5–7 out of 10”. Onereason given for delaying antibiotic therapy wasthe potential for osteomyelitis – it was stated by apodiatrist working in a tertiary referral centre thattherapy would await a bone biopsy if osteomyelitiswas suspected. Another factor affecting thedecision to prescribe empirically or to await resultswas the day of the week on which the patient wasseen – as a patient seen in the early part of theweek could be seen again in 24/48 hours to checkon progress, whereas someone seen on a Fridaycould not be reassessed easily, and therefore weremore likely to be given antibiotics.

Sources of information on wound bacteriology. Swabswere the most common type of sample taken foranalysis (4/6 respondents) with a deep tissuebiopsy taken at centre where a bone infection teamwas available and curettage of neuropathic ulcersat one centre. The role of swabbing wassummarised by one respondent who stated thatthey treat the symptoms, not the swab result(respondent A). Practices following uninformativeswabs were variable.

Managing uninfected ulcers For apparentlyuninfected ulcers, the period of time over whichan assessment of ‘non-healing’ was made rangedfrom 3 to 8 weeks, although one expert stated thatthey used the percentage reduction in area byweek 4 as a guide.

Caputo’s definition of clinical infection25 All expertsagreed with Caputo’s definition of infection indiabetic foot ulceration,25 “erythema, indurationand discharge”, but one pointed out that the lackof erythema in a neuropathic ulcer may reflectpathology rather than prove the absence ofinfection. This expert also said that thecharacteristics of the discharge were important –changes in type/amount of discharge wereimportant as waiting for pus were leaving it “toolate”. Only one expert stated that the presence oftwo of the three signs was sufficient, and it is notclear whether the remaining experts required thepresence of all three signs for most ulcers.

Other findings from the interviews. The three medicaldoctors described different empirical regimens forfirst-line treatment, with two of the threementioning metronidazole and two mentioningclindamycin.

Summary The interviewees lacked agreement overall on thediagnostic criteria for clinical infection, theprevalence of infection, the best course of actionregarding treatment, length of treatment before analternative would be tried and the use ofdiagnostic testing.

DiscussionThe variations in clinical practice regarding thetype of bacteriological sample taken and use ofantimicrobial therapy from the questionnaire’sresponses raised concerns regarding theappropriateness of using clinicians’ estimates toinform the decision analytic model. The variationspresented in the clinical estimates were so widelydispersed that it was not possible to obtain acentral estimate and use sensitivity analysis overplausible ranges to address the uncertainty in ourchosen estimate.

It was decided that the degree of variationreflected in the data suggested that it would not bepossible to reach consensus about any of theparameters of interest based on the informationfrom the interviews with the clinicians. At thispoint, it was decided that the decision analyticmodel could not be populated.

After considering the response of the interviewees,and looking at the literature available, we wereable to revise the clinical pathway initial proposed(Figure 1) to reflect the actual pathways thatclinicians took. This is summarised in Figure 8. Inbrief, it indicates that antimicrobial analysis fordetermining the choice of antibiotics to be usedfor an episode of infection is reserved for patientsin whom there are no frank signs or symptoms ofinfection, but whose ulcer is non-healing. Forpeople with an ulcer infection, a sample may betaken but, as antibiotic therapy is commencedimmediately, then the choice of antibiotics is notinformed by the results. The results frombacteriological analyses were consulted, accordingto our interviewees, only if the infection was notresolving or the ulcer was not healing.

Results

60

Diagnostic studiesLimitations of the researchWhat is the diagnostic performance of clinicalexamination in the identification of infection inDFU?One study was identified that addressed the aboveresearch question.90 The overall sample size wassmall (n = 36), which meant that some sensitivity,specificity and predictive values were estimated at100% (likely to be inflated) and therefore that acorrection factor of 0.5 was required to calculatesome LRs. The derived estimates are likely to havewide CIs, indicating a large degree of uncertaintyaround the central estimates. The use of a largersample size would have increased the precision ofthe estimates.

The sample was heterogeneous with respect towound type. It is possible that different woundtypes present differently with respect to differentclinical signs and symptoms of infection and thatthe usefulness of individual signs and symptomsmay vary according to wound aetiology. This wasreflected in the slightly different profile ofsensitivity values seen in venous leg ulcers whencompared with the overall sample. Of particularinterest is the higher sensitivity for purulentexudate as compared with the overall sample ofwounds of mixed aetiologies (67% versus 18%).However, it may be argued that a sensitivity of67% is still not high enough to be clinically useful,and it would be necessary to consider the clinicaland economic consequences of failing to identifyone-third of wound infections. Another potentialreason for the difference between estimatedoutcomes across different wound types is randomerror (chance). Since there were only two patientswith DFUs and seven patients with venous legulcers, it is difficult to infer from the findings ofthis small study in a way that is useful to theresearch questions posed for this project. It islikely that all patients with a chronic wound arelikely to be subject to clinical examination of thelesion in clinical practice. However, owing to thestrict inclusion criteria in terms of the baselinehaematological status of patients in three out ofthe four study centres, this study is likely to haveexcluded some patients for whom the index testwould be relevant. It is difficult, therefore, to

generalise the results of this study to a populationseen in clinical practice. Another consideration isthat this study estimated diagnostic outcomes for arange of individual clinical signs or symptoms. Itmay be the case that, in reality, clinicians tend todefine infection based on clusters of signs andsymptoms rather than relying on any oneindividually, as described by the expertrespondents in Appendix 7.

The assessment of inter-rater reliability of theindividual checklist items resulted in � statisticsranging from 0.53 to 1.00. The authors providedmore detail about this assessment in a separatepaper.145 The following can be deduced with theassistance of guidelines for interpreting� statistics:146,147 very good agreement(� = 0.81–1.00) was attained for the symptom ofincreasing pain, and signs of oedema, delayedhealing and wound breakdown; there was goodagreement (� = 0.61–0.80) for erythema, purulentexudate, serous exudate, discoloration and friablegranulation; moderate agreement (�= 0.41–0.60)for heat and foul odour; and no agreement betterthan chance was found for pocketing of the woundbase. In terms of percentage agreement, the study authors made use of recommendationssuggesting that an agreement of at least 70% isnecessary, at least 80% is adequate and at least90% is good.145,148,149 Four of the checklist items had agreement values <70%: heat(occurrence agreement 44%); discoloration (non-occurrence agreement 65%); foul odour(occurrence agreement 50%); and pocketing of thewound base (occurrence agreement 0%). All exceptpocketing of the wound base, which did not occurin the sample, had favourable alternativeagreement values in terms of total percentageagreement, occurrence percentage agreement,non-occurrence percentage agreement and/or �statistics.145

Two clinical indicators (increasing pain and wound breakdown) may be useful individually for identifying infection in chronic wounds, andboth showed good inter-rater reliability. However,these findings should be viewed with cautionowing to the small size of the study and theheterogeneity of the study group with regard towound type.


61


Chapter 5

Discussion

When interpreting outcomes from diagnosticevaluations, it is important to recognise possiblesources of bias that may impact on the derivedestimates. It was unclear from the paper whetherresults for each patient for the index test wereinterpreted without knowledge of the associatedresult of the reference test, and vice versa. Ifinterpretation was not blind, bias could arise as aresult of non-independent assessment of indexand reference tests, which is thought usually toresult in overestimation of the accuracy of theindex test (test review bias).150 The longer time lagbetween tests for one of the study sites could havemeant that some wounds changed their infectionstatus during the interim period, leading todisease progression bias.

What is the diagnostic performance of specimenacquisition techniques in the identification ofinfection in DFU?Findings suggested a limited usefulness for thewound swab in detecting infection in chronicwounds.91 However, it should be noted that thereare several limitations to this study. The overallgroup size is small and it is heterogeneous withregard to wound type. It is possible that the testcould perform differently in different woundtypes, therefore the estimates reported for theoverall sample should be interpreted with caution.It is not clear whether participants had to havewound infection suspected from clinical signs andsymptoms in order to be recruited. If not, then theusefulness of taking a swab for all wounds may bequestionable, and may not reflect procedures inclinical practice. However, patients had to havewounds present for at least 6 months, and it maybe that the study authors considered that delayedhealing indicated the presence of wound infection.It is possible that the inflammatory response, andtherefore the usual presentation of clinical signsand symptoms of wound infection, may bereduced in people with DFUs, owing to reducedskin vasodilation and/or neuropathy.24,60 Somesources suggest that the presence of bacteria inwounds may delay healing.151 However, thecurrently available evidence on the link betweenpresence of pathogens and wound healing is bothsparse and inconsistent.48,151

The estimates of diagnostic accuracy gleaned fromthis study may have been influenced by test review bias.

There was difficulty in identifying a universallyaccepted reference standard in this field ofresearch. This problem has been observed in otherclinical areas and it has been asserted that ‘gold

standards providing full certainty are rare’.152

Tissue biopsy was employed as the referencestandard for the two studies described above.90,91

Other sources also suggest that tissue biopsy is areliable reference standard.153,154 Given that thedifficulty lies in deriving a standard as close aspossible to the theoretical reference standard,152 itseems likely that researchers will continue toregard tissue biopsy as the optimum referencestandard for evaluations of diagnostic accuracy. Instudies where a reference standard has not beendefined and justified, the evaluation should beregarded as assessing the agreement betweendiagnostic tests as opposed to accuracy. TheNational Coordinating Centre for ResearchMethodology (NCCRM) has recently proposed amethodological research project to review methodsin diagnostic evaluations when there is noreference standard, which may eventually provideguidance for conducting systematic reviews of thistype.155

What is the diagnostic performance of differentlaboratory analysis techniques in theidentification of infection in DFU?Findings, again from a single study, suggest thatsemi-quantitative analysis may be a usefulalternative to quantitative analysis, particularly forsettings where the equipment and materialsnecessary for the latter are not available.92 Thestudy group was heterogeneous in terms of woundtype, and the impact of the use of differenttechniques of laboratory analysis of swabs in DFUsis unclear. It is not known whether analysis resultsvary across samples from different wound typeswhen bacterial loads are similar. Owing to theapparent dearth of research in this important area,it is difficult to say whether the use of aquantitative analysis of wound swab is anacceptable reference standard. Test review bias anddisease progression bias may have had an impacton the derived estimates, therefore the findingsfrom this study should be viewed with caution,particularly when inferring to a particular woundtype.

Reporting issuesIn recent years, several initiatives have beendeveloped to help improve the standard ofreporting of biomedical research. Initially theConsolidated Standards of Reporting Trials(CONSORT) statement was issued with the aim ofimproving the reporting of randomised controlledtrials.156 Later, the Quality of Reporting of Meta-Analyses (QUOROM) statement was introduced, asimilar tool to the assist reporting of systematicreviews and meta-analyses.157 More recently, the

Discussion

62

Standards for Reporting of Diagnostic Accuracy(STARD) initiative has been described to improvethe quality of reporting of studies of diagnosticaccuracy and therefore help readers to judge theinternal and external validity of an evaluation.158

The STARD initiative includes the use of achecklist developed by a project steeringcommittee who used literature searches and aconsensus procedure to develop the range ofconstituent items. The checklist covers thefollowing: ease of identification of the article as astudy of diagnostic accuracy; description ofresearch questions; methods used for participantselection, test execution and statistical analysis;results in terms of participant characteristics, timeinterval between tests, distribution of diseaseseverity, diagnostic outcomes and adverse effects;and discussion of the clinical applicability of studyfindings. With respect to the three studiesincluded in this review, the following were themost important problems with regard to quality ofreporting. None of the studies reported whetherresults of the index test were interpreted withoutknowledge of the results of the reference test, andvice versa. Only one reported test reliability anddescribed the number, training and expertise ofthe people performing and interpreting the indextest, but no description for the reference test,90,145

and only one considered the possible impact ofadverse effects of the tests in terms of the clinicalconsequences of false negative and false positiveresults.92 Two studies did not state the methodsused for selecting participants.90,92 None of thestudies stated whether treatment was delivered tothe wound between administration of tests, and inone study the time interval between tests was notstated.92 In two studies, no information wasprovided about when the study was done orrecruitment dates.90,91 Although there are clearlysome improvements that could have been made tothe reporting of all three studies, it is important toacknowledge that all three studies fulfilled manyof the items on the 25-item STARD checklist.158

Other systematic reviewsNo existing systematic reviews addressing thethree diagnostic research questions were identifiedfrom this project. As far as we can ascertain, thisproject is the first attempt at combining data fromstudies of clinical examination and microbiologicalsampling in DFUs. Two systematic reviews wereidentified in a related area, not within the scope ofthis project, the diagnosis of osteomyelitis.159,160

The earlier review evaluated the diagnosticaccuracy of technetium bone scanning fordetecting lower extremity osteomyelitis in patientswith diabetes, neuropathy or vasculopathy.159 The

more recent review assessed the diagnosticperformance of a variety of methods (includingimaging techniques, probe to bone and bonebiopsy) to identify osteomyelitis in patients with aDFU.160

Novel techniquesNo evaluations meeting the inclusion criteria wereidentified for the two novel techniques of woundinfection detection, the electronic nose/tongue andPCR. Should these techniques eventually prove tobe of value for management of infection in DFUs,they could potentially modify clinicians’ decision-making processes, owing to reducing the waitingtime for test results.

Recommendations from clinicalguidelines on DFUsA review of clinical guidelines on management ofdiabetic foot disease shows varyingrecommendations to inform clinicians about thebest ways of identifying infection in DFUs. Somesources recommend the use of clinicalexamination only, and suggest that cultures are oflimited value.76,78 Other documents suggest thatthere are problems with clinical examinationowing to the absence of many of the classical signsand symptoms of systematic or local infection indiabetic patients.79 However, swabs should only beused following debridement or curettage of theulcer bed.77,79 One recommendation is tocommence antibiotic therapy according to clinicalsigns and symptoms, then modify treatmentaccording to culture results.161

The uncertainty reflected by these varyingrecommendations perhaps reflects the paucity ofrelevant data, and supports our finding of threeeligible studies representing the true extent of theavailable evidence. Several other relevant clinicalguidelines do not contain any information aboutdiagnosis of infection in DFU, which again maycorrespond to the dearth of researchevidence.162–164

Adverse effects of diagnostic testsAs identified above with reference to the STARDchecklist,158 only one of the included studiesreported on possible adverse effects of the tests interms of the impact of false negative and falsepositive results.92 None of the studies investigatedthe possible psychological effects of false negativeand false positive results (e.g. anxiety) or theimpact of pain or discomfort associated withundergoing the tests. Even in the case of clinicalassessment of the wound, the patient may berequired to assume an uncomfortable position


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while the examination takes place. In addition, theacquisition of microbiological samples using tissuebiopsy or swab may be painful. Some swabbingtechniques require that sufficient pressure isapplied to the wound in order to express tissuefluid.91,92

A further related concern is whether the woundflora may be altered through the use of differentacquisition techniques, such as applying pressureto the wound surface using a swab. It is possiblethat transient and resident bacterial populationscould be differentially sampled using gentle oraggressive swabbing techniques. As far as we couldascertain, this aspect of microbiological samplinghas not been evaluated.

Effectiveness studiesLimitations of the research What impact does microbiological analysis haveon therapy?We did not find any studies evaluating the impactof microbiological analysis on the treatment ofinfection, pain, exudate, healing, HRQoL or thedevelopment of complications. It is possible thatin industrialised countries the availability ofmicrobiological testing means that this is routinelydone, and the opportunity to conduct a trial maybe minimal. In interviews with experts to informthe review (Appendix 7), it was stated that aculture and sensitivity result from a swab or biopsywould be necessary to adjust therapy if theempirically chosen therapy was inappropriate or ifthe infection failed to resolve. If there is noclinical improvement over a period of a few days,then the swab or biopsy results are consulted toguide the choice of antibiotic. It is not clear howuseful the results from a microbiological sampleare at this point. As the sample has been drawnfrom the wound prior to the commencement ofantibiotic therapy, the wound flora may havechanged. However, without rapid microbiologicalanalysis techniques the initial swab may be theonly source of information on the cause ofinfection, even if it is imperfect.

What are the effects of treatments on clinicaleffectiveness and cost-effectiveness?Our second effectiveness question addressed theclinical and cost-effectiveness of techniques fortreating infection in DFUs. Outcomes of interestwere infection resolution, amputation, healing andthe transfer of drug-resistant organisms to staffand other patients. Overall, the strength of theevidence to guide the selection of antimicrobial

agents for the treatment of diabetic foot ulcers ispoor. This is due to the poor quality of many ofthe trials and the lack of replication of mostcomparisons.

PopulationWhile the review aimed to summarise the effect ofinterventions for treating infection, it becameapparent that studies reported the ulcercharacteristics in a number of ways. Somedescribed infections associated with foot ulcers asulcer infection, some as soft tissue infection andothers as cellulitis. A number of trials includedmixed populations, either people with diabetesand ulcers or soft tissue infection but noulceration, or people with infected wounds, someof whom had diabetes and foot ulcers. Weincluded trials in which data for infected DFUswere available separately, or where at least 80% ofa population of people with infected wounds hadfoot ulcers and diabetes. A few studies evaluatedthe impact of antimicrobial agents in themanagement of apparently uninfected DFUs andthese were also included as the clinical diagnosisof ‘infected/uninfected’ may not be straightforwardin people with diabetes owing to suppression ofthe normal immunological response to infection.165

Some authors believe that a non-healing wound,even if apparently uninfected, may be delayed inhealing due to a ‘critical colonisation’ of thewound bed by a high bacterial load.166 Wetherefore decided to include all trials where anantimicrobial intervention was used, as this wouldreduce any chance of excluding studies in peoplewith delayed wound healing due to bacterial load.

Defining antimicrobial agents was straightforwardfor antibiotics, but not for other agents which actby direct ingestion of bacteria (larvae), or reducingosmotic potential for bacterial proliferation(sugar), as a number of different agents potentiallyredress the host–bacterial balance.167 We decidedto include an agent if it was a recognisedantimicrobial (antibiotics and antiseptics, forexample) or if the authors of the study stated whatantimicrobial action the agent possessed. Agentswere included in the review regardless of theirmode of administration or their current licensingstatus. With this definition in use we also includeda growth factor which increases neutrophil activity,and which is used in infected ulcers alongsidesystemic antibiotics.

Comparisons madeThe comparisons in the trials tended to be of twoactive interventions. Notable exceptions were thetrial comparing oral antibiotics with a placebo

Discussion

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tablet in 44 people with ‘uncomplicated’neuropathic foot ulcers (ulcer grade up to 2A),74

and the four growth factors trials, in whichplacebo or standard care alone were thecomparators.100,118–120 For people with a clinicaldiagnosis of established severe wound/footinfection, it is unlikely that a placebo or standardcare controlled trial could be performed asclinicians are convinced of the need to instituteimmediate antibiotic therapy (see Appendix 7)and delay, for example to culture the causativeorganisms, or a placebo treatment could threatenthe limb. It may be more feasible to conduct a trialcomparing antimicrobial agents againstplacebo/standard care alone in people without asevere infection. This would help inform whetherthere is a net benefit associated with antibiotictreatment in this group. Such studies, however,rely upon clinicians having access to reliabletechnologies to distinguish between people withsevere or non-severe infections. Interviews withclinicians indicated that decisions to treatempirically or adopt a watchful waiting approachalso depended on factors such as their confidencein the patient returning if the ulcer deteriorated,and the proximity to the weekend, whenimmediate access to the foot clinic is not possible(Appendix 7).

Study qualityWe assessed the quality of each trial and presentedthe Jadad scores for each characteristic separatelyas simple addition of the scores may bemisleading. Overall – the quality was poor –median score for double-blinding was 0 (i.e. trialwas not described as double-blind); median scorefor randomisation was 1 (i.e. trial was simplydescribed as randomised with no details aboutmethods used to achieve randomisation); medianscore for withdrawals was 1 (i.e. number ofwithdrawals was reported by groups and reason).Allocation concealment was scored as adequate,unclear or inadequate and the mode was ‘unclear’.Two trials described inadequate methods ofallocation.106,122 Two trials described adequatemethods of concealing the allocation from theperson randomising the participant into thetrial.100,101 Two trials allowed patients to selecttheir own treatment.110–112

From the information available, the trial thatscored the highest in terms of quality was anevaluation of subcutaneous growth factors,100 as itdescribed adequate randomisation procedures,allocation concealment, appropriate methods fordouble-blinding, and reported withdrawals bygroup and reason.

One study of systemic antibiotics, by Peterson andcolleagues,101 described allocation concealment,appropriate randomisation, described themselvesas double-blinded (but did not report how this wasachieved), and reported withdrawals by group andreason.

These two studies reported attempts to minimisebias but were too small to allow robust conclusionsto be drawn, hence we did not give themadditional weight in the narrative review.

Statistical powerMost trials (20/23) did not report a calculation,a priori, of the sample size required to be able todetect clinically important difference in outcomesas statistically significant. This means that theyhad a very high risk of concluding that there wasno difference in the effectiveness of thecomparator regimens when in reality there wasinsufficient power to be able to determine whetherthere was a difference or not (a Type II error). Forexample, Chantelau and colleagues concludedthat there was no benefit to the addition ofantibiotics for uncomplicated neuropathic ulcers,but the trial was too small (n = 44) to allow one toexclude a clinically important benefit.74

Baseline comparabilityA large, well-organised RCT with adequaterandomisation should distribute people with poorprognosis for healing/resolution of infectionequally between the treatment groups. It isdesirable, however, to present the characteristics ofthe people in the trial both to allow readers toassess the similarity of the trial participants totheir patient population and to provide these databy treatment groups to see if there were importantimbalances in baseline risk at the outset. In amodest-sized trial, this can happen purely bychance, and visual inspection of the results allowsone to see if there are imbalances. In addition, itcan point one to problems with the randomisationprocedure, for example if the people with moresevere disease tended to be allocated to onegroup, then one might investigate whether therandomisation schedule was subverted byclinicians trying to ensure that people with severedisease received the (in their opinion) ‘better’intervention. Margolis and colleagues undertookan analysis of the risk factor for healing diabeticneuropathic ulcers in 20 weeks and found that therisk factors for non-healing were increasedduration of ulceration, increased area of ulcerationand being Caucasian.168 The above characteristicsshould be reported as baseline characteristics intrials to allow one to determine if the samples


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were comparable at the outset for known factors.Any imbalances in the distribution of risk factorscan then be accounted for in an adjusted analysis.

No trials reported ulcer duration, ulcer area atbaseline and ethnicity by treatment groups. Fivetrials reported ulcer area,74,105,114,119 two trialsreported ulcer duration,75,100 and four trialsreported ethnicity.108,109,114 Other trials reportedbaseline characteristics such as duration ofdiabetes, arterial blood supply (reported as a ratioof ankle and brachial systolic blood pressure toankle brachial pressure to index, or ABPI), orWagner grade. These may inform external validitybut not be as important for determiningprognosis.

OutcomesOwing to the large number of different outcomesreported, it was considered inappropriate tosynthesise results. In addition, the definitions ofthe outcomes used, such as ‘clinical cure ofinfection’, were not specified. There appears to belittle agreement on what is the key outcomemeasure for assessing the effectiveness of anantimicrobial in the management of DFUs. Itcould be resolution of infection, healing of theulcer, prevention of amputation (all amputationsor only major amputations) or maintenance ofHRQoL. The relationship between resolution ofinfection, ulcer healing and the need foramputation is not completely understood so wecannot be confident that an intervention whichleads to quicker resolution of infection wouldnecessarily lead also to quicker healing and hencereduce the need for amputation. In designingclinical studies, there is a need to trade off theneed for an efficient use of trial resources and thedesire to have a lengthy follow-up period in orderto capture sufficient events of interest. However,for an outcome such as major amputation this maybe prohibitively expensive, hence commonerevents such as ‘resolution of infection’, healing orminor amputations may also be reported. A minoramputation may be considered as an outcome initself or as a part of the therapeutic armoury –removal of an ulcerated toe, for example, maylead to dramatic improvement in a patient’squality of life, compared with, for example,sustained non-weight bearing while the ulcer healsconservatively.

It is possible that an intervention could acceleratethe rate at which the infection appears ‘resolved’,but delay healing and increase the risk of majoramputation, for example, by keeping the ulceropen for longer. Having sufficient follow-up to

allow reporting all these outcomes would increaseour knowledge about the relationship betweeninfection, healing and amputation and increaseour confidence in the relevance of the trials thatonly reported resolution of infection or healing.

It is also possible that an intervention could leadto a higher healing rate but lead to reducedHRQoL in patients – for example, having dailyinjections of growth factors, or dressing changesmay be unacceptable for some patients owing totheir effect on their normal activities. No trialsreported the impact of these interventions onHRQoL.

Furthermore, an intervention might delay healingminimally compared with a comparator but reducethe chances of microbial resistance developing,e.g. MRSA, and therefore be desirable from asocietal perspective. It is not clear how these twoperspectives, the individual and the societal,should be weighed against each other.

A number of trials reported both ‘eradication ofpathogens’ and ‘clinical cure’ data. It may beinteresting to investigate the relationship betweenthese two outcomes and eventualhealing/amputation. If it were established thatthere was a known relationship between clinicalcure and amputation or healing outcomes, thentrials could be powered on this outcome and havefollow-up for the length of time needed to captureclinical resolution of infection. Only group-leveldata were available to us and therefore we couldnot do this. If clinical cure and eradication ofpathogens were congruent, then it may be possibleto reduce the number of bacteriology swabsrequested in clinical trials. If they are not inagreement, it would be interesting to see whetherthe false positive and false negative rate is relatedto the diabetes, due to sampling error or otherreasons.

There is some suggestion that people withdiabetes do not exhibit the same response toinfection as those without diabetes owing tochanges in the immune system, hence classicalsigns of clinical resolution of infection may not bea reliable indication for cure or for trial outcomemeasures.165

Applicability of the resultsThe majority of trials (17/23) had more men thanwomen taking part, in two trials there were nodata on the gender of participants, in one trialonly one woman was included101 and in threetrials there were no women participating.75,110–112

Discussion

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Margolis and colleagues did not find any differencein prognosis for healing of neuropathic ulcers withgender,168 but qualitative studies suggest that menand women adjust to life with a diabetic foot ulcerdifferently,169 and this may affect thegeneralisability of the results from these trials.

The majority of these trials reported that theyincluded people with neuropathic ulceration (n = 12),44,74,105,107,110–112,114,118,122,124,125 orspecified a minimum arterial blood supply (n = 4).100,106,109,119 Four trials43,75,108,123 did notprovide information on the proportion of peoplewith neuropathic, ischaemic or neuroischaemiculceration. Within trials where ulcer aetiologies areprovided, it is also important that the degree ofneuropathy or ischaemia is described so that therelevance of the findings to other patient groupscan be ascertained.

The patient characteristics may also affect theeffectiveness of the intervention. A trial ofantibiotics in people with neuropathic ulcerationmay not be applicable to patients in whom arterialsupply is limited, as the delivery of thisintervention relies upon sufficient arterial supplyto allow the antibiotics to penetrate the tissues at atherapeutic concentration.

The majority of studies were conducted oninpatients and only one study described outpatienttreatment of infected diabetic foot infection.75 Theother trials of antimicrobial agents in outpatientsincluded people without frank ulcer infection.

Trade-offs between the benefits, harmsand costs of the interventionAdministering antimicrobial agents may haveharms in addition to any anticipated benefits.From an individual perspective, the use ofantibiotics can lead to adverse effects rangingfrom relatively common stomach upsets/diarrhoeato rare and potentially fatal reactions.

From a community perspective, the administrationof antibiotics to people with DFUs needs to beweighed against the increasing use of antibioticsand the association to the spread of resistance toantibiotics, for example MRSA. The generalprinciple for reducing the spread of resistance isthat broad-spectrum antibiotics should be avoidedand therapy should be based on culture results.While clinical guidelines reinforce the approach ofprescribing antibiotics according to bacteriologyresults, they also mention the need for empiricaltherapy in limb-threatening infection. Waiting forlaboratory results is not always possible owing to

the potential consequences of delay for theinfection, such as amputation. Reserving antibiotictreatment for people with suspected severe ulcerinfection might help limit the growth of resistantorganisms. Developments in rapid diagnosis ofinfecting organisms, such as PCR or near-patienttesting techniques, may permit rapid diagnosis ofbacterial colonisation/infection, but we knownothing about their usefulness in wounds. Ifuseful, this may help reduce the use of broad-spectrum antibiotics, but if the most infections aretruly polymicrobial then they may still require abroad-spectrum antibiotic and therefore rapidassessment may change the therapeutic regimenin a proportion of patients.

In addition, the majority of the trials of antibioticsused a combination of two agents. It is not clearwhether using multiple agents is of added benefitover single agents in the patient group. Multipleagents might lead to net benefit if, for example,two narrower spectrum agents could be used tocover the most common pathogens (Staphylococcusaureus, Streptococcus spp., Pseudomonas aeruginosaand the anaerobes), but using more than one drugalso puts the patient at risk of more than one setof adverse events/reactions.

In some cases the intervention regimen was verycomplex, involving combinations of intravenous,oral and intramuscular therapies, e.g. in thestudies of Seidel and colleagues.110–112 In somecases there were a number of additional antibioticswhich could be added to the regimen underevaluation, as required, and the lack of objectivecriteria for the use of adjuvant therapies meansthat one cannot be confident that any differencein outcomes is due to the antibiotic under test.109

Costs of these treatments vary. The costs ofantimicrobial agents range from $1.44 to $104 perday,170 but the cost of the antimicrobial agents isusually minimal compared with the costs ofdelivering care such as hospitalisation and nurse’svisits or the costs of interventions such asamputation.

A number of expensive interventions such asgrowth factors and sterile medical larval therapyare relatively new and therefore there may be areduction in costs if more providers come on-stream, e.g. larval therapy costs around £55 perdose (only a few doses are usually needed).171

Growth factors such as G-CSF (filgrastim) cost£540 for 7 days.121 It is not clear if improvementsin the technology to produce these would lead to areduction in costs or whether licensing restrictions


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mean that these costs would be maintained. Twostudies had economic analyses alongside aneffectiveness trial and two additional studiesreported costs.121,124 Further cost-effectivenessstudies need to be run in parallel to effectivenesstrials in order to inform decision-makers of thecosts and benefits of the intervention on offer. Anexpensive intervention may be cost-effective if itreduces the time to healing, the rate ofamputation or the number of days inhospital/clinician visits.

One important advance in reducing the costs oftreatment of established infections could be inmoving the setting of care from hospital toprimary care. Until recently, all the antibioticsrecommended for use in the treatment of limb-threatening infections were administeredintravenously and therefore the patient washospitalised. The development of oral antibioticssuitable for this population might lead to morepeople being treated at home, thus reducing coststo the health service. Hospitalisation not onlyallows antibiotics to be administered intravenously,but also permits close monitoring of diabeticcontrol and ensuring that the patient remainsnon-weight bearing. Outpatient treatmenttherefore may not always be as effective or cost-effective if, for example, it is associated with slowerhealing or requires a different configuration ofservices to ensure close monitoring of progress. Inaddition, people with limb-threatening infectionmay be so unwell that hospitalisation is required.

Strengths and weaknesses of thereviewStrengths of the reviewThe review strengths include the extensiveelectronic search strategies developed to retrievecontrolled trials regardless of publication status,date or language of publication, and theexamination of bibliographies of systematic andnon-systematic reviews and all included studies toidentify additional citations. The wide-rangingsteering group, in terms of professionalbackground and geography, also may haveincreased our chances of identifying unpublished,ongoing or unindexed studies in the area.

Decisions to include or exclude studies were madeby two researchers independently and thenresolved by discussion. We have also set out thereasons for the exclusion of 20 diagnostic studies,140 effectiveness studies and 24 economic studiesin Appendix 6. Data extraction and quality

assessment were done by one person and checkedby a second. These steps sought to reduce error orbias in the review process.

We enlisted a large group of collaborators to peerreview the review protocol, with input from expertsin many disciplines and two people withexperience of diabetic foot ulceration. Thesteering group for the project also represents arange of disciplines and supported the reviewersthroughout.

Weaknesses of the review Weaknesses of the review process included beingunable to undertake handsearching of conferenceproceedings beyond those listed in Table 2(six conferences). Research into the treatment ofDFU infection is presented at conferencesorganised by vascular surgical societies, woundcare societies, diabetologists, podiatrists, clinicalmicrobiologists and experts in infection control.We were able to access only a small proportion ofconference proceedings from these cognate areasthrough our collaborators and may have missedabstracts from other conferences. However, theelectronic databases HELMIS and SIGLE alsoindex some conference proceedings and thereforeour searches will probably have reached otherrelevant conferences.

There may have been research conducted into theeffect of antimicrobial agents with funding fromcommercial concerns and these may not be in thepublic domain. Given the tendency for selectivereporting of research with ‘positive’ findings(publication bias), then it is possible that there areadditional studies published in abstract format orin journals which are unindexed by the databasesthat we used, or indeed not published at all. Whatwe know about publication bias leads us to suggestthat if we have missed other studies, then thesewould tend to be small studies with ‘negative’ orequivocal results.172

Our search for studies to answer the questionabout the effect of microbiological analysis wasconfined to RCTs or CCTs, and it is possible that controlled before and after studies could have been reported in this area. Locatingcontrolled before and after studies is notstraightforward, as the search filters to identifythem from electronic databases are less welldeveloped than for, for example, RCTs. Ourbibliography checking and contact with a largeexpert panel who were not aware of any suchstudies suggest that few, if any, controlled beforeand after studies exist.

Discussion

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Integration of this review withprevious workWe identified two previous systematic reviews ofintervention for diabetic foot ulceration98,99 andone of the authors led a previous systematic reviewin this area. The reviews by Mason andcolleagues99 and Kaltenthaler and colleagues98

included evaluation of systemic and topicalantimicrobial agents within their scope. Ourprevious review (by O’Meara and colleagues48)evaluated the impact of antimicrobial agents in thehealing of DFUs. In the current review we decidedto include studies if they reported any of thefollowing objective outcomes of interest:

� mortality� ulcer recurrence� incidence/type of amputation� number/duration hospital admissions for DFU

problems� incidence of osteomyelitis� bacterial profile of ulcer� pain� acquisition of resistant organisms� proportion of ulcers healing� relationship between ulcer healing and

bacteriology� time to complete healing� change in mobility� change in ulcer area� change in level of dependence/independence� healing rate� impact on HRQoL� change in ulcer depth or volume.

This is in contrast to the earlier review in whichonly studies which reported wound area/volume,time to healing, healing rate or proportion ofhealed outcomes were included, as we hoped thatwe would identify high-quality data on the effectof these interventions on outcomes that guideclinicians, such as resolution of infection, and toinvestigate the relationship between bacteriologyand healing. We found no such research.

Decision analytic modelWe were unable to identify data on the transitionprobabilities for our two populations of interest.These were people in whom a first course ofantibiotics had failed, and people with apparentlyuninfected ulcers being offered antimicrobialtherapy (presumably as the clinician suspects thatlack of progress towards ulcer healing is due to ahigh bacterial load). None of the existing models

provided transition probabilities for these twogroups as they were designed to evaluate theimpact of therapeutic interventions in either newlyinfected or uninfected populations. No trialsstated that they recruited people for whom a firstcourse of antibiotics had failed. A few trialsinvolved people with apparently clinicallyuninfected ulcers, but these trials did not reportclear criteria for the definition of recalcitrantulceration.

We identified in interviews with six experts thatpeople with clinically infected ulcers are almostinvariably treated with antibiotics without waitingfor the results of microbiological analysis andtherefore the results of a diagnostic test do notinform their therapy, unless they fail to respond.Similarly, patients whose ulcers appear uninfectedand are healing are not considered to requireantimicrobial therapy and are not subjected tomicrobiological analysis. The performance ofdiagnostic tests (following clinical assessment) isunlikely to inform the management of thesepatients unless they fail to heal. Trials ofantibiotics for clinically infected ulcers confirmedthat treatment was decided empirically rather thanafter receiving the results of a microbiological test.Our experts confirmed that this was due to thedanger of waiting for microbiological results andthe high risk of progressive infection which couldresult in amputation. Diagnostic tests appear to beused to guide therapy when a clinical assessmenthas indicated that the ulcer, although apparentlyuninfected, is failing to heal (determined by arange of criteria).

A number of substitute strategies were proposed inan attempt to inform the decision analytic model.The review of the literature indicated thatinformation regarding the populations of interestmight have been collected as part of some studies,and there may have been subgroups within thesestudies which could have provided data on the‘hard to heal’ ulcers. Although direct contact withthe principal investigators of studies reporting on‘hard to heal’ DFUs was considered as an option,we decided not to pursue this avenue as there wassufficient variation in the characterisation of a‘hard to heal’ DFU (from our clinician interviews)to suggest that not much would be gained if accessto the primary data was granted.

It is possible that non-comparative studies, such ascase series, may have described these populationsin sufficient detail to ascertain if individualsbelonged to either of the two target groups and toprovide some transition probabilities, but we were


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unable to search for case series within the staff andtime constraints of this project.

It can be argued that the existing evidenceprovided in the literature indirectly providesinformation about the two groups of patients thatwere identified as the target populations. Forexample, the probability of having an ulcer clear ofinfection after a second course of antibiotics mightbe a function of the probability of having an ulcerclear of infection after a first course of antibiotics

and the effectiveness associated with specificantibiotics in patients with an infected foot ulcer.This can be described as a network of evidence, i.e.information about the parameters of interest couldbe constructed as functions of estimates reported inthe literature. Statistical methods for synthesisingevidence could be used to estimate indirectly therequired parameters for the decision analyticmodel.173 However, the human resources and thetime required to conduct this type of analysis wereoutside the scope of this project.

Discussion

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Implications for clinical practiceThe available evidence is too weak to draw reliableimplications for practice. This means that, interms of diagnosis, we do not know how to identifyinfection reliably by clinical assessment, whichpatients need formal diagnostic testing forinfection, whether empirical treatment withantibiotics (before the results of diagnostic testsare available) leads to better outcomes and whatthe optimal methods of diagnostic testing are.With respect to treatment, we do not knowwhether treatment with systematic or localantibiotics leads to better outcomes, or whetherany particular agent is more effective. Limitedevidence suggests that both G-CSF and cadexomeriodine dressings are less expensive than ‘standardcare’, that A/S is a less costly treatment than I/C,and that an unlicensed cream (pexiganan) may beas effective as oral ofloxacin.

Implications for researchQuestions to be answered1. What characteristics of infection in people with

DFU influence healing and amputationoutcomes?

2. Does diagnosis of infection-producing bacteriaprior to treatment offer any benefit overempirical therapy?

3. If detecting infection-producing bacteria offersclinical benefit, then what are the most effectiveand cost-effective methods for detectinginfection, for example clinical assessment, woundswabbing or wound biopsy and microbiologicalanalysis, or novel techniques such as electronicnose/tongue, and PCR analysis?

4. What are the relative effectiveness and cost-effectiveness of antimicrobial interventions forDFU infection, for example combinations ofbroad-spectrum antibiotics, larval therapy,growth factors and topical agents/dressings?

Nature of the research� Research needs to have adequate sample sizes

and robust methods to minimise bias.� Future research should attempt to use ‘real-life’

methods as far as possible in order to improvethe clinical applicability of findings.

� Outcomes should include pain, quality of lifeand acceptability associated with diagnosticprocedures and interventions.

� Economic evaluations of diagnosis andantimicrobial agents should be undertaken,where possible, alongside primary studies. Theseshould be undertaken using appropriate methodsas determined by experts in health economics.

� Future research should include sufficient detailsof the quality of sample acquisition, laboratoryprocedures, concurrent therapies and outcomeassessment.

� Attention should be paid to the potential forthe development of resistant organismsassociated with the use of long-term, broad-spectrum antibiotics and the balance of societaland individual benefit.

� Future trials should report the baselinecharacteristics of both patients and theirwounds by study group and analysis shouldattempt to adjust for any imbalances inprognostic factors present at baseline.

Future trials need to be reported using CONSORTguidelines, and evaluations of diagnostic accuracyusing STARD guidelines.

Information regarding the following is required topopulate the decision analytic model:

� Incidence of DFU patients who have failed toheal after a first course of antibiotics and thosewho do not show any clinical symptoms ofinfection but whose ulcer is not healing (targetpopulation).

� Natural history of the target population.� Diabetic foot ulcer recurrences in target

population.� Healthcare resource use of target population in

the UK.� Quality of life scores for the target population.� Diagnostic performance of clinical assessments

and investigations in the target population.� Effects of different strategies or interventions

for the management of DFU infection in thetarget population.

A register including both patient- and ulcer-levelcharacteristics and foot ulcer and systemictreatments and outcomes may provide information


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Chapter 6

Conclusions

to populate the decision analytic model and serveto suggest fruitful areas of study in diagnosis,prognosis and therapeutics, in addition toproviding feedback on quality of care, but it is

unclear whether it would be simple to collect dataon these elements in a diabetic foot register or toextend data collection in existing general diabetesregisters.

Conclusions

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We would like to thank Dr Stephen Brealey(University of York) for help with the ROC

analysis and the expert advisory panel (seeAppendix 2) for advice and feedback throughout.

Contribution of the authorsE Andrea Nelson (Reader, health research)conceived the study, contributed to the protocoldevelopment, search strategy development andstudy selection. She carried out data extractionand methodological appraisal for some diagnosticstudies, all clinical effectiveness studies andeconomic evaluations and data analysis for theeffectiveness studies. She wrote the results sectionfor effectiveness studies and economic evaluationsand commented on all other sections. She was theoverall supervisor and is the guarantor for theproject. Susan O’Meara (Research Fellow,systematic reviews) contributed to the protocoldevelopment, search strategy development, studyselection for all sections of the project andupdating/maintenance of the bibliographicdatabase. She carried out data extraction andmethodological appraisal for all diagnostic studiesand some of the clinical effectiveness studies andeconomic evaluations and data analysis for thediagnostic studies. She wrote the followingsections: introduction, methods, results fordiagnostic studies and discussion. She read andoffered comments on the other sections. DawnCraig (Research Fellow, health economics) andCynthia Iglesias (Research Fellow, healtheconomics) performed the systematic review ofeconomic models and quality of life studies. Theywere also responsible for the construction of thedecision analytic model and the preparation of themanuscript describing the economic component of

the DASIDU project. C Iglesias (Research Fellow)reviewed the economic and utility evidence andworked on the draft of the economic section of thereport. Su Golder (Information Officer, literaturesearching) devised search strategies, carried outliterature searches and wrote part of themethodology and Appendix 1. Jane Dalton(Reviewer, systematic reviews) undertookhandsearching, assessed papers for inclusion andcontacted authors. She carried out data extractionand quality assessment of papers, data analysis anddrafting report section for effectiveness results. Shealso commented on the final version of the report.Karl Claxton (Senior Lecturer, health economics)provided expert advice on the construction of thedecision analytic model and commented onprevious versions of the economic section of thisreport. Sally Bell-Syer (Research Fellow, systematicreviews) contributed to the protocol developmentand search strategy development. She read andoffered comments on all sections of the report.Edward Jude (Consultant Physician, diabetes care)contributed to the analysis of clinical data andcommented on the draft report. ChristopherDowson (Professor, microbiology) contributed tothe protocol development, analysis andinterpretation of microbiological sections of thereport, and read and commented on the draftreport. Roger Gadsby (Senior Clinical Lecturer,primary care) contributed to the protocoldevelopment, interpretation of outcome data, andcommented on the draft report. Paul O’Hare(Honorary Senior Lecturer, medicine) contributedto the protocol and commented on the draft report.Janet Powell (Visiting Professor, vascular surgery)contributed to the development of the protocol,and the interpretation of the clinical data, and alsocommented on the final draft report.


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313. Steed DL, Goslen JB, Holloway GA, Malone JM,Bunt TJ, Webster MW. Randomized prospectivedouble-blind trial in healing chronic diabetic footulcers. Diabetes Care 1992;15:1598–604.

314. Storm AJ, Bouter KP, Diepersloot RJA, Banga JD,Beerens RG, Erkelens DW. Tissue concentrationsof an orally administered antibiotic in diabeticpatients with foot infections [6]. J AntimicrobChemother 1994;34:449–51.

315. Stromberg BV, Reines HD, Hunt P. Comparativeclinical study of sulbactam and ampicillin andclindamycin and tobramycin in infections of softtissues. Surg Gynecol Obstet 1986;162:575–8.

316. Sussman KE, Reiber G, Albert SF. The diabeticfoot problem – a failed system of health care?Diabetes Res Clin Pract Suppl 1992;17:1–8.

317. Tammelin A, Lindholm C, Hambraeus A. Chroniculcers and antibiotic treatment. J Wound Care1998;7:435–7.

318. Tan JS, File TM, Salstrom S-J. Timentin versusmoxalactam in the treatment of skin and softtissue infections. Am J Med 1985;79(Suppl 5B):130–3.

319. Tan JS, Friedman NM, Hazelton-Miller C,Flanagan JP, File TM Jr. Can aggressive treatmentof diabetic foot infections reduce the need forabove-ankle amputation? Clin Infect Dis1996;23:286–91.

320. Tannenbaum GA, Pomposelli FB Jr, Marcaccio EJ,Gibbons GW, Campbell DR, Freeman DV, et al.Safety of vein bypass grafting to the dorsal pedalartery in diabetic patients with foot infections.J Vasc Surg 1992;15:982–90.

321. Tassler H. Comparative efficacy and safety of oralfleroxacin and amoxicillin/clavulanate potassiumin skin and soft tissue infections. Am J Med1993;94(Suppl 3A):159–65.

322. Tassler H, Cullman W, Elhardt D. Therapy of softtissue infections with piperacillin/tazobactam.J Antimicrob Chemother 1993;31(Suppl A):105–12.

323. Temple ME, Nahata MC. Pharmacotherapy oflower limb diabetic ulcers. J Am Geriatr Soc2000;48:822–8.

324. van der Meer JW, Koopmans PP, Lutterman JA.Antibiotic therapy in diabetic foot infection. DiabetMed 1996;13:S48–51.

325. Vanscheidt W, Jost V, Wolna P, Lucker PW, MullerA, Theurer C, et al. Efficacy and safety of aButcher’s broom preparation (Ruscus aculeatus L.extract) compared to placebo in patients sufferingfrom chronic venous insufficiency.Arzneimittelforschung 2002;52:243–50.

326. Wheatley C, Shaw E. Audit protocol: part two:management of diabetic foot ulcers – the ‘at risk’foot. J Clin Governance 2001;9:157–62.

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References

86

Clinical effectiveness searchstrategiesInternal CRD administration databasesThe Database of Abstracts of Reviews ofEffectiveness (DARE) and the Health TechnologyAssessment (HTA) Database (searched: 12 November 2002)The Database of Abstracts of Reviews ofEffectiveness (DARE) and Health TechnologyAssessment (HTA) Database were searched via theNHS CRD’s internal administration databases.This provides more detailed and more up-to-dateversions of the databases than those on theCochrane Library or the Internet and includesadditional records to those in the public databases.The same search strategy was used for bothdatabases;

1. S (neuroisch?emic or isch?emic or diabetic orneuropathic)(3w)(foot or feet or ulcer$)

2. S (pedal or plantar or foot or feet orheel)(3w)(ulcer$ or septic or wound$)

3. S (foot or feet)(6w)diabet$4. S deep foot infection$5. S (crural or leg)(5w)ulcer$6. S (venous or stasis or varicos*)(5w)(leg or

ulcer$)7. S (lower extremit$ or lower limb$)(5w)(ulcer$

or wound$)8. S s1 or s2 or s3 or s4 or s5 or s6 or s7

This identified 154 DARE records and 20 HTArecords.

Internet databases(Allied And Complementary Medicine) AMED(1985–2002 November) (searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)

1. exp Acetic Acid/2. (acetic acid$ or acetate$ or acetamide$ or

acetoxyacetylaminofluorene$ orhydroxyacetylaminofluorene$ orallylisopropylacetamide$).ti,ab.

3. (idoacetamide$ or idoacetate$ or piracetam$or thioacetamide$ or gadolinium$ ortechnetium$ or dichoroacetate$ orfluoroacetate$ or iodoacetate$).ti,ab.

4. (foscarnet$ or thioglycolate$ or aceticanhydride$).ti,ab.

5. ((aminooxyacetic or edetic or egtazic oriodoacetic or nitrilotriacetic or pentetic orperacetic or phosphonoacetic or trichloroaceticor trifluoroacetic) adj acid$).ti,ab.

6. (therapeutic fungicide$ or antifungal agent$or antifungals).ti,ab.

7. (benzoate$ or butenafine$ or chlorquinaldol$or cyclosporine$ or dichlorophen$ orfluconazole$ or flucytosine$ or glycyrrhizicacid$ or hexetidine$ or itraconazole$ ormonensin$ or nifuratel$ orpentamidine$).ti,ab.

8. (co-amoxiclav$ or sodium benzoate$ orthimerosal$ or thiram$ or thymol$ ortolnaftate$ or tomatine$ or triacetin$ ortrimetrexate$).ti,ab.

9. (amoroldine$ or benzoic acid$ orclotrimazole$ or econazole$ or ketoconazole$or miconazole$ or nystatin$ or Salicylic acid$or sulconazole$ or terbinafine$ ortioconazole$ or undecenoate$).ti,ab.

10. (antiviral$ or anti viral$ or idoxuridine$).ti,ab.11. (acetylcysteine$ or acyclovir$ or amantadine$

or aphidicolin$ or aprotinin$ or brefeldin orbromodeoxyuridine$ or cytarabine$ ordeoxyglucose$ or dextran sulfate$).ti,ab.

12. (dideoxyadenosine$ or dideoxynucleoside$ ordihematoporphyrin ether$ or ditiocarb$ orfilipin$ or floxuridine$ or ganciclovir$ orinosine pranobex or interferon alfa$ orinterferon type$ or interferon beta orinterferon gamma or interferons).ti,ab.

13. (methisazone$ or phosphonoacetic acid$ orpoly a-u or poly i-c or pyran copolymer$ orribavirin$ or rimantadine$ or streptovaricin$or tenuazonic acid$ or tilorone$ ortrifluridine$ or tunicamycin$ orvidarabine$).ti,ab.

14. (bacitracin$ or povidone iodine$ orbetaisodona$ or polyvinylpyrrolidone iodine$or betadine$ or disadine$ or isodine$ or pvp-ior pharmadine$).ti,ab.

15. (cetyltrimethylammonium or cetrimide$ orcetrimonium).ti,ab.

16. (chlorate$ or cisplatin or hydrochloric acid$ orchloride$ or hypochlorous acid$ orhypochlorite$ or perchloric acid$ orruthenium red$).ti,ab.


87


Appendix 1

Search strategies

17. exp "Eosine Yellowish-(YS)"/18. (eusol or phenoxyethanol$ or dextranomer$

or framycetin sulphate$ or mandelic acid$ ortetrabromofluorescein$ or eosin or eosine orchlortetracycline$ or chloroxylenolsolution$).ti,ab.

19. (edinburgh adj university adj solution adj2lime).ti,ab.

20. (cyclandelate$ or vanilmandelic acid$).ti,ab.21. hexachloroph#ne$.ti,ab.22. (triclosan$ or polymyxin$ or

polynoxylin$).ti,ab.23. (silver adj2 dressing$).ti,ab.24. (gentian violet or crystal violet or methyl violet

or methylrosaniline chloride$ orhexamethylpararosanine chloride$).ti,ab.

25. (potassium permanganate$ or permanganicacid$ or potassium salt$).ti,ab.

26. (mupirocin$ or pseudomonic acid$ orbactroban$).ti,ab.

27. (neomycin$ or fradiomycin$ or neamin$).ti,ab.28. (benzyol peroxide$ or benzyol superoxide$ or

diphenylglyoxal superoxide$ orpanoxyl$).ti,ab.

29. exp Hydrogen Peroxide/30. (hydrogen peroxide$ or hydroperoxide$ or

oxydol$ or perhydrol$ or superoxol$ ordiphenylglyoxal superoxide$ orpanoxyl$).ti,ab.

31. (fucithalmic$ or fusidate$ or fusidin$ orstanicide$).ti,ab.

32. (liposome$ adj hydrogel$).ti,ab.33. (fusidic acid$ or inadine$ or betadine$).ti,ab.34. (cadexomer iodine$ or chlorhexidine$ or

novalsan$ or sebidin$ or tubulicid$).ti,ab.35. exp Larva/36. (maggot$ or larva or larvae or larval).ti,ab.37. exp Complementary Therapies/38. (plant extract$ or aromatherap$ or marigold

extract$ or calendula officinalis or tagetespatula or rubia cordifolia or manjishtha orwithania somnifera or ashvagandha).ti,ab.

39. exp Plant Extracts/40. exp Plants, Medicinal/41. (phytotherapy or cascara$ or curare$ or

chinese herb$ or guaiac$ or ipecac$ orpodophyll$ or psyllium$ or senna extract$ ortragacanth$ or turpentine$).ti,ab.

42. exp oils, volatile/ or exp plant oils/43. exp Sucrose/44. exp HONEY/45. (essential oil$ or plant oil$ or tea tree or

lavender or chamomile or camomile orrosemary).ti,ab.

46. (sucrose or sugar paste$ or granulatedsugar).ti,ab.

47. exp Propolis/

48. (propolis or honey or beebread$ or bee bread$or bee glue$).ti,ab.

49. exp Antiviral Agents/50. (disinfect$ or antisept$ or anti-sept$ or

antiviral$ or anti-viral$).ti,ab.51. ((neuroisch?emic or isch?emic or diabetic or

neuropathic) adj3 (foot or feet or ulcer$)).ti,ab.52. ((pedal or plantar or foot or feet or heel) adj3

(ulcer$ or septic or wound$)).ti,ab.53. ((foot or feet) adj6 diabet$).ti,ab.54. deep foot infection$.ti,ab.55. exp Foot Ulcer/56. or/51-5557. Leg Ulcer/58. Varicose Ulcer/59. ((crural or leg) adj5 ulcer$).ti,ab.60. ((venous or stasis or varicos$) adj5 (leg or

ulcer$)).ti,ab.61. ((venous or stasis or leg) adj5 wound$).ti.62. ((lower extremit$ or lower limb$) adj5 (ulcer$

or wound$)).ti,ab.63. or/57-6264. 56 or 6365. (penicillin$ or amdinocillin$ or amox#cillin$

or ampicillin$ or azlocillin$).ti,ab.66. (carbenicillin$ or carfecillin$ or cloxacillin$ or

dicloxacillin$ or floxacillin$ or flucloxacillin$or methicillin$ or mazlocillin$ or nafcillin$ oroxacillin$ or penicillanic acid$).ti,ab.

67. (penicillic acid$ or phenoxymethylpenicillin$or piperacillin$ or pivampicillin$ orsulbencillin$ or talampicillin$ or sultamicillin$or ticarcillin$ or ticercillin$).ti,ab.

68. (cefaclor$ or cefadroxil$ or cefalexin$ orcefazolin$ or cefamandole$ or cefixime$ orcefotaxime$ or cefoxitin$ or cefpirome$ orcefpodoxime$ or cefprozil$).ti,ab.

69. (cefradine$ or ceftazidime$ or ceftizoxime$ orceftriaxone$ or cefuroxime$).ti,ab.

70. (cefonicid$ or cefmenoxine$ or cefoperazone$or cefotiam$ or cefsulodin$ or cephacetrile$or cephalexin$ or cephaloglycin$ orcephaloridine or cephalosporanic acid$ orcephalothin$ or cephapirin$ orcephradine$).ti,ab.

71. (beta lactam$ or aztreonam$ or cilastin$ orimipenem$ or meropenem$ or sulbactam$ ortazobactam$).ti,ab.

72. (caprolactam$ or clavulan$ ormoxalactam$).ti,ab.

73. (Aminoglycoside$ or anthracycline$ oraclarubicin$ or daunorubicin$ or carubicin$ ordoxorubicin$ or epirubicin$ or idarubicin$ ornogalamycin$ or menogaril$ orplicamycin$).ti,ab.

74. (gentamicin$ or neomycin$ or netilmicin$ ortobramycin$).ti,ab.

Appendix 1

88

75. (amphotericin$ or antimycin$ or candicidin$or roxithromycin$ or josamycin$ orleucomycin$ or kitasamycin$ or lucensomycin$or maytansine$ or mepartricin$ ormiocamycin$).ti,ab.

76. (natamycin$ or oleandomycin$ ortroleandomycin$ or oligomycin$ orrutamycin$ or sirolimus$ or tacrolimus$ ortylosin$ or propiolactone$ or spironolactone$or venturicidin$ or zearalenone$ orzeranol$).ti,ab.

77. (azithromycin$ or clarithromycin$ orerythromycin$ or spiramycin$).ti,ab.

78. (moxifloxacin$ or quinolone$ orciprofloxacin$ or clinafloxacin$ orfluoroquinolone$ or levofloxacin$ orofloxacin$).ti,ab.

79. (fleroxacin$ or enoxacin$ or norfloxacin$ orpefloxacin$ or nalidixic acid$ or nedocromil$or oxolinic acid$ or quinpirole$ or quipazine$or saquinavir$).ti,ab.

80. (dmso or sulfoxide$ or sulphoxide$ orsulfonamide$ or sulphonamide$ ortrimethoprim$ or sulfamethoxazole$ orsulphamethoxazole$ or co-trimoxazole$ orsulfadiazine$ or sulphadiazine$ orsulfametopyrazine$ or sulfalene$ orsulphametopyrazine$ or sulphalene$).ti,ab.

81. (benzolamide$ or bumetanide$ orchloramine$ or chlorthalidone$ or clopamide$ or dichlorphenamide$ orethoxzolamide$ or indapamide$ or mafenide$or mefruside$ or metolazone$ or prodenecid$or sulfanilamide$ or sulphanilamide$ orfurosemide$ or sulfacetamide$ orsulphacetamide$).ti,ab.

82. (sulfachlorpyridazine$ or sulfadimethoxine$or sulfadoxine$ or sulfaguanidine$ orsulfamerazine$ or sulfameter$ orsulfamethazine$ or sulfamethoxypyridazine$or sulphachlorpyridazine$ orsulphadimethoxine$ or sulphadoxine$ orsulphaguanidine$ or sulphamerazine$ orsulphameter$ or sulphamethazine$ orsulphamethoxypyridazine$).ti,ab.

83. (sulfamonomethoxine$ or sulfamoxole$ orsulfaphenazole$ or sulfapyridine$ orsulfaquinoxaline$ or sulfathiazole$ orsulfamethizole$ or sulfisomidine$ orsulfisoxazole$ or sulfasalazine$ orsumatriptan$ or xipamide$ or thioamide$ orthioacetamide$ or sulphamonomethoxine$ orsulphamoxole$ or sulphaphenazole$ orsulphapyridine$ or sulphaquinoxaline$ orsulphathiazole$ or sulphamethizole$ orsulphisomidine$ or sulphisoxazole$ orsulphasalazine$).ti,ab.

84. (tetracycline$ or demeclocycline$ ordoxycycline$ or lymecycline$ or minocycline$or oxytetracycline$).ti,ab.

85. (chlortetracycline$ or methacycline$ orrolitetracycline$).ti,ab.

86. (cloranfenicol$ or chloramphenicol$).ti,ab.87. (thiamphenicol$ or kloramfenikol$ or

levomycetin$ or chlornitromycin$ orchlorocid$ or chloromycetin$ or detreomycin$ or ophthochlor$ orsyntomycin$).ti,ab.

88. (clindamycin$ or dalacin c or cleocin$ orchlo?lincocin$).ti,ab.

89. (linezolid$ or trivazol$ or vagilen$ or clont$ ordanizol$ or fagyl$ or ginefavir$ or metrogel$or metrodzhil$ or satric$ or trichazol$ ortrichopol$).ti,ab.

90. (granulocyte colony stimulating factor or gcsfor ozone).ti,ab.

91. (fusidate$ adj (sodium or silver)).ti,ab.92. (antibiotic$ or antimicrobial$).ti,ab.93. (griseofulvin or synercid or dalfopristin or

quinupristin).ti,ab.94. exp Complementary medicine/95. exp antiinfective agents/96. or/1-5097. or/65-9598. 64 and (96 or 97)

This identified 49 records.

British Nursing Index (BNI) (1994–2002 August)(searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)

1. (clinical trial$ or random$ or placebo$ orcontrol or controls or controlled).mp.

2. (single blind$ or double blind$ or trebl$blind$ or tripl$ blind$).mp.

3. (meta-analys$ or meta analys$ or comparisongroup or standard treatment$ or systematicreview$).mp.

4. (acetic acid$ or acetate$ or acetamide$ oracetoxyacetylaminofluorene$ orhydroxyacetylaminofluorene$ orallylisopropylacetamide$).mp.

5. (idoacetamide$ or idoacetate$ or piracetam$or thioacetamide$ or gadolinium$ ortechnetium$ or dichoroacetate$ orfluoroacetate$ or iodoacetate$).mp.

6. (foscarnet$ or thioglycolate$ or aceticanhydride$).mp.

7. ((aminooxyacetic or edetic or egtazic oriodoacetic or nitrilotriacetic or pentetic orperacetic or phosphonoacetic or trichloroaceticor trifluoroacetic) adj acid$).mp.

8. (therapeutic fungicide$ or antifungal agent$or antifungals).mp.


89


9. (benzoate$ or butenafine$ or chlorquinaldol$or cyclosporine$ or dichlorophen$ orfluconazole$ or flucytosine$ or glycyrrhizicacid$ or hexetidine$ or itraconazole$ ormonensin$ or nifuratel$ or pentamidine$).mp.

10. (co-amoxiclav$ or sodium benzoate$ orthimerosal$ or thiram$ or thymol$ ortolnaftate$ or tomatine$ or triacetin$ ortrimetrexate$).mp.

11. (amoroldine$ or benzoic acid$ orclotrimazole$ or econazole$ or ketoconazole$or miconazole$ or nystatin$ or Salicylic acid$or sulconazole$ or terbinafine$ ortioconazole$ or undecenoate$).mp.

12. (antiviral$ or anti viral$ or idoxuridine$).mp.13. (acetylcysteine$ or acyclovir$ or

amantadine$ or aphidicolin$ or aprotinin$ orbrefeldin or bromodeoxyuridine$ orcytarabine$ or deoxyglucose$ or dextransulfate$).mp.

14. (dideoxyadenosine$ or dideoxynucleoside$ ordihematoporphyrin ether$ or ditiocarb$ orfilipin$ or floxuridine$ or ganciclovir$ orinosine pranobex or interferon alfa$ orinterferon type$ or interferon beta orinterferon gamma or interferons).mp.

15. (methisazone$ or phosphonoacetic acid$ orpoly a-u or poly i-c or pyran copolymer$ orribavirin$ or rimantadine$ or streptovaricin$or tenuazonic acid$ or tilorone$ ortrifluridine$ or tunicamycin$ orvidarabine$).mp.

16. (bacitracin$ or povidone iodine$ orbetaisodona$ or polyvinylpyrrolidone iodine$or betadine$ or disadine$ or isodine$ or pvp-ior pharmadine$).mp.

17. (cetyltrimethylammonium or cetrimide$ orcetrimonium).mp.

18. (chlorate$ or cisplatin or hydrochloric acid$ orchloride$ or hypochlorous acid$ orhypochlorite$ or perchloric acid$ orruthenium red$).mp.

19. (eusol or phenoxyethanol$ or dextranomer$or framycetin sulphate$ or mandelic acid$ ortetrabromofluorescein$ or eosin or eosine orchlortetracycline$ or chloroxylenolsolution$).mp.

20. (edinburgh adj university adj solution adj2lime).mp.

21. (cyclandelate$ or vanilmandelic acid$).mp.22. hexachloroph#ne$.mp.23. (triclosan$ or polymyxin$ or

polynoxylin$).mp.24. (silver adj2 dressing$).mp.25. (gentian violet or crystal violet or methyl violet

or methylrosaniline chloride$ orhexamethylpararosanine chloride$).mp.

26. (potassium permanganate$ or permanganicacid$ or potassium salt$).mp.

27. (mupirocin$ or pseudomonic acid$ orbactroban$).mp.

28. (neomycin$ or fradiomycin$ or neamin$).mp.29. (benzyol peroxide$ or benzyol superoxide$ or

diphenylglyoxal superoxide$ or panoxyl$).mp.30. (hydrogen peroxide$ or hydroperoxide$ or

oxydol$ or perhydrol$ or superoxol$ ordiphenylglyoxal superoxide$ or panoxyl$).mp.

31. (fucithalmic$ or fusidate$ or fusidin$ orstanicide$).mp.

32. (liposome$ adj hydrogel$).mp.33. (fusidic acid$ or inadine$ or betadine$).mp.34. (cadexomer iodine$ or chlorhexidine$ or

novalsan$ or sebidin$ or tubulicid$).mp.35. exp Larva/36. (maggot$ or larva or larvae or larval).mp.37. exp alternative medicine/38. (plant extract$ or aromatherap$ or marigold

extract$ or calendula officinalis or tagetespatula or rubia cordifolia or manjishtha orwithania somnifera or ashvagandha).mp.

39. (phytotherapy or cascara$ or curare$ orchinese herb$ or guaiac$ or ipecac$ orpodophyll$ or psyllium$ or senna extract$ ortragacanth$ or turpentine$).mp.

40. (essential oil$ or plant oil$ or tea tree orlavender or chamomile or camomile orrosemary).mp.

41. (sucrose or sugar paste$ or granulatedsugar).mp.

42. (propolis or honey or beebread$ or bee bread$or bee glue$).mp.

43. (disinfect$ or antisept$ or anti-sept$ orantiviral$ or anti-viral$).mp.

44. ((neuroisch?emic or isch?emic or diabetic orneuropathic) adj3 (foot or feet or ulcer$)).mp.

45. ((pedal or plantar or foot or feet or heel) adj3(ulcer$ or septic or wound$)).mp.

46. ((foot or feet) adj6 diabet$).mp.47. deep foot infection$.mp.48. Leg Ulcer/49. ((crural or leg) adj5 ulcer$).mp.50. ((venous or stasis or varicos$) adj5 (leg or

ulcer$)).mp.51. ((venous or stasis or leg) adj5 wound$).mp.52. ((lower extremit$ or lower limb$) adj5 (ulcer$

or wound$)).mp.53. (penicillin$ or amdinocillin$ or amox#cillin$

or ampicillin$ or azlocillin$).mp.54. (carbenicillin$ or carfecillin$ or cloxacillin$ or

dicloxacillin$ or floxacillin$ or flucloxacillin$or methicillin$ or mazlocillin$ or nafcillin$ oroxacillin$ or penicillanic acid$).mp.

55. (penicillic acid$ or phenoxymethylpenicillin$or piperacillin$ or pivampicillin$ or

Appendix 1

90

sulbencillin$ or talampicillin$ or sultamicillin$or ticarcillin$ or ticercillin$).mp.

56. (cefaclor$ or cefadroxil$ or cefalexin$ orcefazolin$ or cefamandole$ or cefixime$ orcefotaxime$ or cefoxitin$ or cefpirome$ orcefpodoxime$ or cefprozil$).mp.

57. (cefradine$ or ceftazidime$ or ceftizoxime$ orceftriaxone$ or cefuroxime$).mp.

58. (cefonicid$ or cefmenoxine$ or cefoperazone$or cefotiam$ or cefsulodin$ or cephacetrile$or cephalexin$ or cephaloglycin$ orcephaloridine or cephalosporanic acid$ orcephalothin$ or cephapirin$ orcephradine$).mp.

59. (beta lactam$ or aztreonam$ or cilastin$ orimipenem$ or meropenem$ or sulbactam$ ortazobactam$).mp.

60. (caprolactam$ or clavulan$ ormoxalactam$).mp.

61. (Aminoglycoside$ or anthracycline$ oraclarubicin$ or daunorubicin$ or carubicin$ ordoxorubicin$ or epirubicin$ or idarubicin$ ornogalamycin$ or menogaril$ orplicamycin$).mp.

62. (gentamicin$ or neomycin$ or netilmicin$ ortobramycin$).mp.

63. exp Macrolide/64. (amphotericin$ or antimycin$ or candicidin or

roxithromycin$ or josamycin$ or leucomycin$or kitasamycin$ or lucensomycin$ ormaytansine$ or mepartricin$ ormiocamycin$).mp.

65. (natamycin$ or oleandomycin$ ortroleandomycin$ or oligomycin$ orrutamycin$ or sirolimus$ or tacrolimus$ ortylosin$ or propiolactone$ or spironolactone$or venturicidin$ or zearalenone$ orzeranol$).mp.

66. (azithromycin$ or clarithromycin$ orerythromycin$ or spiramycin$).mp.

67. (moxifloxacin$ or quinolone$ orciprofloxacin$ or clinafloxacin$ orfluoroquinolone$ or levofloxacin$ orofloxacin$).mp.

68. (fleroxacin$ or enoxacin$ or norfloxacin$ orpefloxacin$ or nalidixic acid$ or nedocromil$or oxolinic acid$ or quinpirole$ or quipazine$or saquinavir$).mp.

69. (dmso or sulfoxide$ or sulphoxide$ orsulfonamide$ or sulphonamide$ ortrimethoprim$ or sulfamethoxazole$ orsulphamethoxazole$ or co-trimoxazole$ orsulfadiazine$ or sulphadiazine$ orsulfametopyrazine$ or sulfalene$ orsulphametopyrazine$ or sulphalene$).mp.

70. (benzolamide$ or bumetanide$ orchloramine$ or chlorthalidone$ or clopamide$

or dichlorphenamide$ or ethoxzolamide$ orindapamide$ or mafenide$ or mefruside$ ormetolazone$ or prodenecid$ or sulfanilamide$or sulphanilamide$ or furosemide$ orsulfacetamide$ or sulphacetamide$).mp.

71. (sulfachlorpyridazine$ or sulfadimethoxine$or sulfadoxine$ or sulfaguanidine$ orsulfamerazine$ or sulfameter$ orsulfamethazine$ or sulfamethoxypyridazine$or sulphachlorpyridazine$ orsulphadimethoxine$ or sulphadoxine$ orsulphaguanidine$ or sulphamerazine$ orsulphameter$ or sulphamethazine$ orsulphamethoxypyridazine$).mp.

72. (sulfamonomethoxine$ or sulfamoxole$ orsulfaphenazole$ or sulfapyridine$ orsulfaquinoxaline$ or sulfathiazole$ orsulfamethizole$ or sulfisomidine$ orsulfisoxazole$ or sulfasalazine$ orsumatriptan$ or xipamide$ or thioamide$ orthioacetamide$ or sulphamonomethoxine$ orsulphamoxole$ or sulphaphenazole$ orsulphapyridine$ or sulphaquinoxaline$ orsulphathiazole$ or sulphamethizole$ orsulphisomidine$ or sulphisoxazole$ orsulphasalazine$).mp.

73. (tetracycline$ or demeclocycline$ ordoxycycline$ or lymecycline$ or minocycline$or oxytetracycline$).mp.

74. (chlortetracycline$ or methacycline$ orrolitetracycline$).mp.

75. (cloranfenicol$ or chloramphenicol$).mp.76. (thiamphenicol$ or kloramfenikol$ or

levomycetin$ or chlornitromycin$ orchlorocid$ or chloromycetin$ or detreomycin$or ophthochlor$ or syntomycin$).mp.

77. (clindamycin$ or dalacin c or cleocin$ orchlo?lincocin$).mp.

78. (linezolid$ or trivazol$ or vagilen$ or clont$ ordanizol$ or fagyl$ or ginefavir$ or metrogel$or metrodzhil$ or satric$ or trichazol$ ortrichopol$).mp.

79. (granulocyte colony stimulating factor or gcsfor ozone).mp.

80. (fusidate$ adj (sodium or silver)).mp.81. (antibiotic$ or antimicrobial$).mp.82. (griseofulvin or synercid or dalfopristin or

quinupristin).mp.83. exp microbiology/84. exp Drug Therapy/85. or/4-4386. (or/4-43) or (or/53-84)87. or/44-5288. or/1-389. (87 and 86) or (87 and 88)



91


CINAHL (1982–2002 October, week 4) (searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)

1. exp clinical trials/ or random assignment/ orplacebos/ or meta analysis/ or exp prospectivestudies/

2. systematic review/ or comparative studies/ orclinical trial.pt. or review.pt. or systematicreview.pt.

3. (clinical adj trial$).ti,ab.4. ((singl$ or doubl$ or trebl$ or tripl$) adj

blind$).ti,ab.5. (control or controls or controlled or

controlling or metaanalys$).ti,ab.6. (meta adj analys$).ti,ab.7. (random$ or prospective$ or (comparison

adj group$) or (standard adjtreatment$)).ti,ab.

8. (placebo$ or (systematic adj review$)).ti,ab.9. or/1-8

10. exp Acetic Acid/11. (acetic acid$ or acetate$ or acetamide$ or




14. ((aminooxyacetic or edetic or egtazic oriodoacetic or nitrilotriacetic or pentetic orperacetic or phosphonoacetic ortrichloroacetic or trifluoroacetic) adjacid$).ti,ab.





19. (antiviral$ or anti viral$ oridoxuridine$).ti,ab.

20. (acetylcysteine$ or acyclovir$ or amantadine$or aphidicolin$ or aprotinin$ or brefeldin or

bromodeoxyuridine$ or cytarabine$ ordeoxyglucose$ or dextran sulfate$).ti,ab.

21. (dideoxyadenosine$ or dideoxynucleoside$or dihematoporphyrin ether$ or ditiocarb$or filipin$ or floxuridine$ or ganciclovir$ orinosine pranobex or interferon alfa$ orinterferon type$ or interferon beta orinterferon gamma or interferons).ti,ab.


23. exp BACITRACIN/24. (bacitracin$ or povidone iodine$ or

betaisodona$ or polyvinylpyrrolidone iodine$or betadine$ or disadine$ or isodine$ or pvp-i or pharmadine$).ti,ab.

25. (cetyltrimethylammonium or cetrimide$ orcetrimonium).ti,ab.

26. exp Chloride Compounds/27. (chlorate$ or cisplatin or hydrochloric acid$

or chloride$ or hypochlorous acid$ orhypochlorite$ or perchloric acid$ orruthenium red$).ti,ab.

28. (eusol or phenoxyethanol$ or dextranomer$or framycetin sulphate$ or mandelic acid$ ortetrabromofluorescein$ or eosin or eosine orchlortetracycline$ or chloroxylenolsolution$).ti,ab.


30. (cyclandelate$ or vanilmandelic acid$).ti,ab.31. hexachloroph#ne$.ti,ab.32. (triclosan$ or polymyxin$ or

polynoxylin$).ti,ab.33. (silver adj2 dressing$).ti,ab.34. (gentian violet or crystal violet or methyl

violet or methylrosaniline chloride$ orhexamethylpararosanine chloride$).ti,ab.

35. (potassium permanganate$ or permanganicacid$ or potassium salt$).ti,ab.

36. exp Mupirocin/37. (mupirocin$ or pseudomonic acid$ or

bactroban$).ti,ab.38. exp Neomycin/39. (neomycin$ or fradiomycin$ or

neamin$).ti,ab.40. (benzyol peroxide$ or benzyol superoxide$

or diphenylglyoxal superoxide$ orpanoxyl$).ti,ab.



Appendix 1

92


44. (liposome$ adj hydrogel$).ti,ab.45. (fusidic acid$ or inadine$ or betadine$).ti,ab.46. (cadexomer iodine$ or chlorhexidine$ or

novalsan$ or sebidin$ or tubulicid$).ti,ab.47. exp Larva/48. (maggot$ or larva or larvae or larval).ti,ab.49. exp alternative Therapies/50. (plant extract$ or aromatherap$ or

marigold extract$ or calendula officinalis ortagetes patula or rubia cordifolia ormanjishtha or withania somnifera orashvagandha).ti,ab.



54. exp plant oils/55. exp Sucrose/56. exp HONEY/57. (essential oil$ or plant oil$ or tea tree or



59. (propolis or honey or beebread$ or beebread$ or bee glue$).ti,ab.

60. exp Anti-Infective Agents/61. (disinfect$ or antisept$ or anti-sept$ or


neuropathic) adj3 (foot or feet orulcer$)).ti,ab.

63. ((pedal or plantar or foot or feet or heel)adj3 (ulcer$ or septic or wound$)).ti,ab.

64. ((foot or feet) adj6 diabet$).ti,ab.65. deep foot infection$.ti,ab.66. exp Foot Ulcer/67. or/62-6668. Leg Ulcer/69. venous Ulcer/70. ((crural or leg) adj5 ulcer$).ti,ab.71. ((venous or stasis or varicos$) adj5 (leg or


or wound$)).ti,ab.74. or/68-7375. 67 or 7476. (penicillin$ or amdinocillin$ or amox#cillin$

or ampicillin$ or azlocillin$).ti,ab.77. (carbenicillin$ or carfecillin$ or cloxacillin$

or dicloxacillin$ or floxacillin$ orflucloxacillin$ or methicillin$ or mazlocillin$

or nafcillin$ or oxacillin$ or penicillanicacid$).ti,ab.

78. (penicillic acid$ or phenoxymethylpenicillin$or piperacillin$ or pivampicillin$ orsulbencillin$ or talampicillin$ orsultamicillin$ or ticarcillin$ orticercillin$).ti,ab.

79. (cefaclor$ or cefadroxil$ or cefalexin$ orcefazolin$ or cefamandole$ or cefixime$ orcefotaxime$ or cefoxitin$ or cefpirome$ orcefpodoxime$ or cefprozil$).ti,ab.

80. (cefradine$ or ceftazidime$ or ceftizoxime$or ceftriaxone$ or cefuroxime$).ti,ab.

81. (cefonicid$ or cefmenoxine$ orcefoperazone$ or cefotiam$ or cefsulodin$ orcephacetrile$ or cephalexin$ orcephaloglycin$ or cephaloridine orcephalosporanic acid$ or cephalothin$ orcephapirin$ or cephradine$).ti,ab.

82. (beta lactam$ or aztreonam$ or cilastin$ orimipenem$ or meropenem$ or sulbactam$ ortazobactam$).ti,ab.


84. exp Aminoglycosides/85. (Aminoglycoside$ or anthracycline$ or

aclarubicin$ or daunorubicin$ or carubicin$or doxorubicin$ or epirubicin$ oridarubicin$ or nogalamycin$ or menogaril$or plicamycin$).ti,ab.


87. (amphotericin$ or antimycin$ or candicidin$or roxithromycin$ or josamycin$ orleucomycin$ or kitasamycin$ orlucensomycin$ or maytansine$ ormepartricin$ or miocamycin$).ti,ab.



90. (moxifloxacin$ or quinolone$ orciprofloxacin$ or clinafloxacin$ orfluoroquinolone$ or levofloxacin$ orofloxacin$).ti,ab.

91. (fleroxacin$ or enoxacin$ or norfloxacin$ orpefloxacin$ or nalidixic acid$ or nedocromil$or oxolinic acid$ or quinpirole$ orquipazine$ or saquinavir$).ti,ab.

92. exp Trimethoprim/93. (dmso or sulfoxide$ or sulphoxide$ or

sulfonamide$ or sulphonamide$ ortrimethoprim$ or sulfamethoxazole$ or


93


sulphamethoxazole$ or co-trimoxazole$ orsulfadiazine$ or sulphadiazine$ orsulfametopyrazine$ or sulfalene$ orsulphametopyrazine$ or sulphalene$).ti,ab.

94. (benzolamide$ or bumetanide$ orchloramine$ or chlorthalidone$ orclopamide$ or dichlorphenamide$ orethoxzolamide$ or indapamide$ ormafenide$ or mefruside$ or metolazone$ orprodenecid$ or sulfanilamide$ orsulphanilamide$ or furosemide$ orsulfacetamide$ or sulphacetamide$).ti,ab.


96. (sulfamonomethoxine$ or sulfamoxole$ orsulfaphenazole$ or sulfapyridine$ orsulfaquinoxaline$ or sulfathiazole$ orsulfamethizole$ or sulfisomidine$ orsulfisoxazole$ or sulfasalazine$ orsumatriptan$ or xipamide$ or thioamide$ orthioacetamide$ or sulphamonomethoxine$or sulphamoxole$ or sulphaphenazole$ orsulphapyridine$ or sulphaquinoxaline$ orsulphathiazole$ or sulphamethizole$ orsulphisomidine$ or sulphisoxazole$ orsulphasalazine$).ti,ab.

97. (tetracycline$ or demeclocycline$ ordoxycycline$ or lymecycline$ or minocycline$or oxytetracycline$).ti,ab.


99. (cloranfenicol$ or chloramphenicol$).ti,ab.100. (thiamphenicol$ or kloramfenikol$ or

levomycetin$ or chlornitromycin$ orchlorocid$ or chloromycetin$ ordetreomycin$ or ophthochlor$ orsyntomycin$).ti,ab.

101. (clindamycin$ or dalacin c or cleocin$ orchlo?lincocin$).ti,ab.

102. exp Metronidazole/103. (linezolid$ or trivazol$ or vagilen$ or clont$

or danizol$ or fagyl$ or ginefavir$ ormetrogel$ or metrodzhil$ or satric$ ortrichazol$ or trichopol$).ti,ab.

104. (fusidate$ adj (sodium or silver)).ti,ab.105. (antibiotic$ or antimicrobial$).ti,ab.106. (griseofulvin or synercid or dalfopristin or

quinupristin).ti,ab.107. (granulocyte colony stimulating factor or gcsf

or ozone).ti,ab.

108. or/10-61109. or/76-107110. 108 or 109111. 75 and 110 and 9


The Cochrane Database of Systematic Reviews(CDSR) and the Cochrane Controlled TrialsRegister (CCTR) [Searched: 12 November 2002via the Cochrane Library (2002, Issue 4)]

#1. (neuroischemic near foot) #2. (neuroischaemic near foot) #3. (neuroischemic near feet) #4. (neuroischaemic near feet) #5. (neuroischemic near ulcer*) #6. (neuroischaemic near ulcer*) #7. (ischemic near foot) #8. (ischemic near feet) #9. (ischemic near ulcer*)

#10. (ischaemic near foot) #11. (ischaemic near feet) #12. (ischaemic near ulcer*) #13. (diabetic near foot) #14. (diabetic near feet) #15. (diabetic near ulcer*) #16. (neuropathic near foot) #17. (neuropathic near feet)#18. (neuropathic near ulcer*) #19. (pedal near ulcer*) #20. (pedal near septic) #21. (pedal near wound*) #22. (plantar near ulcer*) #23. (plantar near septic) #24. (plantar near wound*) #25. (foot near ulcer*) #26. (foot near septic) #27. (foot near wound*) #28. (feet near ulcer*) #29. (feet near septic) #30. (feet near wound*) #31. (heel near ulcer*) #32. (heel near septic) #33. (heel near wound*) #34. (foot near diabet*) #35. (feet near diabet*) #36. (deep next foot next infection*) #37. (crural near ulcer*) #38. (leg near ulcer*) #39. (venous near leg) #40. (venous near ulcer*) #41. (stasis near leg) #42. (stasis near ulcer*) #43. (varicos* near leg) #44. (varicos* near ulcer*) #45. ((lower next extremit*) near ulcer*) #46. ((lower next extremit*) near wound*)

Appendix 1

94

#47. ((lower next limb*) near ulcer*) #48. ((lower next limb*) near wound*) #49. (#1 or #2 or #3 or #4 or #5 or #6 or #7

or #8 or #9 or #10 or #11 or #12 or #13or #14 or #15 or #16 or #17 or #18 or#19 or #20 or #21 or #22 or #23 or #24or #25 or #26 or #27 or #28 or #29 or#30 or #31 or #32 or #33 or #34 or #35or #36 or #37 or #38 or #39 or #40 or#41 or #42 or #43 or #44 or #45 or #46or #47 or #48)

#50. LEG ULCER explode all trees (MeSH) #51. (#49 or #50) #52. ACETIC ACID explode all trees (MeSH)#53. ((acetic next acid*) or acetate* or

acetamide* or acetoxyacetyaminofluorene*or hydrooxyacetylaminofluorene* orallylisopropylacetamide*)

#54. (idoacetamide* or idoacetate* orpiracetam* or thioacetamide* orgalolinium* or technetium* ordichoroacetate* or fluoroacetate* oridoacetate*)

#55. (foscarnet* or thioglycolate* or (acetic nextanhydride*))

#56. (aminooxyacetic or edetic or egtazic oridoacetic or nitrilotriacetic or pentetic orperacetic or phosphonoacetic ortrichloroacetic or trifluoroacetic)

#57. ((therapeutic next fungicide*) or (antifungalnext agent*) or antifungal*)

#58. (benzoate* or butenafine* orchlorquinaldol* or cyclosporine ordichlorophen* or fluconazole* orflucytosine* or (glycyrrhizic next acid*) orhexetidine* or itraconazole* or monensin*or nifuratel* or pentamidine*)

#59. (co-amoxiclav* or (sodium next benzoate*)or thimerosal* or thiram* or thymol* ortolnaftate* or tomatine* or triacetin* ortrimetrexate*)

#60. (amoroldine* or (benzoic next acid*) orclotrimazole* or econazole* orketoconazole* or miconazole* or nystatin*or (salicyclic next acid*) or sulconazole* orterbinafine* or tioconazole* orundecenoate*)

#61. (antiviral* or (anti next viral*) oridoxuridine*)

#62. (acetylcysteine* or acyclovir* or amantadine*or aphidicolin* or aprotinin* or brefeldin orbromodeoxyuridine* or cytarabine* ordeoxyglucose* or (dextran next sulfate*))

#63. (dideoxyadenosine* or dideoxynucleoside*or (dihematoporphyrin next ether*) orditiocarb* or filipin* or floxuridine* organciclovir* or (inosine next pranobex) or

(interferon next alfa*) or (interferon nexttype*) or (interferon next beta) or(interferon next gamma) or interferons)

#64. (methisazone* or (phosphonoacetic nextacid*) or (poly next a-u) or (poly next i-c) or(pyran next copolymer*) or ribavirin* orrimantadine* or streptovaricin* or(tenuazonic next acid*) or tilorone* ortrifluridine* or tunicamycin* or vidarabine*)

#65. (bacitracin* or (povidone next iodine*) orbetaisodona* or (polyvinylpyrrolidone nextiodine*) or betadine* or disadine* orisodine* or pvp-i or pharmadine*)

#66. (cetyltrimethylammonium or cetrimide* orcetrimonium)

#67. (chlorate* or cisplatin or (hydrochloric next acid*) or chloride* or (hypochlorousnext acid*) or hypochlorite* or (perchloricnext acid*) or (ruthenium next red*))

#68. (eusol or phenoxyethanol* ordextranomer* or (framycetin nextsulphate*) or (mandelic next acid*) ortetrabromofluorescein* or eosin or eosineor chlortetracycline* or (chloroxylenol nextsolution*))

#69. (edinburgh next adj next university next adjnext solution next adj2 next lime)

#70. (cyclandelate* or (vanilmandelic nextacid*))

#71. hexachloroph* #72. (triclosan* or polymyxin* or polynoxylin*) #73. (silver near dressing*) #74. ((gentian next violet) or (crystal next violet)

or (methyl next violet) or (methylrosanilinenext chloride*) or (hexamethylpararosaninenext chloride*))

#75. ((potassium next permanganate*) or(permanganic next acid*) or (potassiumnext salt*)) 36

#76. (mupirocin* or (pseudomonic next acid*)or bactroban*)

#77. (neomycin* or fradiomycin* or neamin*) #78. ((benzyol next peroxide*) or (benzyol next

superoxide*) or (diphenylglyoxal nextsuperoxide*) or panoxyl*)

#79. ((hydrogen next peroxide*) orhydroperoxide* or oxydol* or perhydrol*or superoxol* or (diphenylglyoxal nextsuperoxide*) or panoxyl*)

#80. (fucithalmic* or fusidate* or fusidin* orstanicide*)

#81. (liposome* near hydrogel*) #82. ((fusidic next acid*) or inadine* or

betadine*) #83. ((cadexomer next iodine*) or

chlorhexidine* or novalsan* or sebidin* ortubulicid*)


95


#84. (maggot* or larva or larvae or larval) #85. ((plant next extract*) or aromatherap* or

(marigold next extract*) or (calendula nextofficinalis) or (tagetes next patula) or (rubianext cordifolia) or manjishtha or (withanianext somnifera) or ashvagandha)

#86. (phytotherapy or cascara* or curare* or(chinese next herb*) or guaiac* or ipecac* or podophyll* or psyllium* or(senna next extract*) or tragacanth* orturpentine*)

#87. ((essential next oil*) or (plant next oil*) or(tea next tree) or lavender or chamomile orcamomile or rosemary)

#88. (sucrose or (sugar next paste*) or(granulated next sugar))

#89. (propolis or honey or beebread* or (beenext bread*) or (bee next glue*))

#90. (disinfect* or antisept* or anti-sept* orantiviral* or anti-viral*)

#91. (penicillin* or amdinocillin* or amox* orampicillin* or azlocillin*)

#92. (carbenicillin* or carfecillin* or cloxacillin*or dicloxacillin* or floxacillin* orflucloxacillin* or methicillin* ormazlocillin* or nafcillin* or oxacillin* or(penicillanic next acid*))

#93. ((penicillic next acid*) orphenoxymethylpenicillin* or piperacillin*or pivampicillin* or sulbencillin* ortalampicillin* or sultamicillin* orticarcillin* or ticercillin*)

#94. (cefaclor* or cefadroxil* or cefalexin* orcefazolin* or cefamandole* or cefixime* orcefotaxime* or cefoxitin* or cefpirome* orcefpodoxime* or cefprozil*)

#95. (cefradine* or ceftazidime* or ceftizoxime*or ceftriaxone* or cefuroxime*)

#96. (cefonicid* or cefmenoxine* orcefoperazone* or cefotiam* or cefsulodin*or cephacetrile* or cephalexin* orcephaloglycin* or cephaloridine or(cephalosporanic next acid*) orcephalothin* or cephapirin* orcephradine*)

#97. ((beta next lactam*) or aztreonam* orcilastin* or imipenem* or meropenem* orsulbactam* or tazobactam*)

#98. (caprolactam* or clavulan* ormoxalactam*)

#99. (aminoglycoside* or anthracycline* oraclarubicin* or daunorubicin* or carubicin*or doxorubicin* or epirubicin* oridarubicin* or nogalamycin* or menogaril*or plicamycin*)

#100. (gentamicin* or neomycin* or netilmicin*or tobramycin*)

#101. (amphotericin* or antimycin* orcandicidin* or roxithromycin* orjosamycin* or leucomycin* or kitasamycin*or lucensomycin* or maytansine* ormepartricin* or miocamycin*)

#102. (natamycin* or oleandomycin* ortroleandomycin* or oligomycin* orrutamycin* or sirolimus* or tacrolimus* ortylosin* or propiolactone* orspironolactone* or venturicidin* orzearalenone* or zeranol*)

#103. (azithromycin* or clarithromycin* orerythromycin* or spiramycin*)

#104. (moxifloxacin* or quinolone* orciprofloxacin* or clinafloxacin* orfluoroquinolone* or levofloxacin* orofloxacin*)

#105. (fleroxacin* or enoxacin* or norfloxacin*or pefloxacin* or (nalidixic next acid*) ornedocromil* or (oxolinic next acid*) orquinpirole* or quipazine* or saquinavir*)

#106. (dmso or sulfoxide* or sulphoxide* orsulfonamide* or sulphonamide* ortrimethoprim* or sulfamethoxazole* orsulphamethoxazole* or co-trimoxazole* orsulfadiazine* or sulphadiazine* orsulfametopyrazine* or sulfalene* orsulphametopyrazine* or sulphalene*) 2593

#107. (benzolamide* or bumetanide* orchloramine* or chlorthalidone* orclopamide* or dichlorphenamide* orethoxzolamide* or indapamide* ormafenide* or mefruside* or metolazone* orprodenecid* or sulfanilamide* orsulphanilamide* or furosemide* orsulfacetamide* or sulphacetamide*) 2041

#108. (sulfachlorpyridazine* or sulfadimethoxine*or sulfadoxine* or sulfaguanidine* orsulfamerazine* or sulfameter* orsulfamethazine* orsulfamethoxypyridazine* orsulphachlorpyridazine* orsulphadimethoxine* or sulphadoxine* orsulphaguanidine* or sulphamerazine* orsulphameter* or sulphamethazine* orsulphamethoxypyridazine*) 290

#109. (sulfamonomethoxine* or sulfamoxole* orsulfaphenazole* or sulfapyridine* orsulfaquinoxaline* or sulfathiazole* orsulfamethizole* or sulfisomidine* orsulfisoxazole* or sulfasalazine* orsumatriptan* or xipamide* or thioamide*)892

#110. (thioacetamide* or sulphamonomethoxine*or sulphamoxole* or sulphaphenazole* orsulphapyridine* or sulphaquinoxaline* orsulphathiazole* or sulphamethizole* or

Appendix 1

96

sulphisomidine* or sulphisoxazole* orsulphasalazine*) 222

#111. (tetracycline* or demeclocycline* ordoxycycline* or lymecycline* orminocycline* or oxytetracycline*) 1988

#112. (chlortetracycline* or methacycline* orrolitetracycline*) 77

#113. (cloranfenicol* or chloramphenicol*) 402 #114. (thiamphenicol* or kloramfenikol* or

levomycetin* or chlornitromycin* orchlorocid* or chloromycetin* ordetreomycin* or ophthochlor* orsyntomycin*) 53

#115. ((clindamycin* or (dalacin next c) orcleocin* or (chlo next lincocin*)) orchlolincocin*) 796

#116. (linezolid* or trivazol* or vagilen* or clont*or danizol* or fagyl* or ginefavir* ormetrogel* or metrodzhil* or satric* ortrichazol* or trichopol*) 19

#117. ((granulocyte next colony next stimulatingnext factor) or gcsf or ozone) 892

#118. (griseofulvin or synercid or dalfopristin orquinupristin) 139

#119. (antibiotic* or antimicrobial*)#120. (fusidate* near sodium) #121. (fusidate* near silver) #122. ANTI-INFECTIVE AGENTS explode all

trees (MeSH) #123. BACITRACIN explode all trees (MeSH) #124. CHLORIDES explode all trees (MeSH) #125. MUPIROCIN explode all trees (MeSH) #126. HYDROGEN PEROXIDE explode all trees

(MeSH) #127. LARVA explode all trees (MeSH) #128. COMPLEMENTARY THERAPIES explode

all trees (MeSH) #129. PLANT OILS explode all trees (MeSH) #130. PLANT EXTRACTS explode all trees

(MeSH) #131. SUCROSE explode all trees (MeSH) #132. HONEY explode all trees (MeSH) #133. aminoglycosides #134. TRIMETHOPRIM explode all trees

(MeSH) #135. METRONIDAZOLE explode all trees

(MeSH) #136. (#52 or #53 or #54 or #55 or #56 or #57

or #58 or #59 or #60 or #61 or #62 or#63 or #64 or #65 or #66 or #67 or #68or #69 or #70 or #71 or #72 or #73 or#74 or #75 or #76 or #77 or #78 or #79or #80 or #81 or #82 or #83 or #84 or#85 or #86 or #87 or #88 or #89 or #90or #91 or #92 or #93 or #94 or #95 or#96 or #97 or #98 or #99 or #100 or#101 or #102 or #103 or #104 or #105 or

#106 or #107 or #108 or #109 or #110 or #111 or #112 or #113 or #114 or #115 or #116 or #117 or #118 or #119 or #120 or #121 or #122 or #123 or #124 or #125 or #126 or #127 or #128 or #129 or #130 or #131 or #132 or #133or #134 or #135)

#137. #51 and #136

This identified 35 reviews in the CDSR (of which12 were protocols) and 176 potential trials inCCTR.

EMBASE (1980–2002 week 44) (searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)

1. exp clinical trial/2. Single Blind Procedure/3. double Blind Procedure/4. placebo/5. meta-analysis/6. randomization/7. randomized-controlled-trial/8. controlled-study/9. exp evidence-based-medicine/

10. exp comparative-study/11. (clinical trial$ or random$ or placebo$ or

control or controls or controlled).ti,ab.12. (single blind$ or double blind$ or trebl$

blind$ or tripl$ blind$).ti,ab.13. (meta-analys$ or meta analys$ or comparison

group or standard treatment$ or systematicreview$).ti,ab.

14. or/1-1315. exp animal/16. exp human/17. nonhuman/18. 15 not (15 and 16)19. 17 not (17 and 16)20. 14 not (18 or 19)21. exp Acetic Acid/22. (acetic acid$ or acetate$ or acetamide$ or





26. exp ANTIFUNGAL AGENTS/


97







32. (acetylcysteine$ or acyclovir$ or amantadine$or aphidicolin$ or aprotinin$ or brefeldin orbromodeoxyuridine$ or cytarabine$ ordeoxyglucose$ or dextran sulfate$).ti,ab.



35. exp BACITRACIN/36. exp Povidone-Iodine/37. (bacitracin$ or povidone iodine$ or


38. exp Cetrimide/39. (cetyltrimethylammonium or cetrimide$ or

cetrimonium).ti,ab.40. exp Chlorine Derivative/41. (chlorate$ or cisplatin or hydrochloric acid$


42. exp Eosin/43. (eusol or phenoxyethanol$ or dextranomer$



45. exp Framycetin/46. exp Mandelic Acid derivative/47. (cyclandelate$ or vanilmandelic acid$).ti,ab.48. exp Hexachlorophene/49. hexachloroph#ne$.ti,ab.50. exp Triclosan/51. exp Polymyxin/52. (triclosan$ or polymyxin$ or

polynoxylin$).ti,ab.53. (silver adj2 dressing$).ti,ab.54. exp crystal Violet/55. (gentian violet or crystal violet or methyl


56. exp Permanganate Potassium/57. (potassium permanganate$ or permanganic

acid$ or potassium salt$).ti,ab.58. exp pseudomonic acid/59. (mupirocin$ or pseudomonic acid$ or


neamin$).ti,ab.62. exp Benzoyl Peroxide/63. (benzyol peroxide$ or benzyol superoxide$





67. (liposome$ adj hydrogel$).ti,ab.68. (fusidic acid$ or inadine$ or betadine$).ti,ab.69. exp Chlorhexidine/70. (cadexomer iodine$ or chlorhexidine$ or

novalsan$ or sebidin$ or tubulicid$).ti,ab.71. exp Larva/72. (maggot$ or larva or larvae or larval).ti,ab.73. exp alternative medicine/74. (plant extract$ or aromatherap$ or

marigold extract$ or calendula officinalis ortagetes patula or rubia cordifolia ormanjishtha or withania somnifera orashvagandha).ti,ab.

75. exp Plant Extract/76. exp Medicinal Plant/77. (phytotherapy or cascara$ or curare$ or


78. exp essential oil/ or exp vegetable oil/79. exp Sucrose/80. exp HONEY/81. (essential oil$ or plant oil$ or tea tree or

Appendix 1

98



83. exp Propolis/84. (propolis or honey or beebread$ or bee

bread$ or bee glue$).ti,ab.85. exp Disinfectant Agent/86. exp Anti-Infective Agent/87. exp Antivirus Agent/88. (disinfect$ or antisept$ or anti-sept$ or




91. ((foot or feet) adj6 diabet$).ti,ab.92. deep foot infection$.ti,ab.93. exp Foot Ulcer/94. or/89-9395. Leg Ulcer/96. leg varicosis/97. ((crural or leg) adj5 ulcer$).ti,ab.98. ((venous or stasis or varicos$) adj5 (leg or

ulcer$)).ti,ab.99. ((venous or stasis or leg) adj5 wound$).ti.

100. ((lower extremit$ or lower limb$) adj5 (ulcer$or wound$)).ti,ab.

101. or/95-100102. 94 or 101103. exp Penicillin Derivative/104. (penicillin$ or amdinocillin$ or amox#cillin$

or ampicillin$ or azlocillin$).ti,ab.105. (carbenicillin$ or carfecillin$ or cloxacillin$

or dicloxacillin$ or floxacillin$ orflucloxacillin$ or methicillin$ or mazlocillin$or nafcillin$ or oxacillin$ or penicillanicacid$).ti,ab.


107. exp Cephalosporin Derivative/108. (cefaclor$ or cefadroxil$ or cefalexin$ or

cefazolin$ or cefamandole$ or cefixime$ orcefotaxime$ or cefoxitin$ or cefpirome$ orcefpodoxime$ or cefprozil$).ti,ab.



111. exp Lactam/112. (beta lactam$ or aztreonam$ or cilastin$ or

imipenem$ or meropenem$ or sulbactam$ ortazobactam$).ti,ab.


114. exp Aminoglycoside/115. (Aminoglycoside$ or anthracycline$ or



117. exp Macrolide/118. (amphotericin$ or antimycin$ or candicidin$

or roxithromycin$ or josamycin$ orleucomycin$ or kitasamycin$ orlucensomycin$ or maytansine$ ormepartricin$ or miocamycin$).ti,ab.



121. exp Quinolone Derivative/122. (moxifloxacin$ or quinolone$ or

ciprofloxacin$ or clinafloxacin$ orfluoroquinolone$ or levofloxacin$ orofloxacin$).ti,ab.


124. exp Sulfonamide/125. exp Trimethoprim/126. (dmso or sulfoxide$ or sulphoxide$ or

sulfonamide$ or sulphonamide$ ortrimethoprim$ or sulfamethoxazole$ orsulphamethoxazole$ or co-trimoxazole$ orsulfadiazine$ or sulphadiazine$ orsulfametopyrazine$ or sulfalene$ orsulphametopyrazine$ or sulphalene$).ti,ab.


128. (sulfachlorpyridazine$ or sulfadimethoxine$or sulfadoxine$ or sulfaguanidine$ orsulfamerazine$ or sulfameter$ or


99


sulfamethazine$ or sulfamethoxypyridazine$or sulphachlorpyridazine$ orsulphadimethoxine$ or sulphadoxine$ orsulphaguanidine$ or sulphamerazine$ orsulphameter$ or sulphamethazine$ orsulphamethoxypyridazine$).ti,ab.


130. exp Tetracycline Derivative/131. (tetracycline$ or demeclocycline$ or

doxycycline$ or lymecycline$ or minocycline$or oxytetracycline$).ti,ab.


133. exp Chloramphenicol/134. (cloranfenicol$ or chloramphenicol$).ti,ab.135. (thiamphenicol$ or kloramfenikol$ or

levomycetin$ or chlornitromycin$ orchlorocid$ or chloromycetin$ or detreomycin$or ophthochlor$ or syntomycin$).ti,ab.

136. exp Clindamycin/137. (clindamycin$ or dalacin c or cleocin$ or

chlo?lincocin$).ti,ab.138. exp Metronidazole/139. (linezolid$ or trivazol$ or vagilen$ or clont$


140. exp Fusidic Acid/141. (granulocyte colony stimulating factor or gcsf

or ozone).ti,ab.142. (fusidate$ adj (sodium or silver)).ti,ab.143. exp Antibiotic Agent/144. (antibiotic$ or antimicrobial$).ti,ab.145. (griseofulvin or synercid or dalfopristin or

quinupristin).ti,ab.146. or/103-145147. or/21-88148. (146 or 147) and 20 and 102


MEDLINE (1966–2002/10 week 4) andPREMEDLINE (up to 5 November 2002)(searched: 6 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)

1. exp Acetic Acid/

2. (acetic acid$ or acetate$ or acetamide$ oracetoxyacetylaminofluorene$ orhydroxyacetylaminofluorene$ orallylisopropylacetamide$).ti,ab.




6. exp ANTIFUNGAL AGENTS/7. (therapeutic fungicide$ or antifungal agent$

or antifungals).ti,ab.8. (benzoate$ or butenafine$ or chlorquinaldol$

or cyclosporine$ or dichlorophen$ orfluconazole$ or flucytosine$ or glycyrrhizicacid$ or hexetidine$ or itraconazole$ ormonensin$ or nifuratel$ orpentamidine$).ti,ab.




12. (acetylcysteine$ or acyclovir$ or amantadine$or aphidicolin$ or aprotinin$ or brefeldin orbromodeoxyuridine$ or cytarabine$ ordeoxyglucose$ or dextran sulfate$).ti,ab.



15. exp BACITRACIN/16. exp Povidone-Iodine/17. (bacitracin$ or povidone iodine$ or


Appendix 1

100

18. exp Cetrimonium Compounds/19. (cetyltrimethylammonium or cetrimide$ or

cetrimonium).ti,ab.20. exp Chlorine Compounds/21. (chlorate$ or cisplatin or hydrochloric acid$


22. exp "Eosine Yellowish-(YS)"/23. (eusol or phenoxyethanol$ or dextranomer$



25. exp Framycetin/26. exp Mandelic Acids/27. (cyclandelate$ or vanilmandelic acid$).ti,ab.28. exp Hexachlorophene/29. hexachloroph#ne$.ti,ab.30. exp Triclosan/31. exp Polymyxin/32. (triclosan$ or polymyxin$ or

polynoxylin$).ti,ab.33. (silver adj2 dressing$).ti,ab.34. exp Gentian Violet/35. (gentian violet or crystal violet or methyl


36. exp Potassium Permanganate/37. (potassium permanganate$ or permanganic

acid$ or potassium salt$).ti,ab.38. exp Mupirocin/39. (mupirocin$ or pseudomonic acid$ or


neamin$).ti,ab.42. exp Benzoyl Peroxide/43. (benzyol peroxide$ or benzyol superoxide$





47. (liposome$ adj hydrogel$).ti,ab.48. (fusidic acid$ or inadine$ or betadine$).ti,ab.49. exp Chlorhexidine/50. (cadexomer iodine$ or chlorhexidine$ or

novalsan$ or sebidin$ or tubulicid$).ti,ab.51. exp Larva/52. (maggot$ or larva or larvae or larval).ti,ab.

53. exp Complementary Therapies/54. (plant extract$ or aromatherap$ or marigold

extract$ or calendula officinalis or tagetespatula or rubia cordifolia or manjishtha orwithania somnifera or ashvagandha).ti,ab.



58. exp oils, volatile/ or exp plant oils/59. exp Sucrose/60. exp HONEY/61. (essential oil$ or plant oil$ or tea tree or



63. exp Propolis/64. (propolis or honey or beebread$ or bee

bread$ or bee glue$).ti,ab.65. exp Disinfectants/66. exp Anti-Infective Agents, Local/67. exp Antiviral Agents/68. (disinfect$ or antisept$ or anti-sept$ or




71. ((foot or feet) adj6 diabet$).ti,ab.72. deep foot infection$.ti,ab.73. exp Foot Ulcer/74. or/69-7375. Leg Ulcer/76. Varicose Ulcer/77. ((crural or leg) adj5 ulcer$).ti,ab.78. ((venous or stasis or varicos$) adj5 (leg or

ulcer$)).ti,ab.79. ((venous or stasis or leg) adj5 wound$).ti,ab80. ((lower extremit$ or lower limb$) adj5 (ulcer$

or wound$)).ti,ab.81. or/75-8082. 74 or 8183. random allocation/ or randomized controlled

trials/84. exp clinical trials/85. single-blind method/ or double-blind

method/ or publication bias/ or meta-analysis/86. comparative study/87. (controlled clinical trial or randomized

controlled trial or review).pt.88. meta-analysis.pt.89. random$.ti,ab.90. ((clinical adj trial$) or control$).ti,ab.


101


91. ((standard adj treatment$) or compar$ or(single adj blind$) or (double adjblind$)).ti,ab.

92. (placebo$ or (systematic adj review$)).ti,ab.93. or/83-9294. 82 and 9395. exp Penicillins/96. (penicillin$ or amdinocillin$ or amox#cillin$

or ampicillin$ or azlocillin$).ti,ab.97. (carbenicillin$ or carfecillin$ or cloxacillin$ or

dicloxacillin$ or floxacillin$ or flucloxacillin$or methicillin$ or mazlocillin$ or nafcillin$ oroxacillin$ or penicillanic acid$).ti,ab.


99. exp Cephalosporins/100. (cefaclor$ or cefadroxil$ or cefalexin$ or

cefazolin$ or cefamandole$ or cefixime$ orcefotaxime$ or cefoxitin$ or cefpirome$ orcefpodoxime$ or cefprozil$).ti,ab.



103. exp Lactams/104. (beta lactam$ or aztreonam$ or cilastin$ or

imipenem$ or meropenem$ or sulbactam$ ortazobactam$).ti,ab.


106. exp Aminoglycosides/107. (Aminoglycoside$ or anthracycline$ or



109. exp Macrolides/110. (amphotericin$ or antimycin$ or candicidin$

or roxithromycin$ or josamycin$ orleucomycin$ or kitasamycin$ orlucensomycin$ or maytansine$ ormepartricin$ or miocamycin$).ti,ab.



113. exp Quinolones/114. (moxifloxacin$ or quinolone$ or

ciprofloxacin$ or clinafloxacin$ orfluoroquinolone$ or levofloxacin$ orofloxacin$).ti,ab.


116. exp Sulfonamides/117. exp Trimethoprim/118. (dmso or sulfoxide$ or sulphoxide$ or

sulfonamide$ or sulphonamide$ ortrimethoprim$ or sulfamethoxazole$ orsulphamethoxazole$ or co-trimoxazole$ orsulfadiazine$ or sulphadiazine$ orsulfametopyrazine$ or sulfalene$ orsulphametopyrazine$ or sulphalene$).ti,ab.




122. exp Tetracyclines/123. (tetracycline$ or demeclocycline$ or

doxycycline$ or lymecycline$ or minocycline$or oxytetracycline$).ti,ab.


125. exp Chloramphenicol/126. (cloranfenicol$ or chloramphenicol$).ti,ab.

Appendix 1

102

127. (thiamphenicol$ or kloramfenikol$ orlevomycetin$ or chlornitromycin$ orchlorocid$ or chloromycetin$ ordetreomycin$ or ophthochlor$ orsyntomycin$).ti,ab.

128. exp Clindamycin/129. (clindamycin$ or dalacin c or cleocin$ or

chlo?lincocin$).ti,ab.130. exp Metronidazole/131. (linezolid$ or trivazol$ or vagilen$ or clont$


132. exp Fusidic Acid/133. (granulocyte colony stimulating factor or gcsf

or ozone).ti,ab.134. (fusidate$ adj (sodium or silver)).ti,ab.135. exp Antibiotics/136. (antibiotic$ or antimicrobial$).ti,ab.137. (griseofulvin or synercid or dalfopristin or

quinupristin).ti,ab.138. or/95-137139. or/1-68140. 94 and (138 or 139)


Controlled-Trials.com (searched 27 November2002)(venous or stasis or varicose or leg or legs or footor feet or heel or pedal or plantar) and (ulcers orulceration or ulcerations or ulcer or wound orwounds or infection or infections or septic ordiabetic or diabetes)

This identified 89 records

Cost-effectiveness searchstrategiesCRD internal administration databases NHS Economic Evaluation Database (NHS EED)(searched 13 November 2002)The NHS Economic Evaluation Database (NHSEED) was searched via the NHS CRD’s internaladministration databases. This provides a moreup-to-date version of the database than theCochrane Library or the Internet and includesadditional records to those in the public database.The search strategy used was as follows:

1. (neuroisch?emic or isch?emic or diabetic orneuropathic)(3W) (foot or feet or ulcer$)

2. (pedal or plantar or foot or feet orheel)(3w)(ulcer$ or septic or wound$)

3. (foot or feet)(6w)diabet$

4. deep foot infection$ 5. 1 or 2 or 3 or 4


CD-ROM resourcesEconLit (1969–2002 October) (searched: 12November 2002 on ARC SilverPlatter)No economic filter was necessary for this database.1. (neuroisch?emic or isch?emic or diabetic or

neuropathic) near3 (foot or feet or ulcer*) 2. (pedal or plantar or foot or feet or heel) near3

(ulcer* or septic or wound*) 3. (foot or feet) near6 diabet* 4. deep foot infection* 5. 1 or 2 or 3 or 4

This identified three records.

Health Economic Evaluation Database (HEED)(Issue: November 2002) (searched: 13 November2002 on stand-alone CD-ROM)(neuroischemic or ischemic or neuroischaemic orischaemic or diabetic or neuropathic) and (foot orfeet or ulcer*) OR(pedal or plantar or foot or feet or heel) and(ulcer* or septic or wound*) OR(foot or feet) and diabet* OR'deep foot infection' within 2 OR 'deep foot infections' within 2


Internet databases(Allied and Complementary Medicine) AMED(1985–2002 November) (searched: 12 November2002 on OvidWeb Gateway athttp://gateway.ovid.com/athens)

1. ((neuroisch?emi$ or isch?emi$ or neuropathic or diabetic) adj3 (foot or feet orulcer$)).ti,ab.

2. ((pedal or plantar or foot or feet or heel) adj3(ulcer$ or septic or wound$)).ti,ab.

3. ((foot or feet) adj6 diabet$).ti,ab.4. deep foot infection$.ti,ab.5. exp Foot Ulcer/6. or/1-57. (cost or costs or costing or costed or

costly).ti,ab.8. (economic$ or pharmacoeconomic$ or price

or prices or pricing).ti,ab.9. decision making/

10. decision analysis.ti,ab.11. decision model$.ti,ab.12. mathematical model$.ti,ab.13. statistical model$.ti,ab.14. markov.ti,ab.


103


15. economics/ or "costs and cost analysis"/ or costbenefit analysis/ or cost of illness/

16. or/7-1517. 6 and 16


British Nursing Index (BNI) (1994–2002 August)(searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)

1. ((neuroisch?emi$ or isch?emi$ or neuropathicor diabetic) adj3 (foot or feet or ulcer$)).mp.


3. ((foot or feet) adj6 diabet$).mp.4. deep foot infection$.mp.5. exp Foot Ulcer/6. or/1-57. exp health economics/8. (cost or costs or costed or costly or

costing).mp.9. (economic$ or pharmacoeconomic$ or price$

or pricing).mp.10. exp decision making process/11. markov.mp.12. decision analysis.mp.13. decision model$.mp.14. mathematical model$.mp.15. statistical model$.mp.16. or/7-1517. 6 and 16


CINAHL (1982–2002 October, week 4)(searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)

1. exp "Costs and Cost Analysis"/2. economics.sh.3. exp "costs and cost analysis"/4. economic aspects of illness.sh.5. economics, pharmaceutical.sh.6. economic value of life.sh.7. exp "fees and charges"/8. budgets.sh.9. (cost or costs or costed or costly or

costing).ab,ti,hw.10. (economic$ or pharmacoeconomic$ or price$

or pricing).ab,ti,hw.11. or/1-1012. markov.ti,ab.13. Decision Making, Clinical/14. decision analysis.ti,ab.15. decision model$.ti,ab.16. mathematical model$.ti,ab.17. Models, Statistical/18. or/12-17

19. ((neuroisch?emi$ or isch?emi$ or neuropathicor diabetic) adj3 (foot or feet or ulcer$)).ti,ab.


21. ((foot or feet) adj6 diabet$).ti,ab.22. deep foot infection$.ti,ab.23. exp Foot Ulcer/24. or/19-2325. 11 or 1826. 24 and 25


EMBASE (1980–2002 week 44) (searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)

1. markov.ti,ab,hw.2. decision analysis.ti,ab.3. decision model$.ti,ab.4. mathematical model$.ti,ab.5. exp Medical Decision Making/6. mathematical model/ or statistical model/ or

stochastic model/7. or/1-68. exp health economics/9. cost/

10. exp health care cost/11. exp economic evaluation/12. (cost or costs or costing or costed or

costly).ti,ab.13. (economic$ or pharmacoeconomic$ or price

or prices or pricing).ti,ab.14. or/8-1315. exp animal/16. exp human/17. nonhuman/18. 15 not (15 and 16)19. 17 not (17 and 16)20. 14 not (18 or 19)21. ((neuroisch?emi$ or isch?emi$ or neuropathic

or diabetic) adj3 (foot or feet or ulcer$)).ti,ab.22. ((pedal or plantar or foot or feet or heel) adj3

(ulcer$ or septic or wound$)).ti,ab.23. ((foot or feet) adj6 diabet$).ti,ab.24. deep foot infection$.ti,ab.25. exp Foot Ulcer/26. or/21-2527. 7 or 2028. 26 and 27


MEDLINE (1966–2002 October. week 5) andPREMEDLINE (up to 11 November 2002)(searched: 12 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)

1. economics/

Appendix 1

104

2. exp "costs and cost analysis"/3. economic value of life/4. exp economics,hospital/5. economics, medical/6. economics, nursing/7. economics, pharmaceutical/8. (econom$ or cost or costs or costly or costing

or price or prices or pricing orpharmacoeconomic$).ti,ab.

9. (expenditure$ not energy).ti,ab.10. (value adj2 money).ti,ab.11. (budget$ or (quality adj adjusted) or

qaly$).ti,ab.12. or/1-1113. ((metabolic adj cost$) or (energy adj cost$) or

(oxygen adj cost$)).ti,ab.14. letter.pt.15. editorial.pt.16. historical article.pt.17. animal/18. human/19. 17 not (17 and 18)20. (or/13-16) or 1921. 12 not 2022. exp decision support techniques/23. markov.ti,ab,hw.24. exp models, economic/25. decision analysis.ti,ab.26. decision model$.ti,ab.27. mathematical model$.ti,ab.28. or/22-2729. ((neuroisch?emi$ or isch?emi$ or neuropathic

or diabetic) adj3 (foot or feet or ulcer$)).ti,ab.30. ((pedal or plantar or foot or feet or heel) adj3

(ulcer$ or septic or wound$)).ti,ab.31. ((foot or feet) adj6 diabet$).ti,ab.32. deep foot infection$.ti,ab.33. exp Foot Ulcer/34. or/29-3335. 21 or 2836. 34 and 35


Diagnostic searchesInternet databases(Allied And Complementary Medicine) AMED(1985–2002 November) (searched: 23 November2002 on OvidWeb Gateway athttp://gateway.ovid.com/athens)

1. (specificit$ or sensitivit$).ti,ab.2. (false negative$ or false positive$ or true

negative$ or true positive$).ti,ab.3. (positive rate$ or negative rate$).ti,ab.4. screening.ti,ab.

5. accuracy.ti,ab.6. reference value$.ti,ab.7. likelihood ratio$.ti,ab.8. (sroc or srocs or roc or rocs).ti,ab.9. receiver operat$ curve$.ti,ab.

10. receiver operat$ character$.ti,ab.11. diagnosis/ or diagnosis differential/ or

diagnostic errors/ or exp "diagnostictechniques and procedures"/

12. (diagnos$ adj3 (efficac$ or efficien$ oreffectiv$ or accura$ or correct$ or reliable orreliability)).ti,ab.

13. (diagnos$ adj3 (error$ or mistake$ orinaccura$ or incorrect or unreliable)).ti,ab.

14. diagnostic yield$.mp. or misdiagnos$.ti,ab.[mp=abstract, heading words, title]

15. (reproductivity or logistical regression).mp. orlogistical model$.ti,ab. [mp=abstract, headingwords, title]

16. (ability adj2 predict$).ti,ab.17. ((test or tests or testing or standard) adj3

(reliable or reliability or performance)).ti,ab.18. (predictive adj (value$ or standard$ or model$

or factor$)).ti,ab.19. ((reference or index) adj (test or tests or

testing)).ti,ab.20. ((clinical or patient) adj (exam$ or asses$ or

recognition or identif$ or inspection)).ti,ab.21. (specimen$ or swab$ or smear$).ti,ab.22. ((tissue or fluid$ or wound$ or cell or cells)

adj2 sample$).ti,ab.23. (sausage toe or dactylitis).ti,ab.24. (puncture or biopsy or biopsies or needle

aspiration$ or (bone adj2 prob$)).ti,ab.25. exp Specimen Handling/26. exp Microbiology/27. (excis$ or curettage or curetage or curet or

curette or aspirate or yeast or gram stain orgas liquid chromatography).ti,ab.

28. Irrigation/ or exp chromatography/ or yeasts/29. (irrigation or lavage).ti,ab.30. (fluorescen$ adj2 (analys$ or imag$ or

antibod$ or microscopy or probe or probes ortag or tags or marker$ or technique$)).ti,ab.

31. Dyes/32. (fluorogenic substrate$ or fluorochrome$ or

immunofluorescence or ryb or red or yellow orblack).ti,ab.

33. (colo?r$ adj2 (asess$ or code or codes orcoding$ or concept or concepts or estimat$ orclassifi$ or system$ or three)).ti,ab.

34. pseudomonas fluorescen$.ti,ab.35. ((Fluorescen$ or vital) adj5 dye$).ti,ab.36. (electronic adj (sensor$ or nose)).ti,ab.37. (e-nose or e-sensor$ or x-ray$ or mri or nmror

(gallium adj2 citrate)).ti,ab.38. exp diagnosic imaging/


105


39. (imaging or scanning or scan or (computedand tomograph$) or ct or cat or (technetiumadj3 bone) or indium 111 or (labelled andwhite and cell) or hmpo or scintigraph$ or(magnetic and resonance) or (nuclear andmagnetic)).ti,ab.

40. (tissue adj (culture$ or diagnos$ orantigen$)).ti,ab.

41. microscopy/42. (aerob$ or anaerob$).ti,ab.43. (biological or mycobacter$ or coloni$ or

contaminat$ or bacter$ or antimicrob$ or anti-microb$ or microb$ or osteomyeliti$ orcelluliti$ or infect$).ti,ab.

44. exp BACTERIA/45. (gram adj (negative or positive)).ti,ab.46. (plate culture$ or colony count$).ti,ab.47. (pus or cicatrix or exudate or suppuration or

oozing or discharge or drainage or odo?r ormalodo?r or erythema or redness or warmthor tender$ or pain$ or induration orfluctuance or swelling or swollen or warm orheat).ti,ab.

48. (signs and symptoms).mp.49. abscess/ or Cicatrix/ or Drainage/ or Erythema/

or smell/ or inflammation/50. pain/ or exp neuralgia/ or pain intractable/51. (public health laboratory or phl).ti,ab.52. (molecular adj (screen$ or diagnos$)).ti,ab.53. (polymerase chain reaction adj3

screening).ti,ab.54. exp polymerase chain reaction/55. (primed adj2 situ label$).ti,ab.56. random amplified polymorphic dna.ti,ab.57. reverse transcriptase pcr.ti,ab.58. (pcr or ctpcr or mlst).ti,ab.59. multi locus sequence typing.ti,ab.60. 16 s rdna.ti,ab.61. (fluoresce$ adj4 diagnos$).ti,ab.62. ((near patient or site or onsite or rapid) adj

(test$ or system$ or assessment$ or diagnos$or analysis)).ti,ab.

63. (point adj2 care adj (test$ or system$ orassessment$ or diagnos$ or analysis)).ti,ab.

64. ((neuroisch?emi$ or isch?emi$ or diabetic orneuropathic) adj3 (foot or feet or ulcer$)).ti,ab.



ulcer$)).ti,ab.

74. ((venous or stasis or leg) adj5 wound$).ti.75. ((lower extremit$ or lower limb$) adj5 (ulcer$

or wound$)).ti,ab.76. or/70-7577. 69 or 7678. or/1-1979. or/20-6380. 77 and 78 and 79


British Nursing Index (BNI) (1994–2002September) (searched: 23 November 2002 onOvidWeb Gateway athttp://gateway.ovid.com/athens)

1. (specificit$ or sensitivit$).mp.2. (false negative$ or false positive$ or true

negative$ or true positive$).mp.3. (positive rate$ or negative rate$).mp.4. screening.mp.5. accuracy.mp.6. reference value$.mp.7. likelihood ratio$.mp.8. (sroc or srocs or roc or rocs).mp.9. receiver operat$ curve$.mp.

10. receiver operat$ character$.mp.11. exp diagnosis/12. (diagnos$ or misdiagnos$).mp.13. (reproductivity or logistical regression or

logistical model$).mp.14. (ability adj2 predict$).mp.15. ((test or tests or testing or standard) adj3

(reliable or reliability or performance)).mp.16. (predictive adj (value$ or standard$ or model$

or factor$)).mp.17. ((reference or index) adj (test or tests or

testing)).mp.18. ((clinical or patient) adj (exam$ or asses$ or

recognition or identif$ or inspection)).mp.19. (specimen$ or swab$ or smear$).mp.20. ((tissue or fluid$ or wound$ or cell or cells)

adj2 sample$).mp.21. (sausage toe or dactylitis).mp.22. (puncture or biopsy or biopsies or needle

aspiration$ or (bone adj2 prob$)).mp.23. exp Microbiology/24. (excis$ or curettage or curetage or curet or

curette or aspirate or yeast or gram stain orgas liquid chromatography).mp.

25. (irrigation or lavage).mp.26. (fluorescen$ adj2 (analys$ or imag$ or

antibod$ or microscopy or probe or probes ortag or tags or marker$ or technique$)).mp.

27. (fluorogenic substrate$ or fluorochrome$ orimmunofluorescence or ryb or red or yellow orblack).mp.

28. (colo?r$ adj2 (asess$ or code or codes or

Appendix 1

106

coding$ or concept or concepts or estimat$ orclassifi$ or system$ or three)).mp.

29. pseudomonas fluorescen$.mp.30. ((Fluorescen$ or vital) adj5 dye$).mp.31. (electronic adj (sensor$ or nose)).mp.32. (e-nose or e-sensor$ or x-ray$ or mri or nmr

or (gallium adj2 citrate)).mp.33. exp imaging/34. (imaging or scanning or scan or (computed

and tomograph$) or ct or cat or (technetiumadj3 bone) or indium 111 or (labelled andwhite and cell) or hmpo or scintigraph$ or(magnetic and resonance) or (nuclear andmagnetic)).mp.

35. (tissue adj (culture$ or diagnos$ orantigen$)).mp.

36. (aerob$ or anaerob$).mp.37. (biological or mycobacter$ or coloni$ or

contaminat$ or bacter$ or antimicrob$ or anti-microb$ or microb$ or osteomyeliti$ orcelluliti$ or infect$).mp.

38. exp BACTERIA/39. (gram adj (negative or positive)).mp.40. (plate culture$ or colony count$).mp.41. (pus or cicatrix or exudate or suppuration or

oozing or discharge or drainage or odo?r ormalodo?r or erythema or redness or warmthor tender$ or pain$ or induration orfluctuance or swelling or swollen or warm orheat).mp.

42. (signs and symptoms).mp.43. (public health laboratory or phl).mp.44. (molecular adj (screen$ or diagnos$)).mp.45. (polymerase chain reaction adj3

screening).mp.46. (primed adj2 situ label$).mp.47. random amplified polymorphic dna.mp.48. reverse transcriptase pcr.mp.49. (pcr or ctpcr or mlst).mp.50. multi locus sequence typing.mp.51. 16 s rdna.mp.52. (fluoresce$ adj4 diagnos$).mp.53. ((near patient or site or onsite or rapid) adj

(test$ or system$ or assessment$ or diagnos$or analysis)).mp.

54. (point adj2 care adj (test$ or system$ orassessment$ or diagnos$ or analysis)).mp.

55. ((neuroisch?emi$ or isch?emi$ or diabetic orneuropathic) adj3 (foot or feet or ulcer$)).mp.


57. ((foot or feet) adj6 diabet$).mp.58. deep foot infection$.mp.59. Leg Ulcer/60. ((crural or leg) adj5 ulcer$).mp.61. ((venous or stasis or varicos$) adj5 (leg or

ulcer$)).mp.

62. ((venous or stasis or leg) adj5 wound$).mp.63. ((lower extremit$ or lower limb$) adj5 (ulcer$

or wound$)).mp.64. or/55-6365. or/1-1766. or/18-5467. 64 and 65 and 66


CINAHL (1982–2002 week 4) (searched: 23November 2002 on OvidWeb Gateway athttp://gateway.ovid.com/athens)

1. exp "Sensitivity and Specificity"/2. False Positive Reactions/3. False Negative Reactions/4. (specificit$ or sensitivit$).ti,ab.5. (false negative$ or false positive$ or true

negative$ or true positive$).ti,ab.6. (positive rate$ or negative rate$).ti,ab.7. screening.ti,ab.8. accuracy.ti,ab.9. reference value$.ti,ab.

10. likelihood ratio$.ti,ab.11. (sroc or srocs or roc or rocs).ti,ab.12. receiver operat$ curve$.ti,ab.13. receiver operat$ character$.ti,ab.14. exp Logistic Regression/15. diagnosis/ or diagnosis, delayed/ or diagnosis,

differential/ or diagnosis, laboratory/ ordiagnostic errors/ or diagnostic tests, routine/or predictive value of tests/



18. diagnostic yield$.mp. or misdiagnos$.ti,ab.[mp=title, cinahl subject heading, abstract,instrumentation]

19. (reproductivity or logistical regression).mp. orlogistical model$.ti,ab. [mp=title, cinahlsubject heading, abstract, instrumentation]




testing)).ti,ab.24. ((clinical or patient) adj (exam$ or asses$

or recognition or identif$ or inspection)).ti,ab.

25. (specimen$ or swab$ or smear$).ti,ab.26. ((tissue or fluid$ or wound$ or cell or cells)

adj2 sample$).ti,ab.27. (sausage toe or dactylitis).ti,ab.


107


28. (puncture or biopsy or biopsies or needleaspiration$ or (bone adj2 prob$)).ti,ab.

29. exp Specimen Handling/30. exp Biopsy/31. exp Microbiological Techniques/32. Curettage/33. (excis$ or curettage or curetage or curet or


34. exp Irrigation/ or exp chromatography/ oryeasts/

35. (irrigation or lavage).ti,ab.36. (fluorescen$ adj2 (analys$ or imag$ or


37. exp Fluorescent Antibody Technique/38. exp Fluorescent Dyes/39. (fluorogenic substrate$ or fluorochrome$ or



41. pseudomonas fluorescen$.ti,ab.42. ((Fluorescen$ or vital) adj5 dye$).ti,ab.43. (electronic adj (sensor$ or nose)).ti,ab.44. (e-nose or e-sensor$ or x-ray$ or mri or nmr

or (gallium adj2 citrate)).ti,ab.45. exp diagnostic imaging/46. (imaging or scanning or scan or (computed

and tomograph$) or ct or cat or (technetiumadj3 bone) or indium 111 or (labelled andwhite and cell) or hmpo or scintigraph$ or(magnetic and resonance) or (nuclear andmagnetic)).ti,ab.


48. exp Tissue Culture/ or exp microscopy/49. (aerob$ or anaerob$).ti,ab.50. (biological or mycobacter$ or coloni$ or




55. (signs and symptoms).mp.56. abscess/ or cellulitis/ or exp Cicatrix/ or

Drainage/ or exp Erythema/ or Odors/57. pain/ or neuralgia/ or "exudates and

transudates"/

58. (public health laboratory or phl).ti,ab.59. (molecular adj (screen$ or diagnos$)).ti,ab.60. (polymerase chain reaction adj3








or wound$)).ti,ab.83. or/77-8284. 76 or 8385. or/1-2386. or/24-7087. 84 and 85 and 86


EMBASE (1980–2002 week 46) (searched: 24November 2002 on OvidWeb Gateway athttp://gateway.ovid.com/athens)

1. "Sensitivity and Specificity"/2. (specificit$ or sensitivit$).ti,ab.3. (false negative$ or false positive$ or true

negative$ or true positive$).ti,ab.4. (positive rate$ or negative rate$).ti,ab.5. screening.ti,ab.6. accuracy.ti,ab.7. reference value$.ti,ab.8. likelihood ratio$.ti,ab.9. (sroc or srocs or roc or rocs).ti,ab.

10. receiver operat$ curve$.ti,ab.11. receiver operat$ character$.ti,ab.12. receiver operating characteristic/ or roc curve/

Appendix 1

108

13. logistic regression analysis/14. diagnos$.ti,ab,hw.15. exp diagnosis/16. misdiagnos$.ti,ab.17. (reproductivity or logistical regression).mp. or

logistical model$.ti,ab. [mp=abstract, headingwords, title]






adj2 sample$).ti,ab.25. (sausage toe or dactylitis).ti,ab.26. (puncture or biopsy or biopsies or needle

aspiration$ or (bone adj2 prob$)).ti,ab.27. biopsy/ or bone biopsy/ or exp biopsy

technique/28. exp microbiological examination/ or exp

"microbiological phenomena and functions"/29. Curettage/30. (excis$ or curettage or curetage or curet or


31. wound irrigation/ or gas liquidchromatography/ or yeast/



34. Fluorescent Antibody Technique/35. exp Fluorescent Dye/36. (fluorogenic substrate$ or fluorochrome$ or



38. Pseudomonas fluorescens/39. pseudomonas fluorescen$.ti,ab.40. ((Fluorescen$ or vital) adj5 dye$).ti,ab.41. (electronic adj (sensor$ or nose)).ti,ab.42. (e-nose or e-sensor$ or x-ray$ or mri or nmr

or (gallium adj2 citrate)).ti,ab.43. tomography/ or exp computer assisted

tomography/ or nuclear magnetic resonanceimaging/ or exp X-Ray/

44. (imaging or scanning or scan or (computedand tomograph$) or ct or cat or (technetiumadj3 bone) or indium 111 or (labelled andwhite and cell) or hmpo or scintigraph$ or

(magnetic and resonance) or (nuclear andmagnetic)).ti,ab.






53. (signs and symptoms).mp.54. abscess/ or cellulitis/ or abscess drainage/ or

wound drainage/ or exp Erythema/ or Odor/55. pain/ or exp bone pain/ or exp leg pain/ or

exp neuralgia/ or exp exudate/ or cyst fluid/56. (public health laboratory or phl).ti,ab.57. (molecular adj (screen$ or diagnos$)).ti,ab.58. (polymerase chain reaction adj3






71. ((foot or feet) adj6 diabet$).ti,ab.72. deep foot infection$.ti,ab.73. exp Foot Ulcer/74. or/69-7375. Leg Ulcer/76. leg varicosis/77. ((crural or leg) adj5 ulcer$).ti,ab.78. ((venous or stasis or varicos$) adj5 (leg or


or wound$)).ti,ab.


109


81. or/75-8082. 74 or 8183. or/1-2184. or/22-6885. 82 and 83 and 8486. exp diagnosis/87. diagnos$.mp.88. 86 or 87 or 8389. 88 and 82 and 84


MEDLINE (1996–2002 October, week 5) andPREMEDLINE (up to 21 November 2002)(searched: 24 November 2002 on OvidWebGateway at http://gateway.ovid.com/athens)

1. exp "Sensitivity and Specificity"/2. False Positive Reactions/3. False Negative Reactions/4. (specificit$ or sensitivit$).ti,ab.5. (false negative$ or false positive$ or true

negative$ or true positive$).ti,ab.6. (positive rate$ or negative rate$).ti,ab.7. screening.ti,ab.8. accuracy.ti,ab.9. reference value$.ti,ab.

10. likelihood ratio$.ti,ab.11. (sroc or srocs or roc or rocs).ti,ab.12. receiver operat$ curve$.ti,ab.13. receiver operat$ character$.ti,ab.14. roc-curve/ or logistic-models/ or likelihood-

functions/15. diagnosis/ or exp "diagnostic errors"/ or exp

"diagnostic techniques and procedures"/ or exp"laboratory techniques and procedures"/



18. diagnostic yield$.mp. or misdiagnos$.ti,ab.[mp=ti, ab, rw, sh]

19. (reproductivity or logistical regression).mp. orlogistical model$.ti,ab. [mp=ti, ab, rw, sh]






adj2 sample$).ti,ab.27. (sausage toe or dactylitis).ti,ab.

28. (puncture or biopsy or biopsies or needleaspiration$ or (bone adj2 prob$)).ti,ab.

29. exp Specimen Handling/30. exp Biopsy/31. exp Microbiological Techniques/32. Curettage/33. (excis$ or curettage or curetage or curet or


34. exp Irrigation/ or exp chromatography/ oryeasts/



37. exp Fluorescent Antibody Technique/38. exp Fluorescent Dyes/39. (fluorogenic substrate$ or fluorochrome$ or



41. exp Pseudomonas fluorescens/42. pseudomonas fluorescen$.ti,ab.43. ((Fluorescen$ or vital) adj5 dye$).ti,ab.44. (electronic adj (sensor$ or nose)).ti,ab.45. (e-nose or e-sensor$ or x-ray$ or mri or nmr

or (gallium adj2 citrate)).ti,ab.46. exp Tomography, X-Ray Computed/ or exp

Magnetic Resonance Imaging/ or exp X-Rays/47. (imaging or scanning or scan or (computed

and tomograph$) or ct or cat or (technetiumadj3 bone) or indium 111 or (labelled andwhite and cell) or hmpo or scintigraph$ or(magnetic and resonance) or (nuclear andmagnetic)).ti,ab.






56. (signs and symptoms).mp.57. suppuration/ or abscess/ or cellulitis/ or

Cicatrix/ or Drainage/ or Erythema/ or Odors/

Appendix 1

110

58. pain/ or neuralgia/ or pain, intractable/ or"exudates and transudates"/ or cyst fluid/

59. (public health laboratory or phl).ti,ab.60. (molecular adj (screen$ or diagnos$)).ti,ab.61. (polymerase chain reaction adj3




72. ((neuroisch?emi$ or isch?emi$ or diabetic or neuropathic) adj3 (foot or feet orulcer$)).ti,ab.



ulcer$)).ti,ab.82. ((venous or stasis or leg) adj5 wound$).ti,ab.83. ((lower extremit$ or lower limb$) adj5 (ulcer$

or wound$)).ti,ab.84. or/78-8385. 77 or 8486. (or/1-23) and (or/24-71) and 85


Generic searchesInternet resources and databasesSearched: 26 August 2002Those Internet sites that contained only a fewreferences were simply browsed for relevantpapers. Other Internet sites were searched using asearch engine/search form. The search interfacesallowed only very simple searching and in mostinstances a series of keywords were entered andthe results scanned for relevant material. Most webinterfaces do not offer date restriction and none ofthe searches were limited by date. There was someduplication between the results and these were

removed before all potentially relevant recordswere entered into an Endnote Library.

Health Evidence Bulletins Wales no hitshttp://www.uwcm.ac.uk/uwcm/1b/pep

Health Services Technology Assessment Text(HSTAT)no hitshttp://text.nlm.nih.gov/

National Coordinating Centre for HealthTechnology Assessment 1 hithttp://www.hta.nhsweb.nhs.uk

National Guideline Clearinghouseno hitshttp://www.ahcpr.gov/clinic/assess.htm

National Institute for Health and ClinicalExcellence (NICE) (published appraisals)1 hithttp://www.nice.org.uk/nice-web/

Scottish Intercollegiate Guidelines Network(SIGN) Guidelines1 hithttp://www.sign.ac.uk/

Turning Research Into Practice (TRIP) Index110 hitshttp://www.ceres.uwcm.ac.uk/framset.cfm?section=trip

CD-ROM resources Health Management Information Consortium(HMIC) Databases; HELMIS 1984–1998/DH-Data & King’s Fund Database 1983–2002/King’sFund Database 1979–2002 (searched: 9 November 2002 on ARCSilverPlatter)1. (neuroisch?emic or isch?emic or diabetic or

neuropathic) near3 (foot or feet or ulcer*)2. (pedal or plantar or foot or feet or heel) near3

(ulcer* or septic or wound*)3. (foot or feet) near6 diabet*4. deep foot infection*5. (crural or leg) near5 ulcer*6. (venous or stasis or varicos*) near5 (leg or

ulcer*)7. (lower extremit* or lower limb*) near5 (ulcer*

or wound*)8. #1 or #2 or #3 or #4 or #5 or #6 or #7



111


National Research Register (NRR) (2002, Issue 4)(searched: 12 November 2002) The National Research Register (NRR) wassearched using the CD-ROM interface.#1 (neuroisch?emic or isch?emic or diabetic or

neuropathic) near (foot or feet or ulcer*)#2 (pedal or plantar or foot or feet or heel) near

(ulcer* or septic or wound*)#3 (foot or feet) near diabet*#4 deep foot infection*#5 (crural or leg) near ulcer*#6 (venous or stasis or varicos*) near (leg or

ulcer*)#7 (lower extremit* or lower limb*) near (ulcer*

or wound*)#8 #1 or #2 or #3 or #4 or #5 or #6 or #7


SIGLE (1980–2002 June) (searched: 6 November2002 on ARC SilverPlatter)#1 (neuroisch?emic or isch?emic or diabetic or

neuropathic) near3 (foot or feet or ulcer*)#2 (pedal or plantar or foot or feet or heel) near3

(ulcer* or septic or wound*)#3 (foot or feet) near6 diabet*#4 deep foot infection*#5 (crural or leg) near5 ulcer*#6 (venous or stasis or varicos*) near5 (leg or

ulcer*)#7 (lower extremit* or lower limb*) near5 (ulcer*

or wound*)#8 #1 or #2 or #3 or #4 or #5 or #6 or #7


Appendix 1

112

ResultsNumber of records retrieved by search type and database

Database Clinical-effectiveness Cost-effectiveness Diagnostic testing

MEDLINE and PREMEDLINE 590 261 1471EMBASE 449 250 1549CINAHL 72 85 68British Nursing Index (BNI) 67 23 54Allied and Complementary Medicine (AMED) 49 15 44EconLit 0 3HEED 0 77NHS EED admin. 0 172SIGLEa 43CDSR 35CCTR 176DARE admin. 154HTA admin. 20Controlled Trials 89NRRa 95HELMISa 189Total/pre- and post-removal of duplicate citations 2028/1310 886/747 3186/2762

a The search strategy covered all three search types: clinical effectiveness, cost-effectiveness and diagnostic testing.

Members of the expert advisory panelprovided feedback on the draft protocol and

review.

Dr Jan ApelqvistDepartment of Internal Medicine, LundUniversity Hospital, Sweden

Dr David G. ArmstrongDirector of Research and Education, Departmentof Surgery, Podiatry Section, Southern ArizonaVeterans Affairs Medical Center, Tucson, AZ, USA

Professor Andrew BoultonSchool of MedicineUniversity of ManchesterManchester, UK

Dr Phil BowlerWound Care & Prevention Global DevelopmentCentre, ConvaTec, Deeside Industrial Park,Flintshire, UK

Dr Gregory CaputoCenter for Locomotion Studies, Pennsylvania StateDiabetes Foot Clinics, Pennsylvania StateUniversity, University ParkPA, USA

Dr Carol DealeyResearch Fellow, School of Health Sciences,University of Birmingham and University HospitalBirmingham NHS Trust, Research andDevelopment Office, UK.

Ms Jacque DinnesSenior Research Fellow, Wessex Institute forHealth Research and Development, University ofSouthampton, UK

Dr Dawn Dowding Department of Health Sciences/Hull York MedicalSchool, University of York, UK

Ms Madeleine FlanaganAssociate Head of Department, Department ofPost-Registration Nursing, University ofHertfordshire, Hatfield, UK

Mr Brian GilchristHead of Pre-registration Education, FlorenceNightingale School of Nursing and Midwifery,King’s College London, UK

Professor Keith HardingDepartment of Rehabilitation Medicine (WoundHealing), University of Wales College of Medicine,Cardiff, UK

Daniel HigmanConsultant SurgeonWalsgrave HospitalCoventry, UK

Professor Derek L. HuntFaculty of Health Sciences, McMaster University,Hamilton, Ontario, Canada

Ms June JonesResearch Fellow/Clinical Nurse Specialist, Healthand Community Care Research Unit (HaCCRU),University of Liverpool, UK

Dr Khalid S. KhanEducation Resource Centre, Birmingham Women'sHealthcare NHS Trust, UK

Dr Christopher LawrenceNewton House, Crick, near Chepstow, UK

Professor DJ LeaperUniversity Hospital of North Tees, Hardwick,Stockton on Tees, UK

Professor BA LipskyAntibiotic Research Clinic, Veterans’ Affairs PugetSound Health Care System and Department ofMedicine, University of Washington, Seattle, WA,USA

Dr Astrid K PetrichMolecular Microbiologist, Department ofPathology and Molecular Medicine, McMasterUniversity, Hamilton, Ontario, Canada

Professor Terence J RyanWound Healing Institute, Oxford, UK


113


Appendix 2

Expert advisory panel

Dr Joseph B SelkonDepartment of Microbiology, John RadcliffeHospital, Oxford, UK

Ms Jude SmithPodiatrist, Department of Podiatry, Selby and YorkNHS Primary Care Trust, Diabetes Centre, YorkDistrict Hospital, UK

Dr Steve ThomasSurgical Materials Testing Laboratory, Princess ofWales Hospital, Bridgend, UK

Dr Carl ThompsonSenior Research Fellow, Department of HealthSciences, University of York, UK

Dr Marie WestwoodResearch Fellow, NHS Centre for Reviews andDissemination, University of York, UK

Mrs Anne WitherowAltnaglevin Hospital Trust, Londonderry, UK

Mr Peter Jackson (Manchester, UK) and ProfessorKeith Wilson (York, UK) kindly provided a patientperspective.

Appendix 2

114


115


Appendix 3

Data extraction forms

Abbreviations used in the following tables are given in the footnote after the final table.

Appendix 3

116 Que

stio

n 1a

: dia

gnos

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f wou

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usin

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Gen

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Mea

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Type

of d

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Evid

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Evid

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117


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d. R

epor

tnu

mbe

r of

pat

ient

s re

ceiv

ing

the

refe

renc

e te

st a

nd e

xpla

inho

w p

atie

nts

wer

e se

lect

ed if

the

num

ber

is di

ffere

nt fr

omth

ose

rece

ivin

g th

e in

dex

test

Stat

e tim

e la

g be

twee

n th

ein

dex

and

refe

renc

e te

sts.

Sta

tew

ho a

dmin

ister

ed t

he t

ests

Stat

istic

al m

etho

ds

Sens

itivi

ty a

nd s

peci

ficity

Like

lihoo

d ra

tios

Dia

gnos

tic o

dds

ratio

Posit

ive

and

nega

tive

pred

ictiv

e va

lues

ROC

ana

lysis

Adv

erse

effe

cts

of t

ests

Hea

lth-r

elat

ed q

ualit

y of

life

Adh

eren

ce w

ith r

egim

en

Num

bers

of

patie

nts

lost

to

follo

w-u

p

Reas

ons

for

loss

to fo

llow

-up

Not

es a

bout

dupl

icat

epu

blic

atio

n

Lim

itatio

ns o

f the

stud

y as

not

ed b

yau

thor

s or

revi

ewer

Stud

y sp

onso

rshi

p

Appendix 3

118 Que

stio

n 2a

: dia

gnos

is –

sam

plin

g m

etho

ds (

diab

etic

foot

ulc

er)

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsR

esul

tsW

ithd

raw

als

Com

men

ts

Firs

t au

thor

, yea

r,co

untr

y

Stud

y de

sign:

case

–con

trol

,co

hort

, oth

er?

Pros

pect

ive

orre

tros

pect

ive?

Met

hod

of p

atie

ntse

lect

ion

(e.g

.co

nsec

utiv

e,ra

ndom

)C

alcu

latio

n of

stat

istic

al p

ower

Out

com

es a

sses

sed

and

met

hods

of

data

col

lect

ion

used

Sett

ing

Elig

ibili

ty c

riter

iafo

r in

clus

ion

in t

hest

udy

Prev

alen

ce o

fdi

seas

e in

the

sam

ple

Des

crip

tion

ofst

udy

popu

latio

n –

spec

trum

com

posit

ion

Gen

der

Ethn

icity

Mea

n ±

SD a

ge

Type

of d

iabe

tes

Mea

n ±

SD d

urat

ion

ofdi

abet

es

Trea

ted

with

ora

l ant

i-dia

betic

med

icat

ion/

insu

lin d

epen

dent

Mea

n ±

SD H

bA1 C

Body

wei

ght/

BMI

Evid

ence

of n

euro

path

y, an

d ty

pe

Evid

ence

of i

scha

emia

, deg

ree

and

met

hod

of a

sses

smen

t (e

.g.

toe

pres

sure

, ABP

I, T

CPO

2) o

rot

her

vasc

ular

dise

ase

Pres

ence

of r

etin

opat

hy

Und

erly

ing

fact

ors

such

as

nutr

ition

al s

tatu

s,im

mun

ocom

pete

nce,

cont

inen

ce, m

obili

ty

Mea

n ±

SD u

lcer

are

a

Mea

n ±

SD u

lcer

dep

th

Mea

n ±

SD u

lcer

vol

ume

Mea

n ±

SD u

lcer

dur

atio

n

Num

ber

of u

lcer

epi

sode

s

Gra

de o

f ulc

er (e

.g. W

agne

r)

Prev

ious

am

puta

tion

Pres

ence

of n

ecro

tic t

issue

Pres

ence

of c

allu

s

Bact

erio

logy

Prio

r/cu

rren

t us

e of

antim

icro

bial

age

nts

Inde

x te

stPr

ovid

e de

scrip

tion

of d

iagn

ostic

inde

x te

st, i

.e. g

ive

deta

ils o

fsa

mpl

ing/

spec

imen

col

lect

ion

met

hods

use

d. R

epor

t nu

mbe

r of

patie

nts

rece

ivin

g th

e te

st

Refe

renc

e te

stPr

ovid

e de

scrip

tion

of r

efer

ence

tes

tus

ed. R

epor

t nu

mbe

r of

pat

ient

sre

ceiv

ing

the

refe

renc

e te

st a

ndex

plai

n ho

w p

atie

nts

wer

e se

lect

ed if

the

num

ber

is di

ffere

nt fr

om t

hose

rece

ivin

g th

e in

dex

test

Stat

e cu

t-of

f crit

erio

n us

ed. S

tate

time

lag

betw

een

the

inde

x an

dre

fere

nce

test

s. S

tate

who

adm

inist

ered

the

tes

ts

Repo

rt t

he fo

llow

ing,

if d

ata

avai

labl

efr

om t

he s

tudy

: typ

e of

sam

ple

used

(tiss

ue, a

spira

te, f

luid

, sw

ab) a

nd h

owit

was

tak

en (e

.g. s

wab

bing

met

hod

used

); if

swab

use

d, s

tate

typ

e (e

.g.

char

coal

tip

ped)

; wou

nd t

reat

men

tpr

ior

to s

ampl

ing

(e.g

. cle

ansin

g,de

brid

emen

t); t

rans

port

med

ium

used

; tra

nspo

rtat

ion

of s

ampl

e(t

imin

g an

d m

ode)

; lab

ellin

g of

sam

ple

(clin

ical

det

ail p

rovi

ded)

;ra

nge

of t

estin

g us

ed in

lab.

; whe

ther

spec

ific

assa

ys o

r ge

nera

l cul

ture

met

hods

use

d; m

etho

d of

rep

ortin

gre

sults

(qua

ntita

tive,

sem

i-qu

antit

ativ

e, c

onfir

med

iden

tific

atio

n,an

tibio

gram

); ot

her

inte

rven

tions

perf

orm

ed in

con

junc

tion

with

test

ing;

spe

ed o

f ret

urn

of r

epor

t;sp

eed

of a

ntib

iotic

pre

scrip

tion

Stat

istic

al m

etho

ds

Sens

itivi

ty a

ndsp

ecifi

city

Like

lihoo

d ra

tios

Dia

gnos

tic o

dds

ratio

Posit

ive

and

nega

tive

pred

ictiv

e va

lues

ROC

ana

lysis

Adv

erse

effe

cts

ofte

sts

Hea

lth-r

elat

ed q

ualit

yof

life

Adh

eren

ce w

ithre

gim

en

Num

bers

of

patie

nts

lost

to

follo

w-u

p

Reas

ons

for

loss

to fo

llow

-up

Not

es a

bout

dupl

icat

epu

blic

atio

n

Lim

itatio

ns o

f the

stud

y as

not

ed b

yau

thor

s or

revi

ewer

Stud

y sp

onso

rshi

p


119


Que

stio

n 2b

: dia

gnos

is –

sam

plin

g m

etho

ds (

veno

us le

g ul

cer)

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsR

esul

tsW

ithd

raw

als

Com

men

ts

Firs

t au

thor

, yea

r,co

untr

y

Stud

y de

sign:

case

–con

trol

,co

hort

, oth

er?

Pros

pect

ive

orre

tros

pect

ive?

Met

hod

of p

atie

ntse

lect

ion

(e.g

.co

nsec

utiv

e,ra

ndom

)

Cal

cula

tion

ofst

atist

ical

pow

er

Out

com

es a

sses

sed

and

met

hods

of

data

col

lect

ion

used

Sett

ing

Elig

ibili

ty c

riter

iafo

r in

clus

ion

in t

hest

udy

Prev

alen

ce o

fdi

seas

e in

the

sam

ple

Des

crip

tion

ofst

udy

popu

latio

n –

spec

trum

com

posit

ion

Gen

der

Ethn

icity

Mea

n ±

SD a

ge

Body

wei

ght/

BMI

Pres

ence

of c

o-m

orbi

ditie

s, e

.g.

diab

etes

Ass

essm

ent

of v

enou

spa

thol

ogy

(usin

g re

flect

ion

rheo

grap

hy, a

irpl

ethy

smog

raph

y, d

uple

xD

oppl

er u

ltras

ound

)

Und

erly

ing

fact

ors

such

as

nutr

ition

al s

tatu

s,im

mun

ocom

pete

nce,

cont

inen

ce, m

obili

ty

Mea

n ±

SD u

lcer

are

a

Mea

n ±

SD u

lcer

dep

th

Mea

n ±

SD u

lcer

vol

ume

Mea

n ±

SD u

lcer

dur

atio

n

Num

ber

of u

lcer

epi

sode

s

Gra

de o

f ulc

er

Pres

ence

of n

ecro

tic t

issue

Bact

erio

logy

Prio

r/cu

rren

t us

e of

antim

icro

bial

age

nts

Inde

x te

stPr

ovid

e de

scrip

tion

of d

iagn

ostic

inde

x te

st, i

.e. g

ive

deta

ils o

fsa

mpl

ing/

spec

imen

col

lect

ion

met

hods

use

d. R

epor

t nu

mbe

r of

patie

nts

rece

ivin

g th

e te

st

Refe

renc

e te

stPr

ovid

e de

scrip

tion

of r

efer

ence

tes

tus

ed. R

epor

t nu

mbe

r of

pat

ient

sre

ceiv

ing

the

refe

renc

e te

st, a

ndex

plai

n ho

w p

atie

nts

wer

e se

lect

ed if

the

num

ber

is di

ffere

nt fr

om t

hose

rece

ivin

g th

e in

dex

test

Stat

e cu

t-of

f crit

erio

n us

ed. S

tate

time

lag

betw

een

the

inde

x an

dre

fere

nce

test

s. S

tate

who

adm

inist

ered

the

tes

ts

Repo

rt t

he fo

llow

ing,

if d

ata

avai

labl

efr

om t

he s

tudy

: typ

e of

sam

ple

used

(tiss

ue, a

spira

te, f

luid

, sw

ab) a

nd h

owit

was

tak

en (e

.g. s

wab

bing

met

hod

used

); if

swab

use

d, s

tate

typ

e (e

.g.

char

coal

tip

ped)

; wou

nd t

reat

men

tpr

ior

to s

ampl

ing

(e.g

. cle

ansin

g,de

brid

emen

t); t

rans

port

med

ium

used

; tra

nspo

rtat

ion

of s

ampl

e(t

imin

g an

d m

ode)

; lab

ellin

g of

sam

ple

(clin

ical

det

ail p

rovi

ded)

;ra

nge

of t

estin

g us

ed in

lab.

; whe

ther

spec

ific

assa

ys o

r ge

nera

l cul

ture

met

hods

use

d; m

etho

d of

rep

ortin

gre

sults

(qua

ntita

tive,

sem

i-qu

antit

ativ

e, c

onfir

med

iden

tific

atio

n,an

tibio

gram

); ot

her

inte

rven

tions

perf

orm

ed in

con

junc

tion

with

test

ing;

spe

ed o

f ret

urn

of r

epor

t;sp

eed

of a

ntib

iotic

pre

scrip

tion

Stat

istic

al m

etho

ds

Sens

itivi

ty a

ndsp

ecifi

city

Like

lihoo

d ra

tios

Dia

gnos

tic o

dds

ratio

Posit

ive

and

nega

tive

pred

ictiv

e va

lues

ROC

ana

lysis

Adv

erse

effe

cts

ofte

sts

Hea

lth-r

elat

ed q

ualit

yof

life

Adh

eren

ce w

ithre

gim

en

Num

bers

of

patie

nts

lost

to

follo

w-u

p

Reas

ons

for

loss

to fo

llow

-up

Not

es a

bout

dupl

icat

epu

blic

atio

n

Lim

itatio

ns o

f the

stud

y as

not

ed b

yau

thor

s or

revi

ewer

Stud

y sp

onso

rshi

p

Appendix 3

120 Que

stio

n 3a

: dia

gnos

is –

labo

rato

ry m

etho

ds (

diab

etic

foot

ulc

er)

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsR

esul

tsW

ithd

raw

als

Com

men

ts

Firs

t au

thor

, yea

r,co

untr

y

Stud

y de

sign:

case

–con

trol

,co

hort

, oth

er?

Pros

pect

ive

orre

tros

pect

ive?

Met

hod

of p

atie

ntse

lect

ion

(e.g

.co

nsec

utiv

e,ra

ndom

)

Cal

cula

tion

ofst

atist

ical

pow

er

Out

com

es a

sses

sed

and

met

hods

of

data

col

lect

ion

used

Sett

ing

Elig

ibili

ty c

riter

iafo

r in

clus

ion

inth

e st

udy

Prev

alen

ce o

fdi

seas

e in

the

sam

ple

Des

crip

tion

ofst

udy

popu

latio

n–

spec

trum

com

posit

ion

Gen

der

Ethn

icity

Mea

n ±

SD a

ge

Type

of d

iabe

tes

Mea

n ±

SD d

urat

ion

of d

iabe

tes

Trea

ted

with

ora

l ant

i-dia

betic

med

icat

ion/

insu

lin d

epen

dent

Mea

n ±

SD H

bA1 C

Body

wei

ght/

BMI

Evid

ence

of n

euro

path

y, a

nd t

ype

Evid

ence

of i

scha

emia

, deg

ree

and

met

hod

of a

sses

smen

t (e

.g.

toe

pres

sure

, ABP

I, T

cPO

2), o

rot

her

vasc

ular

dise

ase

Pres

ence

of r

etin

opat

hy

Und

erly

ing

fact

ors

such

as

nutr

ition

al s

tatu

s,im

mun

ocom

pete

nce,

con

tinen

ce,

mob

ility

Mea

n ±

SD u

lcer

are

a

Mea

n ±

SD u

lcer

dep

th

Mea

n ±

SD u

lcer

vol

ume

Mea

n ±

SD u

lcer

dur

atio

n

Num

ber

of u

lcer

epi

sode

s

Gra

de o

f ulc

er (e

.g. W

agne

r)

Prev

ious

am

puta

tion

Pres

ence

of n

ecro

tic t

issue

Pres

ence

of c

allu

s

Bact

erio

logy

Prio

r/cu

rren

t us

e of

ant

imic

robi

alag

ents

Inde

x te

stPr

ovid

e de

scrip

tion

of d

iagn

ostic

inde

xte

st, i

.e.,

give

det

ails

of la

bora

tory

tech

niqu

es u

sed.

Rep

ort

num

ber

ofsa

mpl

es t

este

d

Refe

renc

e te

stPr

ovid

e de

scrip

tion

of r

efer

ence

tes

tus

ed. R

epor

t nu

mbe

r of

sam

ples

tes

ted,

and

expl

ain

how

the

sam

ples

wer

ese

lect

ed if

the

num

ber

is di

ffere

nt fr

omth

ose

test

ed w

ith t

he in

dex

test

Stat

e cu

t-of

f crit

erio

n us

ed. S

tate

tim

ela

g be

twee

n th

e in

dex

and

refe

renc

ete

sts.

Sta

te w

ho a

dmin

ister

ed t

he t

ests

Repo

rt t

he fo

llow

ing,

if d

ata

avai

labl

efr

om t

he s

tudy

: typ

e of

sam

ple

used

(tiss

ue, a

spira

te, f

luid

, sw

ab) a

nd h

ow it

was

tak

en (e

.g. s

wab

bing

met

hod

used

);if

swab

use

d, s

tate

typ

e (e

.g. c

harc

oal

tippe

d); w

ound

tre

atm

ent

prio

r to

sam

plin

g (e

.g. c

lean

sing,

deb

ridem

ent)

;tr

ansp

ort

med

ium

use

d; t

rans

port

atio

nof

sam

ple

(tim

ing

and

mod

e); l

abel

ling

of s

ampl

e (c

linic

al d

etai

l pro

vide

d);

rang

e of

tes

ting

used

in la

b.; w

heth

ersp

ecifi

c as

says

or

gene

ral c

ultu

rem

etho

ds u

sed;

met

hod

of r

epor

ting

resu

lts (q

uant

itativ

e, s

emi-q

uant

itativ

e,co

nfirm

ed id

entif

icat

ion,

ant

ibio

gram

);in

terp

reta

tion

of m

olec

ular

tes

ts a

ndap

prop

riate

ness

of c

ontr

ols

used

;cl

inic

ian’

s re

spon

se t

o la

bora

tory

resu

lts; o

ther

inte

rven

tions

per

form

edin

con

junc

tion

with

tes

ting;

spe

ed o

fre

turn

of r

epor

t; sp

eed

of a

ntib

iotic

pres

crip

tion

Stat

istic

al m

etho

ds

Sens

itivi

ty a

ndsp

ecifi

city

Like

lihoo

d ra

tios

Dia

gnos

tic o

dds

ratio

Posit

ive

and

nega

tive

pred

ictiv

eva

lues

ROC

ana

lysis

Adv

erse

effe

cts

ofte

sts

Hea

lth-r

elat

edqu

ality

of l

ife

Adh

eren

ce w

ithre

gim

en

Num

bers

of

patie

nts

lost

to

follo

w-u

p

Reas

ons

for

loss

to fo

llow

-up

Not

es a

bout

dupl

icat

epu

blic

atio

n

Lim

itatio

ns o

f the

stud

y as

not

ed b

yau

thor

s or

revi

ewer

Stud

y sp

onso

rshi

p


121


Que

stio

n 3b

: dia

gnos

is –

labo

rato

ry m

etho

ds (

veno

us le

g ul

cer)

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsR

esul

tsW

ithd

raw

als

Com

men

ts

Firs

t au

thor

, yea

r,co

untr

y

Stud

y de

sign:

case

–con

trol

,co

hort

, oth

er?

Pros

pect

ive

orre

tros

pect

ive?

Met

hod

of p

atie

ntse

lect

ion

(e.g

.co

nsec

utiv

e,ra

ndom

)

Cal

cula

tion

ofst

atist

ical

pow

er

Out

com

es a

sses

sed

and

met

hods

of

data

col

lect

ion

used

Sett

ing

Elig

ibili

ty c

riter

iafo

r in

clus

ion

inth

e st

udy

Prev

alen

ce o

fdi

seas

e in

the

sam

ple

Des

crip

tion

ofst

udy

popu

latio

n–

spec

trum

com

posit

ion

Gen

der

Ethn

icity

Mea

n ±

SD a

ge

Body

wei

ght/

BMI

Pres

ence

of c

o-m

orbi

ditie

s, e

.g.

diab

etes

Ass

essm

ent

of v

enou

s pa

thol

ogy

(usin

g re

flect

ion

rheo

grap

hy, a

irpl

ethy

smog

raph

y, d

uple

xD

oppl

er u

ltras

ound

)

Und

erly

ing

fact

ors

such

as

nutr

ition

al s

tatu

s,im

mun

ocom

pete

nce,

con

tinen

ce,

mob

ility

Mea

n ±

SD u

lcer

are

a

Mea

n ±

SD u

lcer

dep

th

Mea

n ±

SD u

lcer

vol

ume

Mea

n ±

SD u

lcer

dur

atio

n

Num

ber

of u

lcer

epi

sode

s

Gra

de o

f ulc

er

Pres

ence

of n

ecro

tic t

issue

Bact

erio

logy

Prio

r/cu

rren

t us

e of

ant

imic

robi

alag

ents

Inde

x te

stPr

ovid

e de

scrip

tion

of d

iagn

ostic

inde

xte

st, i

.e. g

ive

deta

ils o

f lab

orat

ory

tech

niqu

es u

sed.

Rep

ort

num

ber

ofsa

mpl

es t

este

d

Refe

renc

e te

stPr

ovid

e de

scrip

tion

of r

efer

ence

tes

tus

ed. R

epor

t nu

mbe

r of

sam

ples

tes

ted

and

expl

ain

how

the

sam

ples

wer

ese

lect

ed if

the

num

ber

is di

ffere

nt fr

omth

ose

test

ed w

ith t

he in

dex

test

Stat

e cu

t-of

f crit

erio

n us

ed. S

tate

tim

ela

g be

twee

n th

e in

dex

and

refe

renc

ete

sts.

Sta

te w

ho a

dmin

ister

ed t

he t

ests

Repo

rt t

he fo

llow

ing,

if d

ata

avai

labl

efr

om t

he s

tudy

: typ

e of

sam

ple

used

(tiss

ue, a

spira

te, f

luid

, sw

ab) a

nd h

ow it

was

tak

en (e

.g. s

wab

bing

met

hod

used

);if

swab

use

d, s

tate

typ

e (e

.g. c

harc

oal

tippe

d); w

ound

tre

atm

ent

prio

r to

sam

plin

g (e

.g. c

lean

sing,

deb

ridem

ent)

;tr

ansp

ort

med

ium

use

d; t

rans

port

atio

nof

sam

ple

(tim

ing

and

mod

e); l

abel

ling

of s

ampl

e (c

linic

al d

etai

l pro

vide

d);

rang

e of

tes

ting

used

in la

b.; w

heth

ersp

ecifi

c as

says

or

gene

ral c

ultu

rem

etho

ds u

sed;

met

hod

of r

epor

ting

resu

lts (q

uant

itativ

e, s

emi-q

uant

itativ

e,co

nfirm

ed id

entif

icat

ion,

ant

ibio

gram

);in

terp

reta

tion

of m

olec

ular

tes

ts a

ndap

prop

riate

ness

of c

ontr

ols

used

;cl

inic

ian’

s re

spon

se t

o la

bora

tory

resu

lts; o

ther

inte

rven

tions

per

form

edin

con

junc

tion

with

tes

ting;

spe

ed o

fre

turn

of r

epor

t; sp

eed

of a

ntib

iotic

pres

crip

tion

Stat

istic

al m

etho

ds

Sens

itivi

ty a

ndsp

ecifi

city

Like

lihoo

d ra

tios

Dia

gnos

tic o

dds

ratio

Posit

ive

and

nega

tive

pred

ictiv

eva

lues

ROC

ana

lysis

Adv

erse

effe

cts

ofte

sts

Hea

lth-r

elat

edqu

ality

of l

ife

Adh

eren

ce w

ithre

gim

en

Num

bers

of

patie

nts

lost

to

follo

w-u

p

Reas

ons

for

loss

to fo

llow

-up

Not

es a

bout

dupl

icat

epu

blic

atio

n

Lim

itatio

ns o

f the

stud

y as

not

ed b

yau

thor

s or

revi

ewer

Stud

y sp

onso

rshi

p

Appendix 3

122 Que

stio

n 4:

ass

essi

ng im

pact

of m

icro

biol

ogic

al a

naly

sis

on t

hera

py in

dia

beti

c fo

ot u

lcer

s

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsR

esul

tsW

ithd

raw

als

Com

men

ts

Firs

t au

thor

, yea

r,co

untr

y

Stud

y de

sign:

RC

Tor

CC

T

Met

hod

ofra

ndom

isatio

n (o

rm

etho

d of

allo

catio

n if

CC

T)

Uni

t of

allo

catio

n

Cal

cula

tion

ofst

atist

ical

pow

er

Out

com

es a

sses

sed

and

met

hods

of

data

col

lect

ion

used

Sett

ing

Popu

latio

n

Incl

usio

n cr

iteria

Excl

usio

n cr

iteria

Gen

der

Ethn

icity

Mea

n ±

SD a

ge

Type

of d

iabe

tes

Mea

n ±

SD d

urat

ion

of d

iabe

tes

Trea

ted

with

ora

l ant

i-dia

betic

med

icat

ion/

insu

lin d

epen

dent

Mea

n ±

SD H

bA1 C

Body

wei

ght/

BMI

Evid

ence

of n

euro

path

y an

d ty

pe

Evid

ence

of i

scha

emia

, deg

ree

and

met

hod

of a

sses

smen

t (e

.g.

toe

pres

sure

, ABP

I, T

CPO

2) o

rot

her

vasc

ular

dise

ase

Pres

ence

of r

etin

opat

hy

Und

erly

ing

fact

ors

such

as

nutr

ition

al s

tatu

s,im

mun

ocom

pete

nce,

con

tinen

ce,

mob

ility

Mea

n ±

SD u

lcer

are

a

Mea

n ±

SD u

lcer

dep

th

Mea

n ±

SD u

lcer

vol

ume

Mea

n ±

SD u

lcer

dur

atio

n

Num

ber

of u

lcer

epi

sode

s

Gra

de o

f ulc

er (e

.g. W

agne

r)

Prev

ious

am

puta

tion

Pres

ence

of n

ecro

tic t

issue

Pres

ence

of c

allu

s

Bact

erio

logy

Prio

r/cu

rren

t us

e of

ant

imic

robi

alag

ents

I1: d

escr

iptio

n of

stra

tegy

‘tre

at w

ithou

tkn

owin

g re

sults

of

mic

robi

olog

ical

ana

lysis

’,gi

ving

nam

es o

fan

tibio

tics

or o

ther

agen

ts p

resc

ribed

, with

dose

, fre

quen

cy a

nddu

ratio

n of

adm

inist

ratio

n. A

lsore

port

des

crip

tion

ofot

her

conc

omita

ntin

terv

entio

ns u

sed

such

as t

opic

al a

pplic

atio

nsan

d/or

dre

ssin

gs. R

epor

tnu

mbe

r of

pat

ient

sre

ceiv

ing

this

stra

tegy

I2: d

escr

iptio

n of

stra

tegy

‘tre

at a

fter

rece

ivin

g re

sults

of

mic

robi

olog

ical

ana

lysis

’,gi

ving

nam

es o

fan

tibio

tics

or o

ther

agen

ts p

resc

ribed

, with

dose

, fre

quen

cy a

nddu

ratio

n of

adm

inist

ratio

n. A

lsore

port

des

crip

tion

ofot

her

conc

omita

ntin

terv

entio

ns u

sed

such

as t

opic

al a

pplic

atio

nsan

d/or

dre

ssin

gs. R

epor

tnu

mbe

r of

pat

ient

sre

ceiv

ing

this

stra

tegy

Stat

e sp

eed

of r

etur

n of

repo

rt a

nd s

peed

of

antib

iotic

pre

scrip

tion

Stat

istic

al m

etho

ds

Mor

talit

y (a

ll)

Mor

talit

y (r

elat

ed t

o am

puta

tion)

Am

puta

tion

(inci

denc

e an

d ty

pe,

e.g.

maj

or/m

inor

)

Inci

denc

e of

ost

eom

yelit

is

Num

ber/

dura

tion

of h

ospi

tal

adm

issio

ns fo

r D

FU p

robl

ems

Prop

ortio

n of

pat

ient

s ac

hiev

ing

com

plet

e he

alin

g

Tim

e to

com

plet

e he

alin

g

Cha

nge

in u

lcer

are

a (a

bsol

ute

orpe

rcen

tage

val

ues)

Rem

aini

ng w

ound

are

a

Hea

ling

rate

(abs

olut

e or

rel

ativ

e)

Cha

nge

in u

lcer

dep

th (a

bsol

ute

or r

elat

ive)

Cha

nge

in u

lcer

vol

ume

(abs

olut

eor

rel

ativ

e)

Recu

rren

ce o

f ulc

er

Pain

(in

patie

nts

with

out

neur

opat

hy)

Bact

eria

l pro

file

Acq

uisit

ion

of r

esist

ant

orga

nism

s

Rela

tions

hip

betw

een

ulce

rhe

alin

g an

d ba

cter

iolo

gy

Cha

nge

in m

obili

ty

Cha

nge

in le

vel o

f dep

ende

nce

Adv

erse

eve

nts

Qua

lity

of li

fe

Adh

eren

ce w

ith t

reat

men

tre

gim

en

Num

bers

of

with

draw

als

per

trea

tmen

t gr

oup

Reas

ons

for

with

draw

al

Not

es a

bout

dupl

icat

epu

blic

atio

n

Lim

itatio

ns o

f the

stud

y as

not

ed b

yau

thor

s or

revi

ewer

Stud

y sp

onso

rshi

p


123


Que

stio

n 5a

: ass

essi

ng c

linic

al e

ffect

iven

ess

of t

hera

py in

dia

beti

c fo

ot u

lcer

s

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

enti

on d

etai

lsR

esul

tsW

ithd

raw

als

Com

men

ts

Firs

t au

thor

, yea

r,co

untr

y

Stud

y de

sign:

RC

Tor

CC

T

Met

hod

ofra

ndom

isatio

n (o

rm

etho

d of

allo

catio

n if

CC

T)

Uni

t of

allo

catio

n

Cal

cula

tion

ofst

atist

ical

pow

er

Out

com

es a

sses

sed

and

met

hods

of

data

col

lect

ion

used

Sett

ing

Popu

latio

n

Incl

usio

n cr

iteria

Excl

usio

n cr

iteria

Gen

der

Ethn

icity

Mea

n ±

SD a

ge

Type

of d

iabe

tes

Mea

n ±

SD d

urat

ion

of d

iabe

tes

Trea

ted

with

ora

l ant

i-dia

betic

med

icat

ion/

insu

lin d

epen

dent

Mea

n ±

SD H

bA1 C

Body

wei

ght/

BMI

Evid

ence

of n

euro

path

y an

d ty

pe

Evid

ence

of i

scha

emia

, deg

ree

and

met

hod

of a

sses

smen

t (e

.g.

toe

pres

sure

, ABP

I, T

CPO

2) o

rot

her

vasc

ular

dise

ase

Pres

ence

of r

etin

opat

hy

Und

erly

ing

fact

ors

such

as

nutr

ition

al s

tatu

s,im

mun

ocom

pete

nce,

con

tinen

ce,

mob

ility

Mea

n ±

SD u

lcer

are

a

Mea

n ±

SD u

lcer

dep

th

Mea

n ±

SD u

lcer

vol

ume

Mea

n ±

SD u

lcer

dur

atio

n

Num

ber

of u

lcer

epi

sode

s

Gra

de o

f ulc

er (e

.g. W

agne

r)

Prev

ious

am

puta

tion

Pres

ence

of n

ecro

tic t

issue

Pres

ence

of c

allu

s

Bact

erio

logy

Prio

r/cu

rren

t us

e of

ant

imic

robi

alag

ents

I1: d

escr

iptio

n of

antim

icro

bial

age

ntus

ed, g

ivin

g na

mes

of

antib

iotic

s or

oth

erag

ents

pre

scrib

ed, w

ithdo

se, f

requ

ency

and

dura

tion

ofad

min

istra

tion.

Also

repo

rt d

escr

iptio

n of

othe

r co

ncom

itant

inte

rven

tions

use

d su

chas

top

ical

app

licat

ions

and/

or d

ress

ings

. Rep

ort

num

bers

of p

atie

nts

rece

ivin

g th

is re

gim

en

I2: d

escr

iptio

n of

alte

rnat

ive

antim

icro

bial

agen

t us

ed, a

s ab

ove.

Repo

rt n

umbe

rs o

fpa

tient

s re

ceiv

ing

this

regi

men

C: d

escr

iptio

n of

con

trol

regi

men

, e.g

. sta

ndar

dca

re, g

ivin

g de

tails

of

any

agen

ts p

resc

ribed

,w

ith d

ose,

freq

uenc

yan

d du

ratio

n of

adm

inist

ratio

n. A

lsore

port

des

crip

tion

ofot

her

conc

omita

ntin

terv

entio

ns u

sed

such

as t

opic

al a

pplic

atio

nsan

d/or

dre

ssin

gs. R

epor

tnu

mbe

rs o

f pat

ient

sre

ceiv

ing

this

regi

men

Stat

istic

al m

etho

ds

Mor

talit

y (a

ll)

Mor

talit

y (r

elat

ed t

o am

puta

tion)

Am

puta

tion

(inci

denc

e an

d ty

pe,

e.g.

maj

or/m

inor

)

Inci

denc

e of

ost

eom

yelit

is

Num

ber/

dura

tion

of h

ospi

tal

adm

issio

ns fo

r D

FU p

robl

ems

Prop

ortio

n of

pat

ient

s ac

hiev

ing

com

plet

e he

alin

g

Tim

e to

com

plet

e he

alin

g

Cha

nge

in u

lcer

are

a (a

bsol

ute

orpe

rcen

tage

val

ues)

Rem

aini

ng w

ound

are

a

Hea

ling

rate

(abs

olut

e or

rel

ativ

e)

Cha

nge

in u

lcer

dep

th (a

bsol

ute

or r

elat

ive)

Cha

nge

in u

lcer

vol

ume

(abs

olut

eor

rel

ativ

e)

Recu

rren

ce o

f ulc

er

Pain

(in

patie

nts

with

out

neur

opat

hy)

Bact

eria

l pro

file

Acq

uisit

ion

of r

esist

ant

orga

nism

s

Rela

tions

hip

betw

een

ulce

rhe

alin

g an

d ba

cter

iolo

gy

Cha

nge

in m

obili

ty

Cha

nge

in le

vel o

f dep

ende

nce

Adv

erse

eve

nts

Qua

lity

of li

fe

Adh

eren

ce w

ith t

reat

men

tre

gim

en

Num

bers

of

with

draw

als

per

trea

tmen

t gr

oup

Reas

ons

for

with

draw

al

Ratio

nale

for

defin

ing

the

stud

yag

ent

as a

nan

timic

robi

al a

gent

,if

nece

ssar

y

Not

es a

bout

dupl

icat

epu

blic

atio

n

Lim

itatio

ns o

f the

stud

y as

not

ed b

yau

thor

s or

revi

ewer

Stud

y sp

onso

rshi

p

Appendix 3

124 Que

stio

n 5b

: ass

essi

ng t

he c

ost-

effe

ctiv

enes

s of

tre

atm

ent

in d

iabe

tic

foot

ulc

ers

Stud

y id

enti

fier

and

Key

ele

men

ts o

f the

stu

dyC

linic

al e

ffect

iven

ess

data

Econ

omic

ana

lysi

sR

esul

tsC

omm

ents

obje

ctiv

e

Firs

t au

thor

, yea

r,co

untr

y

Obj

ectiv

e(s)

of t

hest

udy

Type

of e

cono

mic

eva

luat

ion,

e.g.

CEA

, CU

A, C

BA

Pers

pect

ive,

e.g

. NH

S,pa

tient

, ins

uran

ce c

ompa

ny,

soci

ety

Sett

ings

of c

linic

alef

fect

iven

ess

stud

y an

dec

onom

ic e

valu

atio

n

Spec

ify d

ates

to

whi

ch d

ata

rela

te fo

r cl

inic

alef

fect

iven

ess

data

, res

ourc

eus

e an

d pr

ices

use

d

Stat

e so

urce

s, e

.g. s

ingl

e st

udy,

synt

hesis

of s

tudi

es, e

xper

top

inio

n/au

thor

s’ a

ssum

ptio

ns,

com

bina

tion

of a

bove

. Spe

cify

stud

y de

sign,

e.g

. RC

T,sy

stem

atic

rev

iew

and

met

hods

of d

ata

anal

ysis

used

(e.g

.in

tent

ion-

to-t

reat

)

Part

icip

ants

– d

escr

ibe

char

acte

ristic

s

Inte

rven

tions

– p

rovi

de d

etai

lsof

inte

rven

tions

/reg

imen

s us

ed

Clin

ical

out

com

es a

sses

sed,

incl

udin

g ad

vers

e ef

fect

s

Brie

f des

crip

tion

of r

esul

ts

If sin

gle

stud

y us

ed, d

escr

ibe

link

betw

een

clin

ical

effe

ctiv

enes

s an

d co

st d

ata

Mea

sure

of h

ealth

ben

efits

use

d

Des

crip

tion

of c

osts

(sep

arat

ede

scrip

tions

for

dire

ct a

ndin

dire

ct c

osts

), in

clud

ing

spec

ific

cost

s ta

ken

into

acc

ount

, sou

rce

of c

ost

data

/met

hods

of

estim

atio

n, d

iscou

ntin

g (if

appl

icab

le)

Cur

renc

y

Met

hods

use

d fo

r st

atist

ical

anal

ysis

of q

uant

ities

and

cos

ts

Met

hod

used

for

sens

itivi

tyan

alys

es (e

.g. o

ne-w

ay o

r m

ulti-

way

ana

lysis

); de

scrib

e re

leva

ntva

riabl

es a

nd a

ny a

ssum

ptio

nsus

ed

Des

crib

e m

odel

s (if

any

) use

d fo

res

timat

ion

of b

enef

its a

nd/o

rco

sts

Repo

rt e

stim

ated

hea

lthbe

nefit

s

Repo

rt e

stim

ated

cos

ts

Repo

rt r

esul

ts o

fsy

nthe

sis o

f cos

ts a

ndbe

nefit

s, e

.g. i

ncre

men

tal

cost

–util

ity o

f tre

atm

ent

Repo

rt r

esul

ts o

fse

nsiti

vity

ana

lyse

s, a

ndde

scrib

e th

e ra

nge

ofva

lues

der

ived

Not

es a

bout

dup

licat

epu

blic

atio

n

Lim

itatio

ns o

f the

stu

dy–

com

men

t on

the

follo

win

g: c

hoic

e of

com

para

tor;

val

idity

of

estim

ates

of

effe

ctiv

enes

s, h

ealth

bene

fits

and

cost

s;ex

tern

al v

alid

ity o

ffin

ding

s; a

utho

rs’ o

wn

note

s ab

out

limita

tions

of t

he s

tudy

. Sta

tew

heth

er t

he a

utho

rs’

conc

lusio

ns w

ere

just

ified

giv

en t

helim

itatio

ns o

f the

stu

dy

Stud

y sp

onso

rshi

p

ABP

I, an

kle

brac

hial

pre

ssur

e in

dex;

BM

I, bo

dy m

ass

inde

x; C

, con

trol

gro

up; C

BA, c

ost–

bene

fit a

naly

sis; C

CT,

con

trol

led

clin

ical

tria

l; C

EA, c

ost–

effe

ctiv

enes

s an

alys

is; C

UA

, cos

t-ut

ility

ana

lysis

; DFU

, dia

betic

foot

ulc

er; H

bA1 C

, gly

cosy

late

d ha

emog

lobi

n co

ncen

trat

ion;

I1, f

irst

inte

rven

tion

grou

p; I2

, sec

ond

inte

rven

tion

grou

p; R

CT,

ran

dom

ised

cont

rolle

d tr

ial;

ROC

, rec

eive

r op

erat

ing

char

acte

ristic

; SD

, sta

ndar

d de

viat

ion;

TCPO

2, t

rans

cuta

neou

s pr

essu

re o

f oxy

gen.


125


Appendix 4

Data extraction tables

Appendix 4

126 Dia

gnos

is d

ata

extr

acti

on

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sTe

st d

etai

lsRe

sults

With

draw

als

Com

men

ts

Gar

dner

(200

1),90

,95,

145

USA

Stud

y de

sign:

Cro

ss-s

ectio

nal

Met

hod

of p

atie

ntse

lect

ion:

Not

stat

ed

Out

com

eas

sess

men

t:A

dry

gauz

edr

essin

g w

asap

plie

d to

the

wou

nd a

nd le

ft in

plac

e fo

r 1ho

ur in

orde

r to

stan

dard

iseco

nditi

ons f

oras

sess

ing

wou

ndex

udat

e. A

fter

1ho

ur, t

hedr

essin

g w

asre

mov

ed a

nd th

ew

ound

and

dres

sing

wer

eas

sess

ed u

sing

the

CSS

C. T

his s

tep

was

repe

ated

inde

pend

ently

by

a se

cond

nur

sera

ter

Setti

ng –

4ce

ntre

s. Si

te A

–ac

ute

care

vete

rans

’ fac

ility

outp

atie

nts c

linics

;

Inclu

sion

crite

ria:

Site

s A–C

: n

= 2

6 (A

20,

B 4

,C

2):

Age

at le

ast

18 y

ears

; pre

senc

eof

full-

thick

ness

,no

n-ar

teria

lch

roni

c w

ound

;w

hite

blo

od c

ell

coun

t >

1500

cel

ls/m

m3

or to

tal

lymph

ocyt

e co

unt

>80

0 ce

lls/m

m3 ;

plat

elet

cou

nt>

125,

000/

mm

; no

coag

ulop

athi

es,

not o

nan

ticoa

gulat

ion

ther

apy

Site

D: n

= 1

0Ag

e at

leas

t18

year

s; pr

esen

ceof

non

-art

erial

chro

nic

wou

nd;

wou

nd b

iops

ype

rform

ed w

ithin

8ho

urs o

f dat

aco

llect

ion

Non

-art

erial

chro

nic

wou

nds

wer

e de

fined

as

wou

nds a

ssoc

iated

with

ven

ous

insu

fficie

ncy,

36 p

artic

ipan

ts re

crui

ted

Gen

der:

M 3

1 (8

6%),

F 5

(14%

)

Ethn

icity

: C

auca

sian:

35

(97%

)

Num

ber o

f wou

nds p

er p

artic

ipan

t:O

ne c

hron

ic w

ound

: 23

(63%

)Tw

o ch

roni

c w

ound

s: 6

(17%

)Th

ree

chro

nic

wou

nds:

6 (1

7%)

Four

chr

onic

wou

nds:

1 (3

%)

For p

artic

ipan

ts w

ith m

ore

than

one

wou

nd, a

sing

lew

ound

was

sele

cted

rand

omly

for s

tudy

.

Verif

ied

infe

ctio

n st

atus

:11

pat

ient

s had

pos

itive

wou

nd b

iops

y25

pat

ient

s had

neg

ative

wou

nd b

iops

y

Cha

ract

erist

ics fo

r tot

al sa

mpl

e; in

fect

ed a

nd n

on-

infe

cted

gro

ups:

Tota

lIn

f.N

on- I

nf.

Mea

n ±

SD65

.1 ±

64.5

±65

.4 ±

age:

13.2

16.9

11.5

Setti

ng:

Site

A20

(56%

)1

(9%

)19

(76%

)Si

te B

4 (1

1%)

0 (0

%)

4 (1

6%)

Site

C2

(5%

)0

(0%

)2

(8%

)Si

te D

10 (2

8%)

10 (9

1%)

0 (0

%)

Diab

etes

:N

one

20 (5

6%)

6 (5

5%)

14 (5

6%)

Type

12

(5%

)1

(9%

)1

(4%

)Ty

pe 2

14 (3

9%)

4 (3

6%)

10 (4

0%)

Nut

ritio

nal p

aram

eter

s (m

ean

±SD

):Re

d bl

ood

3.89

±0.

664.

06 ±

0.78

3.83

±0.

63ce

llsW

hite

blo

od

9.1

±5.

39.

2 ±

5.0

9.1

±5.

5ce

lls(n

= 3

3)(n

= 8

)(n

= 2

5)Al

bum

in3.

4 ±

0.7

3.5

±0.

83.

4 ±

0.7

(n=

32)

(n=

7)

(n=

25)

Tota

l pro

tein

6.9

±0.

97.

6 ±

0.5

6.8

±0.

9(n

= 3

0)(n

= 5

)(n

= 2

5)

Inde

x te

st:

Usin

g a

CSS

C, 5

indi

vidua

l clas

sic si

gns a

ndsy

mpt

oms o

f acu

tein

fect

ion

in c

hron

icw

ound

s wer

e ev

aluat

ed(p

ain, e

ryth

ema,

oed

ema,

heat

and

pur

ulen

tex

udat

e), p

lus 6

indi

vidua

l sign

s and

sym

ptom

s spe

cific

toin

fect

ion

in se

cond

ary

wou

nds (

sero

us e

xuda

tepl

us c

oncu

rren

tin

flam

mat

ion,

del

ayed

heali

ng, d

iscol

orat

ion

ofgr

anul

atio

n tis

sue,

friab

legr

anul

atio

n tis

sue,

foul

odou

r, an

d w

ound

brea

kdow

n). 3

6 pa

tient

sre

ceive

d th

e te

st

Refe

renc

e te

st:

Qua

ntita

tive

cultu

re o

fvia

ble

wou

nd ti

ssue

acco

rdin

g to

pro

cedu

res

outli

ned

by S

totts

.175

Wou

nd c

lean

sed

with

norm

al sa

line

usin

g st

erile

tech

niqu

e. A

ppro

x.1

g of

non-

necr

otic,

viab

lew

ound

tiss

ue o

btain

edfro

m th

e ce

ntre

of t

heul

cer u

sing

3 or

4 m

mde

rmal

punc

h un

der

ster

ile c

ondi

tions

. Tiss

uetr

ansp

orte

d im

med

iatel

yto

micr

obio

logy

labor

ator

y. M

etho

ds o

f

The

stud

y au

thor

s rep

orte

d 2

×2

diag

nost

ic da

ta fo

r eac

h of

11

clini

cal s

igns a

nd sy

mpt

oms o

fch

roni

c w

ound

infe

ctio

n, a

sfo

llow

s:

Incr

easin

g pa

in

Biop

sy

+–

Tota

l

CSS

C+

40

4–

725

32To

tal

1125

36

Eryt

hem

a

Biop

sy

+–

Tota

l

CSS

C+

68

14–

517

22To

tal

1125

36

Oed

ema

Biop

sy

+–

Tota

l

CSS

C+

77

14–

418

22To

tal

1125

36

Hea

t

Biop

sy

+–

Tota

l

CSS

C+

24

6–

921

30To

tal

1125

36

No

with

draw

alsw

ere

repo

rted

Lim

itatio

ns o

f the

stud

y as

not

ed b

yau

thor

s:

Cro

ss-s

ectio

nal

stud

y de

sign

prec

lude

s cau

sean

d ef

fect

relat

ions

hip

analy

sis. R

eliab

ility

of th

e C

SSC

nee

dsfu

rthe

r exp

lora

tion

with

a la

rger

, mor

ere

pres

enta

tive

sam

ple

ofcli

nicia

ns.

Gen

erali

sabi

lity

offin

ding

s lim

ited

owin

g to

non

-pr

obab

ility

sam

plin

g us

ed. T

heen

rolle

dpa

rtici

pant

s migh

tno

t be

repr

esen

tativ

e of

all c

hron

ic w

ound

patie

nts,

and

only

70%

of e

ligib

lepa

tient

s too

k pa

rtin

the

stud

y.Ag

reem

ent

betw

een

clini

cians

not a

ccou

nted

for

in e

stim

ates

of

valid

ity (e

stim

ates

base

d on

asse

ssm

ent o

f onl

yon

e ob

serv

atio

n).

cont

inue

d


127


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sTe

st d

etai

lsRe

sults

With

draw

als

Com

men

ts

Site

B –

vet

eran

s’lo

ng-te

rm c

are

facil

ity; S

ite C

–ve

tera

ns’ i

npat

ient

facil

ity w

ithnu

rsin

g ho

me

beds

,re

habi

litat

ion

beds

and

inte

rmed

iate

psyc

hiat

ry b

eds;

Site

D –

unive

rsity

-bas

edm

edica

l cen

tre

chro

nic

wou

ndcli

nic

serv

ing

inpa

tient

s and

outp

atie

nts

perip

hera

lne

urop

athy

,su

rgica

l inc

ision

, or

trau

ma,

with

adeq

uate

art

erial

perfu

sion

asde

term

ined

by

palp

able

loca

lpu

lses o

r ank

le-

brac

hial

inde

x>

0.5)

Rece

iving

syst

emic

antib

iotic

s at t

ime

of re

crui

tmen

t:N

o24

(67%

)10

(91%

)14

(56%

)Ye

s12

(33%

)1

(9%

)11

(44%

)

Rece

iving

ant

i-inf

lamm

ator

y m

edica

tion

at ti

me

ofre

crui

tmen

t:N

o20

(56%

)9

(82%

)11

(44%

)Ye

s16

(44%

)2

(18%

)14

(56%

)

Rece

iving

ster

oid

med

icatio

n at

tim

e of

recr

uitm

ent:

No

33 (9

2%)

10 (9

1%)

23 (9

2%)

Yes

3 (8

%)

1 (9

%)

2 (8

%)

Wou

nd ty

pe:

Pres

sure

ulce

r19

(53%

)3

(27%

)16

(64%

)Ve

nous

ulce

r7

(19%

)4

(37%

)3

(12%

)Se

cond

ary

incis

ion

6 (1

7%)

2 (1

8%)

4 (1

6%)

Chr

onic

trau

mat

ic2

(5.5

%)

1 (9

%)

1 (4

%)

Diab

etic

ulce

r2

(5.5

%)

1 (9

%)

1 (4

%)

Wou

nd si

ze:

Mea

n ±

SDar

ea (c

m2 )

4.5

±6.

95.

5 ±

6.1

4.1

±7.

3M

ean

±SD

dept

h (c

m)

1.3

±1.

60.

8 ±

0.9

1.4

±1.

8

Mea

n ±

SDw

ound

dur

atio

n (d

ays)

:61

6.6

1002

447.

1±

1742

.8±

2673

.3±

1163

.6

Num

ber (

%) o

f pat

ient

s with

nec

rotic

tiss

ue:

Non

e15

(42%

)1

(9%

)14

(56%

)<

25%

9 (2

5%)

5 (4

5%)

4 (1

6%)

25–5

0%8

(22%

)4

(36%

)4

(16%

)>

50 a

nd <

75%

3 (8

%)

1 (9

%)

2 (8

%)

75–1

00%

1 (3

%)

0 (0

%)

1 (4

%)

Type

of t

opica

l age

nts i

n us

e:N

one

24 (6

7%)

7 (6

4%)

17 (6

8%)

Gro

wth

fact

or4

(11%

)1

(9%

)3

(12%

)Si

lver s

ulfa

diaz

ine

4 (1

1%)

1 (9

%)

3 (1

2%)

Antib

iotic

3 (8

%)

2 (1

8%)

1 (4

%)

Wou

nd g

el

1 (3

%)

0 (0

%)

1 (4

%)

labor

ator

y cu

lturin

gfo

llow

ed th

ose

of K

rizek

and

Robs

on 17

6Ti

ssue

was

wei

ghed

,ho

mog

enise

d an

d se

rially

dilu

ted

and

plat

ed. E

ach

serie

s of d

ilutio

ns w

aspl

ated

und

er a

erob

ic an

dan

aero

bic

cond

ition

s.O

rgan

isms w

ere

iden

tifie

d us

ing

stan

dard

micr

obio

logic

alpr

oced

ures

. 36

patie

nts

rece

ived

the

test

Infe

cted

ulce

rs w

ere

defin

ed a

s tho

se h

avin

g at

leas

t 105

orga

nism

s per

gram

of v

iable

tiss

ue o

rw

ound

s con

tain

ing

haem

olyt

ic St

rept

ococ

cus

at a

ny le

vel.

Non

-in

fect

ed u

lcers

wer

ede

fined

as t

hose

with

spec

imen

s con

tain

ing

less

than

105

orga

nism

s per

gram

of t

issue

Tim

ing:

At

site

s A, B

and

C,

tissu

e bi

opsy

was

obta

ined

less

than

1ho

uraf

ter a

sses

smen

t with

the

CSS

C. A

t site

D, t

hew

ound

bio

psy

was

perfo

rmed

with

in

8 ho

urs o

f ass

essm

ent

with

CSS

C

Asse

ssm

ent o

f int

er-r

ater

relia

bilit

y:Th

e in

ter-

rate

r rel

iabilit

y

Puru

lent

exu

date

Biop

sy

+–

Tota

l

CSS

C+

29

11–

916

25To

tal

1125

36

Sero

us e

xuda

te p

lus c

oncu

rren

tin

flam

mat

ion

Biop

sy

+–

Tota

l

CSS

C+

67

13–

518

23To

tal

1125

36

Del

ayed

hea

ling

Biop

sy

+–

Tota

l

CSS

C+

99

18–

216

18To

tal

1125

36

Disc

olou

ratio

n

Biop

sy

+–

Tota

l

CSS

C+

711

18–

414

18To

tal

1125

36

Friab

le g

ranu

latio

n Biop

sy

+–

Tota

l

CSS

C+

96

15–

219

21To

tal

1125

36

Mix

ture

of

wou

nds/s

mall

sam

ple

prec

lude

dan

alysis

by

type

of

wou

nd

Stud

y sp

onso

rshi

p:pa

rt fu

ndin

g by

Nat

iona

l Pre

ssur

eU

lcer A

dviso

ryPa

nel,

Knol

lPh

arm

aceu

tical,

The

Ger

onto

logic

alN

ursin

gIn

terv

entio

nC

ente

r, th

e VA

Pred

octo

ral N

urse

Fello

wsh

ipPr

ogra

m, O

ffice

of

Acad

emic

Affil

iatio

ns,

Dep

artm

ent o

fVe

tera

ns A

ffairs

,an

Inst

itutio

nal

NRS

A fe

llow

ship

(Res

earc

h Tr

ainin

gin

Ger

onto

logic

alN

ursin

g) fr

om th

eN

atio

nal I

nstit

ute

of N

ursin

gRe

sear

ch, N

atio

nal

Inst

itute

s of

Hea

lth, a

nIn

stitu

tiona

l NRS

Afe

llow

ship

(Inte

rdisc

iplin

ary

Rese

arch

Tra

inin

gPr

ogra

m o

n Ag

ing)

from

the

Nat

iona

l

cont

inue

d

Appendix 4

128

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sTe

st d

etai

lsRe

sults

With

draw

als

Com

men

ts

of th

e ite

ms o

n th

ech

eckl

ist w

as a

sses

sed

usin

g w

ound

obse

rvat

ions

mad

ein

depe

nden

tly b

y th

epr

incip

al in

vest

igato

r and

one

of fi

ve sp

ecifi

cally

train

ed n

urse

sre

pres

entin

g ea

ch st

udy

site.

The

�ra

nge

was

0.53

–1.0

0. N

oag

reem

ent w

as fo

und

for

one

clini

cal s

ign(p

ocke

ting

of th

e w

ound

base

) due

to n

on-

occu

rren

ce o

f the

sign

inth

e st

udy

sam

ple.

Ther

efor

e, th

e di

agno

stic

perfo

rman

ce o

f thi

s sign

was

not

eva

luat

ed

Foul

odo

ur

Biop

sy

+–

Tota

l

CSS

C+

43

7–

722

29To

tal

1125

36

Wou

nd b

reak

dow

n Biop

sy

+–

Tota

l

CSS

C+

50

5–

625

31To

tal

1125

36

Resu

lts fo

r tot

al sa

mpl

e (n

= 3

6)Se

nsiti

vity

and

spec

ificit

y of

eac

hsig

n or

sym

ptom

(calc

ulat

ed b

yst

udy

auth

ors a

nd c

heck

ed b

yre

view

er):

SeSp

Incr

easin

g pa

in36

%10

0%Er

ythe

ma

55%

68%

Oed

ema

64%

72%

Hea

t18

%84

%Pu

rule

nt e

xuda

te18

%64

%Se

rous

+

infla

mm

atio

n55

%72

%D

elay

ed h

ealin

g81

%64

%D

iscol

orat

ion

64%

56%

Friab

le g

ranu

latio

n82

%76

%Fo

ul o

dour

36%

88%

Wou

nd b

reak

dow

n46

%10

0%

Pred

ictive

valu

es (P

PV c

alcul

ated

by st

udy

auth

ors a

nd c

heck

ed b

yre

view

er; N

PV c

alcul

ated

by

revie

wer

):

Inst

itute

on

Agin

g,N

atio

nal I

nstit

utes

of H

ealth

cont

inue

d


129


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sTe

st d

etai

lsRe

sults

With

draw

als

Com

men

ts

PPV

NPV

Incr

easin

g pa

in10

0%78

%Er

ythe

ma

43%

77%

Oed

ema

50%

82%

Hea

t33

%70

%Pu

rule

nt e

xuda

te18

%64

%Se

rous

+

infla

mm

atio

n46

%78

%D

elay

ed h

ealin

g50

%89

%D

iscol

orat

ion

39%

78%

Friab

le g

ranu

latio

n60

%90

%Fo

ul o

dour

57%

76%

Wou

nd b

reak

dow

n10

0%81

%

Like

lihoo

d ra

tios (

+LR

calc

ulat

edby

stud

y au

thor

s and

che

cked

by

revie

wer

/–LR

calc

ulat

ed b

yre

view

er):

+LR

–LR

Incr

easin

g pa

in18

.18

0.64

Eryt

hem

a1.

710.

67O

edem

a2.

270.

5H

eat

1.14

0.97

Puru

lent

exu

date

0.51

a1.

28a

Sero

us +

in

flam

mat

ion

1.95

0.63

Del

ayed

hea

ling

2.27

0.28

Disc

olor

atio

n1.

450.

65Fr

iable

gra

nulat

ion

3.41

0.24

Foul

odo

ur3.

030.

72W

ound

bre

akdo

wn

22.7

30.

55

cont

inue

d

Appendix 4

130

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sTe

st d

etai

lsRe

sults

With

draw

als

Com

men

ts

Resu

lts fo

r pat

ient

s with

ven

ous

leg

ulce

rs (n

= 7

)

Sens

itivit

y (c

alcul

ated

by

stud

yau

thor

s, re

view

er u

nabl

e to

chec

k as

2 ×

2 da

ta n

otpr

ovid

ed):

Incr

easin

g pa

in5%

Eryt

hem

a50

%O

edem

a10

0%H

eat

25%

Puru

lent

exu

date

67%

Sero

us +

infla

mm

atio

n25

%D

elay

ed h

ealin

g10

0%D

iscol

orat

ion

25%

Friab

le g

ranu

latio

n75

%Fo

ul o

dour

25%

Wou

nd b

reak

dow

n75

%

CSS

C, c

linica

l sign

s and

sym

ptom

s che

cklis

t; F,

fem

ale; I

nf, i

nfec

ted;

LR,

like

lihoo

d ra

tio; M

, male

; Non

-inf,

non-

infe

cted

; NPV

, neg

ative

pre

dict

ive v

alue;

PPV

, pos

itive

pre

dict

ive v

alue;

SD

, sta

ndar

d de

viatio

n; S

e, se

nsiti

vity;

Ser

ous +

infla

mm

atio

n, se

rous

exu

date

plu

s con

curr

ent i

nflam

mat

ion;

Sp,

spec

ificit

y; T

ot, t

otal.

a Fo

r pur

ulen

t exu

date

, the

valu

es fo

r LRs

are

the

oppo

site

to w

hat w

ould

nor

mall

y be

exp

ecte

d, th

at is

, the

+LR

in th

is ca

se is

less

than

1 a

nd th

e –L

R is

grea

ter t

han

1. T

his m

ay b

e ex

plain

ed a

s fol

low

s.Fo

r the

+LR

, the

ratio

is d

erive

d fro

m th

e ve

ry lo

w se

nsiti

vity

for t

his c

linica

l sign

(18%

) and

the

relat

ively

high

num

ber o

f fals

e po

sitive

s exp

ress

ed a

s a p

ropo

rtio

n of

the

tota

l with

out d

iseas

e as

verif

ied

by th

e re

fere

nce

stan

dard

. For

the

–LR

the

ratio

is d

erive

d fro

m th

e lar

ge p

ropo

rtio

n of

false

neg

ative

s rel

ative

to th

e to

tal w

ith d

iseas

e an

d th

e sp

ecifi

city

of 6

4%. T

hese

find

ings

are

as w

ould

be e

xpec

ted

for a

test

that

exc

lude

s dise

ase

as o

ppos

ed to

iden

tifyin

g it.

The

con

clusio

n fro

m th

ese

data

is th

at p

urul

ent e

xuda

te is

a v

ery

poor

test

of t

he p

rese

nce

of in

fect

ion

and

that

abs

ence

of t

his

clini

cal s

ign is

mor

e lik

ely

to in

dica

te in

fect

ion

than

its p

rese

nce.


131


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sTe

st d

etai

lsRe

sults

With

draw

als

Com

men

ts

Ratli

ff (2

002)

,92

USA

Stud

y de

sign:

Pros

pect

iveco

hort

Met

hod

of p

atie

ntse

lect

ion:

Patie

nts w

ere

recr

uite

d w

hoat

tend

ed th

e cli

nic

from

Nov

embe

r20

01 to

Apr

il20

02

Out

com

eas

sess

men

t:2

×2

diag

nost

icda

ta w

ere

repo

rted

for

diffe

rent

crit

eria

to d

efin

e in

fect

ion

usin

g se

mi-

quan

titat

ivean

alysis

tech

niqu

es

Setti

ng:

Uni

vers

ity-b

ased

wou

nd c

are

clini

c

Eligi

bilit

y cr

iteria

for i

nclu

sion

in th

est

udy:

Patie

nts w

ithw

ound

s pre

sent

for m

ore

than

6m

onth

s (co

uld

inclu

de a

ny ty

pe o

fcu

tane

ous w

ound

at a

ny b

ody

site)

Exclu

sion

crite

ria:

Wou

nds w

ithgr

oss s

urfa

ceco

ntam

inat

ion,

necr

otic

tissu

e,pu

rule

nt d

rain

age

or e

scha

r

n=

124

wou

nds o

n 12

4 pa

tient

s

Gen

der:

male

74,

fem

ale 5

0

Mea

n ag

e: N

ot re

port

ed

Type

of d

iabet

es: N

ot re

port

ed

Wou

nd ty

pe:

Pres

sure

ulce

rs 4

4Ve

nous

ulce

rs 2

7N

euro

path

ic or

diab

etic

ulce

rs 2

9Lo

wer

ext

rem

ity a

rter

ial u

lcers

8O

ther

aet

iolo

gies 1

6

Wou

nd tr

eatm

ent p

rior t

osa

mpl

ing:

The

wou

nd w

as c

lean

ed to

rem

ove

surfa

ce c

onta

min

atio

nus

ing

a st

erile

4 ×

4 cm

gau

zem

oist

ened

with

ster

ile sa

line

Inde

x te

st: s

emi-q

uant

itativ

ean

alysis

(124

pat

ient

s):

Usin

g st

erile

tech

niqu

e, a

nalg

inat

e-tip

ped

appl

icato

r was

rota

ted

over

a 1

cm

2ar

ea fo

r5

seco

nds w

ith su

fficie

ntpr

essu

re to

cau

se ti

ssue

flui

d to

be e

xpre

ssed

. The

tip

of th

esw

ab w

as b

roke

n of

f int

o a

ster

ile tr

ansp

ort t

ube.

The

sam

ple

was

tran

spor

ted

imm

ediat

ely

to th

e lab

orat

ory

for p

roce

ssin

g. T

he sw

ab w

aspr

oces

sed

usin

g a

sem

i-qu

antit

ative

tech

niqu

e. A

blo

odag

ar p

late

was

stre

aked

thre

etim

es o

n on

e qu

adra

nt a

nd th

enth

ree

times

on

each

rem

ainin

gqu

adra

nt in

sequ

ence

(I, I

I, III

,IV

) usin

g a

ster

ile lo

op fo

r eac

hqu

adra

nt, i

n or

der t

o cr

eate

dilu

tions

of t

he o

rigin

al sw

ab in

each

qua

dran

t. Th

e m

ore

bact

eria

on th

e or

igina

l sw

ab,

the

mor

e qu

adra

nts s

how

ing

bact

erial

gro

wth

. All

plat

edsp

ecim

ens w

ere

incu

bate

dun

der a

erob

ic co

nditi

ons a

t37

ºC. A

fter 2

4ho

urs,

the

plat

esw

ere

visua

lly in

spec

ted

and

colo

nies

of b

acte

ria c

ount

ed in

the

four

qua

dran

ts

2 ×

2 ta

ble

for s

emi-q

uant

itativ

ede

finiti

on o

f inf

ectio

n as

gro

wth

in q

uadr

ant I

II or

qua

dran

ts II

Ian

d IV

:

Qua

ntita

tive

+–

Tota

l

Sem

i-qua

nt.

+42

749

–11

6475

Tota

l53

7112

4

Sens

itivit

y 79

%Sp

ecifi

city

90%

Oth

er m

easu

res (

calcu

lated

by

revie

wer

):

PPV

86%

NPV

85%

+LR

8.0

4–L

R 0.

23

2 ×

2 ta

ble

for s

emi-q

uant

itativ

ede

finiti

on o

f inf

ectio

n as

gro

wth

in q

uadr

ant I

I, qu

adra

nts I

I and

III

or q

uadr

ants

II, I

II an

d IV

:

Qua

ntita

tiv

+–

Tota

l

Sem

i-qua

nt.

+53

2679

–0

4545

Tota

l53

7112

4

Der

ived

mea

sure

s (ca

lculat

ed b

yre

view

er):

Sens

itivit

y 10

0%Sp

ecifi

city

63%

PPV

67%

NPV

100

%

+LR

2.7

3–L

R 0.

015

Ther

e w

ere

now

ithdr

awals

Sugg

estio

ns fo

rfu

ture

rese

arch

, as

sugg

este

d by

the

auth

ors:

Com

paris

on o

fco

tton-

tippe

dsw

abs a

nd c

alciu

malg

inat

e-tip

ped

swab

s sho

uld

bepe

rform

ed(a

lgina

te sw

abs

wer

e us

ed in

this

stud

y be

caus

eco

tton-

tippe

dsw

abs m

ay b

eba

cter

iost

atic

seco

ndar

y to

the

oxid

ative

ster

ilisat

ion

proc

edur

e;alg

inat

e sw

ab is

mor

e ex

pens

iveth

an c

otto

n sw

ab)

Lim

itatio

ns o

f the

stud

y as

not

ed b

yre

view

er:

Mix

ed p

opul

atio

nin

term

s of w

ound

aetio

logy

Stud

y sp

onso

rshi

p:N

ot st

ated

cont

inue

d

Appendix 4

132

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sTe

st d

etai

lsRe

sults

With

draw

als

Com

men

ts

Refe

renc

e te

st: q

uant

itativ

ean

alysis

(124

pat

ient

s):

Follo

win

g th

e ac

quisi

tion

of th

esw

ab sa

mpl

e fo

r sem

i-qu

antit

ative

ana

lysis,

ano

ther

swab

was

obt

ained

from

the

sam

e sit

e us

ing

the

sam

ete

chni

que.

The

tip

of th

e sw

abw

as b

roke

n of

f and

plac

ed in

to a

ster

ile tr

ansp

ort t

ube

cont

ainin

g5

ml o

f nor

mal

salin

e. T

hesa

mpl

e w

as tr

ansp

orte

dim

med

iatel

y to

the

labor

ator

yfo

r pro

cess

ing.

The

swab

was

proc

esse

d us

ing

a qu

antit

ative

tech

niqu

e. S

erial

dilu

tions

of t

hesw

abs w

ere

perfo

rmed

and

plat

ed o

n st

erile

aga

r med

ium

.Al

l plat

ed sp

ecim

ens w

ere

incu

bate

d un

der a

erob

icco

nditi

ons a

t 37º

C. A

fter 2

4ho

urs,

the

plat

es w

ere

visua

llyin

spec

ted

and

colo

nies

of

bact

eria

coun

ted.

CFU

s wer

eut

ilised

to d

eter

min

e th

e to

tal

bact

erial

cou

nt o

n ea

ch p

late

Soft

tissu

e in

fect

ion

was

de

fined

as t

he p

rese

nce

of

>10

5C

FU c

m2

Tim

ing:

The

swab

for q

uant

itativ

ean

alysis

was

obt

ained

afte

r the

swab

for s

emi-q

uant

itativ

ean

alysis

. The

tim

e in

terv

albe

twee

n th

e ac

quisi

tion

of th

etw

o sp

ecim

ens w

as n

ot st

ated

2 ×

2 ta

ble

for s

emi-q

uant

itativ

ede

finiti

on o

f inf

ectio

n as

gro

wth

in q

uadr

ant I

, qua

dran

ts I

and

II,qu

adra

nts I

, II a

nd II

I or

quad

rant

s I, I

I, III

and

IV:

Qua

ntita

tive

+–

Tota

l

Sem

i-qua

nt+

5345

98–

026

26To

tal

5371

124

Der

ived

mea

sure

s (ca

lculat

ed b

yre

view

er):

Sens

itivit

y 10

0%Sp

ecifi

city

37%

PPV

54%

NPV

100

%

+LR

1.5

8–L

R 0.

026

2 ×

2 ta

ble

for s

emi-q

uant

itativ

ede

finiti

on o

f inf

ectio

n as

gro

wth

in q

uadr

ants

I, II

, III

and

IV:

Qua

ntita

tive

+–

Tota

l

Sem

i-qua

nt.

+14

115

–39

7010

9To

tal

5371

124

Der

ived

mea

sure

s (ca

lculat

ed b

yre

view

er):

Sens

itivit

y 26

%Sp

ecifi

city

99%

PPV

93%

NPV

64%

+LR

18.

75–L

R 0.

75


133


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sTe

st d

etai

lsRe

sults

With

draw

als

Com

men

ts

Bill

(200

1),91

USA

Stud

y de

sign:

Cro

ss-s

ectio

nal

Met

hod

of p

atie

ntse

lect

ion:

Con

secu

tive

Out

com

eas

sess

men

t:C

orre

latio

nbe

twee

n re

sults

of q

uant

itativ

ew

ound

bio

psy

and

swab

cul

ture

Setti

ng:

Uni

vers

ity-b

ased

,m

ultid

iscip

linar

ych

roni

c w

ound

cent

re

Eligi

bilit

y cr

iteria

for i

nclu

sion

in th

est

udy:

Willi

ng p

artic

ipan

tsw

ith in

form

edco

nsen

t. An

ycu

tane

ous w

ound

,at

any

bod

y sit

e,pr

esen

t for

mor

eth

an 6

mon

ths.

(Pat

ient

s with

gros

s sur

face

cont

amin

atio

n of

the

wou

nd,

necr

otic

tissu

e,pu

rule

nt d

rain

age

or e

scha

r wer

eno

t cul

ture

d)

n=

38

Gen

der:

M 2

5, F

13

Ethn

icity

: Afri

can–

Amer

ican:

12

Cau

casia

n: 2

6

Mea

n ag

e: 5

9ye

ars

Type

of d

iabet

es: N

ot st

ated

Wou

nd ty

pe:

Pres

sure

ulce

rs 1

8Lo

wer

ext

rem

ity d

iabet

ic w

ound

s10 W

ound

s sec

onda

ry to

ven

ous

stas

is di

seas

e 5

Arte

rial u

lcers

5

Wou

nd tr

eatm

ent p

rior t

o sa

mpl

ing:

A st

erile

4 × 4

cm

gau

ze w

as m

oist

ened

with

ster

ilesa

line

and

the

wou

nd su

rface

wip

edvig

orou

sly to

rem

ove

surfa

ce c

onta

min

atio

n.If

>1

wou

nd w

as p

rese

nt p

er p

atie

nt, t

helar

gest

was

sele

cted

for s

tudy

Inde

x te

st: S

wab

cul

ture

(38

patie

nts)

: us

ing

a st

erile

tech

niqu

e, a

n alg

inat

e-tip

ped

appl

icato

r rot

ated

ove

r a 1

× 1

cm a

rea

for

5se

cond

s with

suffi

cient

pre

ssur

e to

exp

ress

tissu

e flu

id. S

ampl

e ta

ken

from

the

cent

re o

fth

e w

ound

. Tip

of t

he sw

ab b

roke

n of

f int

o a

ster

ile tr

ansp

ort t

ube

cont

ainin

g 5

ml o

fsa

line.

Ser

ial d

ilutio

ns o

f sw

ab sa

mpl

epe

rform

ed a

nd p

lated

on

ster

ile a

gar

med

ium

Refe

renc

e te

st: w

ound

bio

psy

(38

patie

nts)

:5

mm

pun

ch b

iops

y w

as ta

ken

from

the

cent

re o

f the

swab

site

. Ste

rile

forc

eps u

sed

to tr

ansfe

r the

sam

ple

to th

e tr

ansp

ort v

ialbe

fore

imm

ediat

e tr

ansfe

r to

the

labor

ator

y.Ti

ssue

bio

psy

sam

ples

wei

ghed

and

hom

ogen

ised

with

a st

erile

tiss

ue g

rinde

rbe

fore

bei

ng p

lated

on

a st

erile

aga

r med

ium

All p

lated

spec

imen

s inc

ubat

ed u

nder

aero

bic

cond

ition

s (37

°C).

Afte

r 24

hour

s,pl

ates

visu

ally

insp

ecte

d an

d ba

cter

ia co

loni

esco

unte

d. C

FUs u

sed

to d

eter

min

e to

tal

bact

erial

cou

nt o

f eac

h pl

ate

Auth

ors d

efin

ed so

ft tis

sue

infe

ctio

n >

105

CFU

sg o

f tiss

ue fo

r qua

ntita

tive

wou

nd b

iops

y an

d >

105

CFU

scm

2fo

r sw

abcu

lture

.

Tim

ing:

bio

psy

follo

wed

imm

ediat

ely

afte

rsw

ab c

ultu

re o

btain

ed

2 ×

2 ta

ble:

Biop

sy

+–

Tota

l

Swab

+22

426

–6

612

Tota

l28

1038

Der

ived

mea

sure

s (ca

lculat

ed b

yre

view

er):

Sens

itivit

y 79

%Sp

ecifi

city

60%

PPV

85%

NPV

50%

+LR

1.9

6–L

R 0.

36

Num

ber o

fpa

tient

s los

t to

follo

w-u

p: n

one

Lim

itatio

ns o

f the

stud

y as

not

ed b

yau

thor

s: fu

rthe

rre

sear

ch sh

ould

inclu

de m

ore

patie

nts w

ithlar

ger n

umbe

r of

wou

nd a

etio

logie

s

Lim

itatio

ns o

f the

stud

y as

not

ed b

yre

view

er: t

he sm

allnu

mbe

r of p

atie

nts

recr

uite

d ov

erall

and

the

hete

roge

neou

sna

ture

of t

hegr

oup

with

rega

rdto

wou

nd ty

pem

ean

that

the

deriv

ed d

iagno

stic

mea

sure

s sho

uld

be in

terp

rete

dw

ith g

reat

cau

tion

The

stud

y au

thor

sw

ere

cont

acte

dan

d re

ques

ted

topr

ovid

e 2

×2

diag

nost

ic da

ta o

nth

e pa

tient

s with

DFU

s, bu

t dat

aw

ere

unav

ailab

le

Appendix 4

134 Effe

ctiv

enes

s da

ta e

xtra

ctio

n ta

bles

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Apel

qvist

(199

6),12

2,12

6

Swed

en

Stud

y de

sign:

RC

T, o

pen

desig

n

Met

hod

ofra

ndom

isatio

n:C

ompu

ter-

gene

rate

d lis

t.Pa

tient

s wer

e st

ratif

ied

acco

rdin

g to

size

and

type

of t

he u

lcer

(Wag

ner g

rade

1 o

r 2)

Uni

t of a

lloca

tion:

Pat

ient

Calc

ulat

ion

of st

atist

ical

pow

er:

Not

des

crib

ed

Out

com

e as

sess

men

t:Pa

tient

s wer

e ex

amin

edat

the

end

of w

eeks

1, 4

,8

and

12. C

olou

rph

otog

raph

s with

scale

sw

ere

take

n at

the

visits

to th

e fo

ot c

are

team

.Ph

otog

raph

s wer

eev

aluat

ed b

lind

at th

een

d of

the

stud

y by

two

inde

pend

ent p

hysic

ians.

In th

e ev

ent o

fdi

sagr

eem

ent i

n th

eev

aluat

ion

ofph

otog

raph

s, th

eas

sess

men

t by

the

foot

care

team

was

dec

isive

.Th

e ou

tcom

e w

ascla

ssifi

ed a

s suc

cess

ful i

fth

e in

itial

ulce

r are

a w

asre

duce

d by

>50

% o

r an

Inclu

sion

crite

ria:

Cau

casia

n,>

40ye

ars o

ld, w

itha

hist

ory

of d

iabet

esm

ellit

us a

nd a

nex

udin

g ca

vity

ulce

rbe

low

the

ankl

e(W

agne

r gra

de 1

or

2) w

ith u

lcer a

rea

>1

cm2

and

syst

olic

toe

pres

sure

>30

mm

Hg

orsy

stol

ic an

kle

pres

sure

>80

mm

Hg

Wag

ner g

rade

1 w

ascla

ssifi

ed a

s asu

perfi

cial u

lcer

brea

king

thro

ugh

subc

utan

eous

tiss

uean

d gr

ade

2 as

ade

ep u

lcer

Onl

y on

e ul

cer w

asst

udie

d in

eac

hpa

tient

. If t

here

wer

e se

vera

l ulce

rs,

the

large

st fu

lfillin

gth

e in

clusio

n cr

iteria

was

cho

sen

Exclu

sion

crite

ria:

Patie

nts w

ith u

lcer

area

>25

cm

2 ,pr

esen

ce o

f dee

pab

sces

s,os

teom

yelit

is, o

rga

ngre

ne (W

agne

rgr

ade

3 or

4),

Base

line

char

acte

ristic

s wer

e no

tre

port

ed in

det

ail; h

owev

er, t

heau

thor

s sta

ted

that

ther

e w

ere

nom

ajor d

iffer

ence

s bet

wee

n th

e tw

otr

eatm

ent g

roup

s in

clini

cal

char

acte

ristic

s

All p

atie

nts h

ad si

gns o

f sev

ere

sens

ory

neur

opat

hy, a

nd in

all

exce

pt tw

o ca

ses,

a pr

ecip

itatin

gca

use

of th

e ul

cer w

as se

en, o

fw

hich

mec

hani

cal s

tres

s was

the

mos

t com

mon

(n=

27)

Appr

oxim

atel

y 50

% o

f pat

ient

s had

prev

ious

am

puta

tions

, mos

tly d

ue to

deep

infe

ctio

n pr

ior t

o in

clusio

n

I: To

pica

l tre

atm

ent w

ithca

dexo

mer

iodi

ne o

intm

ent

(Iodo

sorb

®).

Dre

ssin

gs w

ere

chan

ged

once

dail

y du

ring

the

first

wee

k an

d da

ily o

r eve

ryse

cond

or t

hird

day

dur

ing

the

follo

win

g w

eeks

dep

endi

ng o

nth

e de

gree

of e

xuda

tion

(n =

22)

C: S

tand

ard

topi

cal t

reat

men

tco

nsist

ing

of:g

enta

mici

nso

lutio

n 80

mg/

ml (

Gar

amyc

in®

,Sc

herin

g-Pl

ough

), pr

escr

ibed

twice

dail

y if

an u

lcer w

asin

fect

ed (i

.e. c

ellu

litis

pres

ent);

stre

ptod

orna

se/st

rept

okin

ase

(Var

idas

e®, L

eder

le),

used

for

moi

st, n

ecro

tic le

sions

,ch

ange

d tw

ice d

aily;

or d

rysa

line

gauz

e (M

esalt

®),

used

as

an a

bsor

ptive

dre

ssin

g an

dch

ange

d on

ce o

r tw

ice d

aily

acco

rdin

g to

the

degr

ee o

fex

udat

ion

(n=

19)

All p

atie

nts:

Ora

l ant

ibio

tics (

cipro

floxa

cin,

ceph

alosp

orin

s, m

etro

nida

zole

,cli

ndam

ycin

) wer

e us

ed if

sign

sof

infe

ctio

n (i.

e. c

ellu

litis)

wer

epr

esen

t. Th

e ul

cers

wer

ecle

aned

with

ster

ile sa

line

and

dres

sed

acco

rdin

g to

the

man

ufac

ture

rs’

reco

mm

enda

tions

by

the

usua

lnu

rsin

g st

aff.

Whe

n ul

cers

wer

eno

long

er p

rodu

cing

exud

ate,

vase

line

gauz

e (Je

lone

t®, S

mith

Stat

istica

l met

hods

:D

iffer

ence

s bet

wee

n or

with

ingr

oups

wer

e te

sted

usin

g th

eM

ann–

Whi

tney

U–t

est (

two-

taile

d). T

he a

nalys

is w

as b

ased

on

trea

tmen

t com

plet

ers o

nly

(18

inC

and

17

in I)

. The

aut

hors

repo

rted

no

majo

r diff

eren

ces

betw

een

the

two

grou

ps in

outc

omes

at 1

2w

eeks

. p-V

alues

of th

e di

ffere

nces

wer

e no

tre

port

ed

Surg

ical r

evisi

on p

erfo

rmed

:I:

3/17

(18%

)C

: 5/1

8 (2

8%)

Com

plet

e he

aling

:I:

5/17

(29%

)C

: 2/1

8 (1

1%)

Wou

nd a

rea

redu

ctio

n of

>50

%or

impr

ovem

ent i

n W

agne

rgr

ade:

I: 12

/17

(71%

)C

: 13/

18 (7

2%)

Adve

rse

effe

cts:

The

auth

ors r

epor

ted

that

non

ew

ere

docu

men

ted

With

draw

als:

C: 4

/22

(18%

)I:

2/19

(11%

)

Reas

ons f

orw

ithdr

awal

(not

repo

rted

per

grou

p):

Viol

atio

n of

inclu

sion

crite

ria

n =

2H

ospi

talis

atio

n n

= 2

Non

-adh

eren

ce

n =

1In

suffi

cient

dat

aon

reso

urce

use

n

= 1

Not

e: th

e da

tash

own

here

are

take

n fro

m tw

opa

pers

122,

126

Eligi

bilit

y of

the

inte

rven

tion

for

this

revie

w:

The

auth

ors

desc

ribe

cade

xom

er io

dine

oint

men

t as b

eing

“high

ly flu

id-

abso

rbin

g,an

tibac

teria

land

able

to d

issol

vede

bris

and

necr

otic

tissu

e”,

and

prov

ide

supp

ortin

gre

fere

nces

Stud

y sp

onso

rshi

p:Pe

rsto

rp P

harm

a,Lu

nd, S

wed

en, a

ndth

e Sw

edish

Diab

etes

Asso

ciatio

n cont

inue

d


135


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

impr

ovem

ent i

n W

agne

rgr

ade

was

seen

. Hea

ling

was

def

ined

as i

ntac

tsk

in. U

lcer a

rea

was

mea

sure

d by

mul

tiplyi

ngm

axim

um le

ngth

by

max

imum

wid

th

Setti

ng a

nd le

ngth

of

trea

tmen

t:Si

ngle

-cen

tre

stud

y.O

utpa

tient

s dep

artm

ent,

invo

lving

am

ultid

iscip

linar

y fo

otca

re te

am (d

iabet

olog

ist,

orth

opae

dic

surg

eon,

orth

otist

, pod

iatris

t,di

abet

es n

urse

). Tr

ialdu

ratio

n 12

wee

ks

unde

rgoi

ng th

yroi

dgla

nd in

vest

igatio

ns,

unlik

ely

to a

dher

ew

ith st

udy

prot

ocol

wer

e ex

clude

d

Patie

nts w

ere

with

draw

n fro

m th

est

udy

in th

e ca

se o

fho

spita

lisat

ion,

lack

of a

dher

ence

, ulce

rde

terio

ratio

n(W

agne

r gra

de 3

or

4), >

100%

incr

ease

in u

lcer a

rea

orad

vers

e re

actio

ns to

the

topi

cal

trea

tmen

t

& N

ephe

w M

edica

l) w

asap

plie

d

Prio

r to

inclu

sion,

foot

wea

rw

as c

orre

cted

or s

pecia

lfo

otw

ear p

rovid

ed if

loca

lpr

essu

re re

lief w

as re

quire

d

Appendix 4

136 Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Bout

er (1

996)

,106

The

Net

herla

nds

Stud

y de

sign:

RC

T, o

pen

Met

hod

ofra

ndom

isatio

n:C

ompu

ter-

gene

rate

dra

ndom

num

bers

tabl

e

Uni

t of a

lloca

tion:

Patie

nt

Calc

ulat

ion

of st

atist

ical

pow

er:

Not

repo

rted

Out

com

e as

sess

men

t:Pa

tient

s wer

e ex

amin

edat

bas

elin

e, c

ompl

etio

nof

ant

ibio

tic tr

eatm

ent,

and

ever

y 3

days

dur

ing

ther

apy.

X-r

ay o

f the

affe

cted

lim

b w

as d

one

at st

udy

entr

y an

d du

ring

stud

y pe

riod

if in

dica

ted.

Clin

ical r

espo

nse

totr

eatm

ent w

as a

sses

sed

afte

r com

plet

ion

ofan

tibio

tic th

erap

y an

dw

as c

lassif

ied

as c

ured

(disa

ppea

ranc

e of

the

initi

al in

fect

ion)

,im

prov

ed (i

nitia

lin

fect

ion

unde

r con

trol

),fa

ilure

(per

siste

nce

orag

grav

atio

n of

initi

alin

fect

ion,

requ

iring

chan

ge o

f the

rapy

), or

deat

h. B

lood

cul

ture

san

d w

ound

cul

ture

s(u

sing

puru

lent

Popu

latio

n:Pa

tient

s hos

pita

lised

for d

iabet

ic fo

otle

sions

with

Wag

ner

class

ifica

tions

of 2

, 3an

d 4

in th

e Bo

sch

Med

iCen

tre,

Den

Bosc

h an

d th

eEe

mlan

d H

ospi

tal,

Amer

sfoor

t, Th

eN

ethe

rland

s

Inclu

sion

crite

ria:

Ankl

e/br

achi

al in

dex

of a

t lea

st 0

.45

(der

ived

by d

ividi

ngth

e an

kle

syst

olic

pres

sure

by

the

brac

hial

arte

rysy

stol

ic pr

essu

re);

norm

al re

nal a

ndliv

er fu

nctio

n

Exclu

sion

crite

ria:

Hyp

erse

nsiti

vity

toan

y of

the

stud

ydr

ugs;

rece

ived

antim

icrob

ialth

erap

y ef

fect

iveag

ainst

the

infe

ctin

gpa

thog

ens w

ithin

48ho

urs p

rior t

ost

udy

trea

tmen

t;hi

gh p

roba

bilit

y of

deat

h w

ithin

48ho

urs;

infe

ctio

nw

ithm

icroo

rgan

isms

resis

tant

to th

est

udy

drug

s

Num

bers

male

/fem

ale:

I1: 8

/14

I2: 1

2/12

Mea

n ±

SDag

e (y

ears

):I1

: 71.

9 ±

8.2

I2: 7

0.9

±11

.3

Num

bers

with

Typ

e 1/

Type

2di

abet

es:

I1: 2

/20

I2: 3

/21

Mea

n ±

SDdu

ratio

n of

diab

etes

(yea

rs):

I1: 9

.9 ±

8.6

I2: 1

1.3

±6.

4

Num

bers

clas

sifie

d as

Wag

ner 2

/3/4

:I1

: 9/9

/4I2

: 9/9

/6

Mea

n ±

SDan

kle

brac

hial

inde

x:I1

: 0.7

0 ±

0.23

I2: 0

.71

±0.

22

Back

grou

nd h

eart

dise

ase

(%):

I1: 3

3.3

I2: 5

4.2

Retin

opat

hy (%

):I1

: 59.

1I2

: 33.

3

Nep

hrop

athy

(%):

I1: 5

4.5

I2: 5

4.2

Neu

ropa

thy

(%):

I1: 4

5.5

I2: 5

4.2

I1: I

/C 5

00m

g q.

d.s i

.v.M

inim

um d

urat

ion

oftr

eatm

ent w

as 1

0da

ys

(n=

22)

The

dose

of i

mip

enem

was

redu

ced

in c

ases

of r

enal

dysfu

nctio

n (5

00 o

r 25

0 m

g b.

d.)

I2: P

iper

acilli

n 30

00m

g q.

d.s.

i.v. i

n co

mbi

natio

n w

ithcli

ndam

ycin

600

mg

t.d.s.

i.v.

Min

imum

dur

atio

n of

trea

tmen

t was

10

days

(n

= 2

4)

The

dose

of p

iper

acilli

n w

asre

duce

d in

cas

es o

f ren

aldy

sfunc

tion

(200

0 or

100

0 m

gq.

d.s.)

. The

dos

e of

clind

amyc

in w

as re

duce

d in

case

s of l

iver d

ysfu

nctio

n.(R

evie

wer

’s no

te: i

t is

pres

umed

that

, sin

cepa

rtici

pant

s had

to h

ave

norm

alre

nal f

unct

ion

to b

e in

clude

d in

the

trial

, the

redu

ced

dose

sw

ere

adm

inist

ered

if re

nal

dysfu

nctio

n w

as d

etec

ted

durin

g th

e st

udy

perio

d)

All p

atie

nts:

Antib

iotic

ther

apy

was

disc

ontin

ued

if th

e pa

tient

’scli

nica

l con

ditio

n w

orse

ned

afte

r 72

hour

s. Pa

tient

s wer

ere

stric

ted

to b

ed re

st d

urin

gth

erap

y an

d th

rom

bolyt

ictr

eatm

ent w

as p

resc

ribed

.To

pica

l app

licat

ion

of a

ntib

iotic

sw

as n

ot p

erm

itted

. In

case

s of

Stat

istica

l met

hods

:�

2te

st w

ith Y

ate’

s cor

rect

ion

orFi

sher

’s ex

act t

est (

both

two-

taile

d)

No

patie

nts r

ecei

ved

conc

omita

nt sy

stem

ic or

topi

cal

antib

iotic

s

Mea

n ±

SDdu

ratio

n of

ther

apy

(day

s):

I1: 2

3.6

±11

.5I2

: 24.

3 ±

20.6

The

foot

infe

ctio

ns w

ere

polym

icrob

ial in

55%

of c

ases

.St

aphy

loco

ccus

aur

eusw

ascu

lture

d in

16

patie

nts,

haem

olyt

ic st

rept

ococ

ci in

8pa

tient

s and

ent

eroc

occi

in10

patie

nts.

Ente

roba

cter

iacea

ew

ere

isolat

ed fr

om 1

7 an

dan

aero

bes f

rom

4 p

atie

nts.

Pseu

dom

onas

spec

ies w

ere

not

cultu

red

at th

e tim

e of

adm

issio

nin

any

pat

ient

alth

ough

Xant

hom

onas

mal

toph

iliaw

ascu

lture

d in

one

pat

ient

with

asu

perin

fect

ion

Num

bers

(%) w

ith c

linica

lre

spon

se to

trea

tmen

t I1/

I2:

Cur

ed: 4

(19.

0)/6

(25.

0)Im

prov

ed: 1

6 (7

6.2)

/12

(62.

2)Fa

iled:

0/2

(8.3

)D

ied:

1 (4

.8)/4

(16.

7)Th

e au

thor

s rep

orte

d th

at n

one

of th

e di

ffere

nces

in c

linica

lou

tcom

es o

f the

two

stud

ygr

oups

wer

e st

atist

ically

signi

fican

t. H

owev

er, p

-valu

esw

ere

not r

epor

ted

One

pat

ient

in I1

was

inad

vert

ently

inclu

ded

twice

and

was

ther

efor

eno

t eva

luab

le

For a

nalys

is of

bact

erio

logic

alre

spon

se to

trea

tmen

t:O

ne p

atie

nt in

each

gro

up w

asno

t eva

luab

leow

ing

to a

nega

tive

base

line

cultu

re

Stud

y sp

onso

rshi

p:N

ot st

ated

It is

not c

lear

whe

ther

all

patie

nts r

ecei

ved

antib

iotic

ther

apy

for t

he st

ipul

ated

min

imum

trea

tmen

t per

iod

of 1

0da

ys

cont

inue

d


137


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

disc

harg

e, in

fect

ed ti

ssue

or su

perfi

cial s

wab

s if

form

er m

ater

ials n

otav

ailab

le) w

ere

obta

ined

prio

r to

enro

lmen

t.G

ram

stain

s wer

epe

rform

ed ro

utin

ely

onsp

ecim

ens f

rom

all

sites

with

kno

wn

orpr

esum

ed in

fect

ion.

Bact

erio

logic

al re

spon

seof

bas

elin

e pa

thog

ens

was

reco

rded

3–5

day

saf

ter s

tart

ing

ther

apy

and

1–3

days

afte

rco

mpl

etio

n of

trea

tmen

t.Re

spon

se w

as c

lassif

ied

as e

radi

catio

n, p

artia

ler

adica

tion,

failu

re,

supe

rinfe

ctio

n, re

lapse

(afte

r com

plet

ion

ofth

erap

y) o

r non

-ev

aluab

le o

win

g to

nega

tive

base

line

cultu

re.

All o

bser

ved

and

mon

itore

d ad

vers

eef

fect

s wer

e re

cord

edan

d cla

ssifi

ed a

s mild

,m

oder

ate

or se

vere

.H

aem

atol

ogy

and

bioc

hem

istry

wer

epe

rform

ed a

t 2–3

day

saf

ter e

nrol

men

t and

3–da

ys a

fter c

ompl

etio

nof

ther

apy

Setti

ng a

nd le

ngth

of

trea

tmen

t:H

ospi

tal.

Min

imum

trea

tmen

t dur

atio

n10

days

chro

nic

oste

omye

litis,

ant

ibio

ticth

erap

y w

as c

ontin

ued

with

cipro

floxa

cin 5

00m

g b.

d. o

rally

or o

floxa

cin 4

00m

g b.

d. o

rally

and/

or c

linda

myc

in 6

00m

gt.d

.s. d

epen

ding

on

cultu

rere

sults

Mor

talit

y:I1

: One

pat

ient

die

d of

back

grou

nd h

eart

dise

ase

whi

lehi

s diab

etic

foot

was

con

sider

edto

be

clini

cally

impr

oved

I2: F

our p

atie

nts d

ied

over

all. I

ntw

o pa

tient

s, di

abet

ic fo

otin

fect

ion

was

con

sider

ed to

be

the

caus

e of

dea

th. O

ne p

atie

nt d

ied

of b

ackg

roun

d ca

rdio

vasc

ular

dise

ase

whi

le th

e co

nditi

on o

f his

diab

etic

foot

was

con

sider

ed to

be

impr

oved

. One

oth

er p

atie

nt d

ied

of b

ackg

roun

d ca

rdio

vasc

ular

dise

ase

befo

re a

mel

iora

tion

of th

edi

abet

ic fo

ot c

ould

be

repo

rted

Num

bers

(%) w

ith b

acte

riolo

gical

resp

onse

to tr

eatm

ent I

1/I2

:Er

adica

tion:

9 (4

5.0)

/16

(70.

0)Pa

rtial

era

dica

tion:

3 (1

5.0)

/1 (4

.3)

Failu

re: 1

(5.0

)/3 (1

3.0)

Supe

rinfe

ctio

n: 4

(20.

0)/3

(13.

0)Re

lapse

: 3 (1

5.0)

/0Th

e au

thor

s rep

orte

d th

atdi

ffere

nces

in b

etw

een

grou

psw

ere

not s

tatis

ticall

y sig

nific

ant

Num

bers

(%) e

xper

ienc

ing

adve

rse

even

ts p

roba

bly

relat

edto

stud

y dr

ugs:

I1: 3

(19.

0)I2

: 12

(50.

0)p

< 0

.05

Clas

sifica

tions

of s

ever

ity o

fad

vers

e ev

ents

(mild

/mod

erat

e/se

vere

) was

not

repo

rted

as d

escr

ibed

in th

em

etho

ds

cont

inue

d

Appendix 4

138

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Diar

rhoe

a w

as th

e sin

gle m

ost

repo

rted

adv

erse

effe

ct (n

= 4

);Cl

ostri

dium

diff

icile

toxi

n w

asde

tect

ed in

one

of t

hese

pat

ient

s.In

I2 o

ne p

atie

nt d

evel

oped

vasc

uliti

s tha

t was

asc

ribed

to th

eus

e of

clin

dam

ycin

. Inc

reas

edliv

er e

nzym

es w

ere

obse

rved

inan

othe

r pat

ient

. In

I1 o

ne p

atie

ntex

perie

nced

Can

dida

stom

atiti

san

d 2

patie

nts c

ompl

ained

of

naus

ea. C

andi

dast

omat

itis w

asals

o ob

serv

ed in

one

pat

ient

inI2

.

NB:

it w

as n

ot c

lear

from

the

text

whi

ch a

dver

se e

vent

soc

curr

ed in

whi

ch g

roup


139


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Brad

sher

(198

4),43

USA

Stud

y de

sign:

RC

T

Met

hod

ofra

ndom

isatio

n:Ra

ndom

num

ber c

ode

Uni

t of a

lloca

tion:

Patie

nt

Calc

ulat

ion

of st

atist

ical

pow

er:

Not

repo

rted

Out

com

e as

sess

men

t:C

ultu

re a

nd se

nsiti

vity

ofm

ater

ial fr

om in

fect

ion

sites

wer

e pe

rform

edbe

fore

initi

atio

n of

ther

apy

and

ever

y2–

3da

ys d

urin

g th

erap

yun

til c

ultu

re n

egat

ive o

rco

nclu

sion

of th

erap

y(a

naer

obic

cultu

res n

otro

utin

ely

take

n). R

esul

tsof

bac

terio

logic

alas

sess

men

t wer

ecla

ssifi

ed a

s elim

inat

ion

(no

furt

her i

solat

ion

ofpa

thog

en),

redu

ctio

n(d

ecre

ased

num

ber o

fsa

me

orga

nism

on

subs

eque

nt c

ultu

res)

,pe

rsist

ent (

sam

e or

grea

ter n

umbe

rs o

f the

origi

nal o

rgan

ism),

relap

se (r

etur

n of

the

origi

nal o

rgan

ism a

fter

com

plet

ion

of th

erap

y),

rein

fect

ion

(isol

atio

n of

ase

para

te p

atho

geni

cor

gani

sm w

ith c

linica

l

Popu

latio

n:Ad

ults

with

susp

ecte

d se

rious

bact

erial

skin

and

soft

tissu

ein

fect

ions

,ho

spita

lised

at t

heU

nive

rsity

of

Arka

nsas

for

Med

ical S

cienc

es o

rth

e C

arra

way

Met

hodi

st C

ente

r

Inclu

sion

crite

ria:

As a

bove

Exclu

sion

crite

ria:

Patie

nts w

ho h

adre

ceive

d an

tibio

tics

in th

e pr

evio

us72

hour

s; pa

tient

sw

ith re

nal f

ailur

e,pr

egna

ncy,

lacta

tion,

neut

rope

nia

orsig

nific

ant p

enici

llinhy

pers

ensit

ivity

Num

ber m

ale/fe

male

:I1

: 15/

27I2

: 24/

18

Num

ber b

lack/

whi

te:

I1: 2

5/17

I2: 2

4/18

Mea

n ag

e (y

ears

):I1

: 57

I2: 5

4

Num

ber w

ith u

nder

lying

dise

ase:

I1: 3

0I2

: 29

The

unde

rlyin

g di

seas

es in

clude

ddi

abet

es m

ellit

us, n

eopl

astic

dise

ase,

ster

oid

imm

unos

uppr

essio

n,alc

ohol

ism a

nd v

ascu

lar in

suffi

cienc

y.Th

e pr

evale

nce

of th

ese

per g

roup

was

not

repo

rted

Num

ber o

f typ

e of

infe

ctio

n tr

eate

dI1

/I2:

Supp

urat

ive D

FU 1

0/10

Bact

erio

logic

ally

prov

en c

ellu

litis

20/1

7C

ultu

re-n

egat

ive c

ellu

litis

6/6

Soft

tissu

e ab

sces

s 3/6

Supp

urat

ive th

rom

boph

lebi

tis 2

/0Su

ppur

ative

dec

ubitu

s ulce

r 0/2

Gon

ococ

cal d

erm

atiti

s 1/0

Surg

ical w

ound

infe

ctio

n 0/

1

Infe

ctio

ns c

ause

d by

mul

tiple

path

ogen

s (in

clude

s sup

pura

tive

diab

etic

foot

and

dec

ubitu

s ulce

rsan

d in

fect

ions

relat

ed to

vas

cular

insu

fficie

ncy)

, num

ber o

f pat

ient

s in

I1/I2

:M

ultip

le G

ram

-neg

ative

bac

illi a

ndSt

aphy

loco

ccus

aure

usiso

lated

6/8

I1: C

eftr

iaxon

e 1

g giv

en a

ssin

gle d

aily

dose

eith

er i.

m. i

nlid

ocain

e 1%

susp

ensio

n or

i.v.

infu

sed

in 1

00m

l of d

extr

ose

5% in

wat

er o

ver 3

0m

inut

es(n

= 4

2)

I2: C

efaz

olin

1g

t.d.s.

at t

heU

nive

rsity

of A

rkan

sas f

orM

edica

l Scie

nces

and

1 g

q.d

.s.at

the

Car

raw

ay M

etho

dist

Med

ical C

entr

e, g

iven

i.v.

infu

sed

in 1

00m

l of d

extr

ose

5% in

wat

er o

ver 3

0m

inut

es(n

= 4

2)

Stat

istica

l met

hods

:N

ot st

ated

. No

p-va

lues

wer

ere

port

ed.

Mea

n da

ily d

ose

of c

epha

losp

orin

used

(mg/

kg) (

all p

atie

nts)

:I1

: 15.

4I2

: 48.

5

Num

ber w

ith b

acte

riolo

gical

resp

onse

I1/I2

(DFU

pat

ient

son

ly):

Elim

inat

ion

6/4

Redu

ctio

n 3/

2Pe

rsist

ence

1/4

Relap

se 0

/0Re

infe

ctio

n 0/

0Th

e ab

ove

was

also

repo

rted

for

othe

r inf

ectio

n ty

pes

Num

ber o

f pat

ient

s with

clin

ical

outc

omes

in I1

/I2 w

ith in

fect

ions

caus

ed b

y m

ultip

le p

atho

gens

(inclu

des s

uppu

rativ

e di

abet

ic fo

otan

d de

cubi

tus u

lcers

and

infe

ctio

ns re

lated

to v

ascu

larin

suffi

cienc

y):

Patie

nts t

reat

ed (h

ad su

rger

y) 1

2(5

)/13

(6)

Clin

ical f

ailur

es (s

urge

ry) 0

/5(4

)C

linica

l im

prov

emen

t 2/2

Clin

ical c

ure

(sur

gery

) 10

(5)/6

(2)

Num

ber u

nder

goin

g su

rgica

lpr

oced

ures

I1/I2

(all

patie

nts)

:Am

puta

tion

7/4

Incis

ion

with

dra

inag

e an

dde

brid

emen

t 8/8

Som

e pa

tient

s had

mor

e th

an o

nepr

oced

ure

Thre

e of

6pa

tient

s with

soft

tissu

e ab

sces

s had

no b

acte

rial

grow

th o

n th

ein

itial

cultu

re a

ndth

eref

ore

wer

eno

t inc

lude

d in

the

bact

erio

logic

alas

sess

men

t

No

with

draw

alsw

ere

repo

rted

for

the

DFU

pat

ient

s

Revie

wer

’s no

tes:

Cul

ture

s and

sens

itivit

ies n

otre

port

ed p

er ty

peof

infe

ctio

n. M

ost

resu

lts w

ere

not

stra

tifie

d by

infe

ctio

n ty

pe.

Give

n th

is an

d th

esm

all p

ropo

rtio

nof

pat

ient

s with

DFU

recr

uite

d(2

4%),

it is

diffi

cult

to d

erive

use

ful

outc

omes

that

coul

d be

conf

iden

tlyge

nera

lised

to a

wid

er p

opul

atio

nw

ith D

FU

Stud

y sp

onso

rshi

p:N

ot st

ated

cont

inue

d

Appendix 4

140

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

signs

of i

nfec

tion)

and

colo

nisa

tion

(org

anism

siso

lated

dur

ing

ther

apy

with

no

asso

ciate

dcli

nica

l sign

s of i

nfec

tion)

.Fo

r the

clin

ical

evalu

atio

n, p

atie

nts w

ere

cons

ider

ed c

ured

whe

nth

ere

was

reso

lutio

n of

signs

and

sym

ptom

s of

infe

ctio

n. T

he n

umbe

r of

days

requ

ired

for

reso

lutio

n of

feve

r was

reco

rded

dail

y, as

wer

eth

e cli

nica

l sign

s of

drain

age

and

infla

mm

atio

n. P

atie

nts

wer

e m

onito

red

daily

for

signs

of t

oxici

ty.

Hae

mat

olog

ical,

rena

lan

d he

patic

par

amet

ers

wer

e m

easu

red

ever

y4

days

dur

ing

ther

apy

and

at th

e en

d of

ther

apy

Setti

ng/le

ngth

of

trea

tmen

t:H

ospi

tal/t

reat

men

tdu

ratio

n no

t rep

orte

d

Gro

up B

stre

ptoc

occi,

Gra

m-n

egat

iveba

cilli

and

Stap

hylo

cocc

us a

ureu

siso

lated

6/6

Gro

up A

stre

ptoc

occi,

Gra

m-

nega

tive

bacil

li an

d St

aphy

loco

ccus

aure

usiso

lated

2/1

Gro

up B

stre

ptoc

occi

wer

eiso

lated

from

the

DFU

s, bu

t no

deta

ils p

rovid

ed p

er g

roup

Num

ber w

ith p

ossib

lece

phalo

spor

in-r

elat

ed a

dver

seef

fect

s I1/

I2 (a

ll pa

tient

s):

Eosin

ophi

lia 7

/5Th

rom

bocy

tosis

2/0

Leuc

opoe

nia

0/1

Elev

ated

tran

sam

inas

e 2/

1Ra

sh 0

/3D

iarrh

oea

1/3

The

num

ber o

f day

s req

uire

d fo

rre

solu

tion

of fe

ver,

as st

ated

inth

e m

etho

ds, w

as n

ot re

port

ed


141


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Cha

ntel

au (1

996)

,74

Ger

man

y

Stud

y de

sign:

RC

T(d

oubl

e-bl

ind)

Met

hod

ofra

ndom

isatio

n:C

ompu

ter-

gene

rate

dco

de

Uni

t of a

lloca

tion:

Patie

nt

Calc

ulat

ion

of st

atist

ical

pow

er:

Not

repo

rted

Out

com

e as

sess

men

t:Ra

te o

f red

uctio

n of

ulce

r size

(sur

face

are

aca

lculat

ed b

y pl

anim

etry

,tr

ansfo

rmed

into

a c

ircle

,ch

ange

s of t

he c

ircle

radi

us o

ver t

ime

wer

ere

cord

ed).

Freq

uenc

y of

com

plet

ehe

aling

(sta

ndar

dise

dph

otog

raph

s).

Adve

rse

effe

cts.

Com

plian

ce w

ithpr

essu

re re

lief (

grad

ed a

sop

timal,

suffi

cient

, or

insu

fficie

nt, a

ccor

ding

tocli

nica

l jud

gem

ent).

Wou

nds c

ultu

res

perfo

rmed

usin

g de

epsw

ab, w

ith m

ater

ialpl

aced

into

tran

spor

tm

ediu

m a

nd se

aled

imm

ediat

ely

for

dete

rmin

atio

n of

aer

obic

and

anae

robi

c ba

cter

ia.

Inclu

sion

crite

ria:

Diab

etic

patie

nts

with

polyn

euro

path

y,w

ith sk

in a

nd so

fttis

sue

lesio

ns o

f the

fore

foot

, age

>18

year

s wer

ein

clude

d, w

ith fo

otle

sions

gra

ded

1A to

2A, a

ccor

ding

toW

agne

r and

Har

kles

scla

ssifi

catio

n

Exclu

sion

crite

ria:

Know

nhy

pers

ensit

ivity

tote

st m

edica

tion,

antib

iotic

trea

tmen

tdu

ring

the

prec

edin

g 7

days

,bi

later

al fo

ot le

sions

,pr

esen

ce o

fos

teom

yelit

is or

perip

hera

l vas

cular

dise

ase,

pre

gnan

cy,

seru

m c

reat

inin

ele

vel >

130

µmol

/1,

imm

une

depr

essio

ndu

e to

und

erlyi

ngdi

seas

e, p

rior o

rgan

tran

splan

tatio

n,im

mun

osup

pres

sive

drug

ther

apy,

micr

oorg

anism

sun

resp

onsiv

e to

test

med

icatio

n, in

abilit

yto

com

ply

with

prot

ocol

Gen

der m

ale/fe

male

:I:

16/6

C: 1

2/10

Mea

n (9

5% C

I) ag

e (y

ear)

:I:

58 (5

4 to

62)

C: 5

9 (5

5 to

63)

Mea

n (9

5% C

I) ul

cer a

rea

(mm

2 ):I:

214

(154

to 2

74)

C: 2

20 (1

62 to

422

)

Dat

a w

ere

not r

epor

ted

for u

lcer

grad

e

Mea

n (9

5% C

I) di

abet

es d

urat

ion

(yea

r):

I: 22

(17

to 2

7)C

: 19

(14

to 2

4)

Insu

lin d

epen

dent

:I:

11/2

2 (5

0%)

C: 1

2/22

(55%

)

Num

ber o

f pat

ient

s cur

rent

lysm

okin

g:I:

2/22

(9%

)C

: 5/2

2 (2

3%)

Num

ber o

f pat

ient

s with

HbA

1 c<

8%:

I: 9

/22

(41%

)C

: 10/

22 (4

5%)

Num

ber o

f pat

ient

s with

diab

etic

retin

opat

hy:

I: 13

/22

(59%

)C

: 12/

22 (5

5%)

Num

ber o

f pat

ient

s with

pro

tein

uria

>50

0m

g/1:

I: 4/

22 (1

8%)

C: 2

/22

(9%

)

I: Am

oxyc

illin

500

mg

plus

clavu

lanic

acid

125

mg,

ora

llytd

s (n

= 2

2)

C: I

dent

ical p

laceb

o t.d

.s.

(n=

22)

All p

atie

nts:

Stud

y m

edica

tion

was

star

ted

with

in 6

hour

s of i

nitia

l wou

ndcu

lture

.

All r

ecei

ved

mec

hani

cal

debr

idem

ent.

The

lesio

n w

ascle

aned

with

a to

pica

ldi

sinfe

ctan

t (D

ibro

mol

solu

tion)

and

dre

ssed

with

cotto

n ga

uze

and

para

ffina

ted

non-

adhe

ring

gauz

e. P

ress

ure

relie

f was

pro

vided

thro

ugh

the

use

of a

half

-sho

e, c

rutc

hes a

ndw

heel

chair

s

Out

patie

nt tr

eatm

ent w

asca

rrie

d ou

t by

a qu

alifie

d nu

rse

repe

atin

g th

e ab

ove

wou

ndca

re p

roce

dure

dail

y at

the

patie

nt’s

hom

e

The

stud

y w

as st

oppe

d w

hen

the

antib

iotic

pro

ved

unsu

itabl

eac

cord

ing

to b

asel

ine

cultu

res

(at d

ays 3

or 6

), or

if n

o cli

nica

lim

prov

emen

t was

seen

with

in6

days

or i

f the

stud

y pr

otoc

olw

as v

iolat

ed o

win

g to

inco

mpl

ete

pres

sure

relie

f or

adve

rse

effe

cts o

f the

med

icatio

n

Stat

istica

l met

hods

:�

2an

d t-

test

s.

At 2

0 da

ys:

Mea

n (9

5% C

I) re

duct

ion

inul

cer r

adiu

s (m

m2 da

y):

I: 0.

27 (0

.15

to 0

.39)

C: 0

.41

(0.2

1 to

0.6

1)(n

s)

Com

plet

e he

aling

:I:

6/2

2 (2

7%)

C: 1

0/22

(45%

)(n

s)

Adve

rse

effe

cts:

One

cas

e of

diar

rhoe

a in

the

antib

iotic

gro

up, w

hich

did

not

requ

ire w

ithdr

awal

Com

plian

ce ra

ted

as o

ptim

al(a

sses

sed

in 3

9 pa

tient

s):

I: 16

/19

(84%

) pat

ient

sC

: 18/

20 (9

0%) p

atie

nts

(ns)

Micr

obio

logy

Num

ber o

f pat

ient

s with

micr

obio

logic

al fin

ding

s at

entr

y/da

y 6/

end

of st

udy:

Gra

m st

ains

Posit

ive c

occi

C: 1

5/6/

2I:

19/9

/4Po

sitive

rods

C: 1

/0/0

I: 5/

0/1

Neg

ative

rods

C: 6

/1/2

I: 4/

4/1

No

micr

obes

C: 0

/13/

6I:

0/6/

7

I: 3/

22 (1

3.6%

)C

: 2/2

2 (9

.1%

)

The

abov

epa

tient

s wer

ew

ithdr

awn

with

in6

days

of t

he st

art

of th

e tr

ial o

win

gto

non

-co

mpl

iance

, or

bact

eria

unre

spon

sive

toth

e an

tibio

tic

Stud

y sp

onso

rshi

p:Th

e au

thor

sac

know

ledg

ed th

eco

oper

atio

n of

Smith

Klin

e-Be

echa

m, M

unich

,G

erm

any,

but i

tw

as u

ncle

ar fr

omth

is w

heth

er th

eco

mpa

nysp

onso

red

the

rese

arch

cont

inue

d

Appendix 4

142

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Cul

ture

s wer

e ta

ken

atba

selin

e, d

ay 6

and

day

20 in

cas

es o

f inc

ompl

ete

ulce

r hea

ling.

Wou

ndas

sess

men

ts a

ndph

otog

raph

s wer

ere

peat

ed o

n da

ys 3

, 6,

14 a

nd 2

0 (o

r at

com

plet

e clo

sure

of t

hele

sion)

Setti

ng a

nd le

ngth

of

trea

tmen

t:It

appe

ars t

hat s

ome

patie

nts w

ere

trea

ted

asin

patie

nts a

nd so

me

asou

tpat

ient

s, bu

t the

re is

no b

reak

dow

n by

num

bers

. The

dur

atio

nof

the

trial

was

20

days

Isolat

esSt

aphy

loco

ccus

aur

eus

C: 5

/5/3

I: 9/

3/2

Stap

hylo

cocc

us e

pide

rmis

C: 4

/3/4

I: 6/

1/1

E. c

oli

C: 0

/0/1

I: 1/

3/0

Stre

ptoc

occu

s BC

: 3/1

/0I:

3/0/

0St

rept

ococ

cus f

aeca

lisC

: 3/0

/0I:

2/1/

0O

ther

sC

: 8/3

/3I:

8/5/

6N

o iso

lates

C: 1

/10/

1I:

0/9/

4


143


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

de L

alla

(200

1),11

9Ita

ly

Stud

y de

sign:

RC

T (1

:1)

Met

hod

ofra

ndom

isatio

n: N

otst

ated

Uni

t of a

lloca

tion:

Patie

nt

Calc

ulat

ion

of st

atist

ical

pow

er:

Not

repo

rted

Out

com

e as

sess

men

t:Fo

ot le

sions

wer

eev

aluat

ed b

y on

ein

vest

igato

r (bl

ind

tora

ndom

isatio

n), b

yre

cord

ing

degr

ee o

fde

brid

emen

t, co

nditi

onof

gra

nulat

ion

tissu

e,st

ate

of u

lcer m

argin

s,an

d ul

cer w

idth

. Aph

otog

raph

of t

he le

sion

was

take

n at

eac

has

sess

men

t.M

icrob

iolo

gical

asse

ssm

ent w

aspe

rform

ed a

t bas

elin

ean

d at

day

s 7 a

nd 2

1.Fo

llow

ing

surg

ical

debr

idem

ent,

scru

bbin

g,an

d cle

ansin

g w

ith st

erile

gauz

e so

aked

in st

erile

salin

e, a

supe

rficia

l sw

absp

ecim

en a

nd a

dee

ptis

sue

biop

sy w

ere

colle

cted

from

the

deep

base

of t

he u

lcer.

Sam

ples

wer

e in

sert

edin

to a

tran

spor

t tub

e

Popu

latio

n:Ad

ult d

iabet

icpa

tient

s of e

ither

gend

er a

dmitt

ed to

the

Diab

etes

Cen

tre

of th

e Sa

n Bo

rtol

oH

ospi

tal,

Vice

nza,

Italy

for s

ever

e,lim

b-th

reat

enin

gfo

ot in

fect

ion

(def

ined

by

the

pres

ence

of f

ull-

thick

ness

ulce

r,m

ore

than

2cm

of

cellu

litis

with

or

with

out

lymph

angit

is, b

one

or jo

int

invo

lvem

ent,

orsy

stem

ic to

xicit

y)

Inclu

sion

crite

ria:

As a

bove

Exclu

sion

crite

ria:

Trea

tmen

t with

antib

iotic

s for

any

prov

en o

r sus

pect

edin

fect

ion

durin

g th

e2

wee

ks p

rece

ding

recr

uitm

ent;

supe

rficia

l, no

n-lim

b-th

reat

enin

gin

fect

ion;

imm

ediat

eris

k of

majo

r abo

ve-

ankl

e am

puta

tion

for c

ritica

l leg

ischa

emia

(ank

lesy

stol

ic bl

ood

pres

sure

<50

mm

Hg

or

Num

ber m

ale/fe

male

:C

: 14/

6I:

16/4

Mea

n ±

SD(r

ange

) age

(yea

rs):

C: 5

9.8

±9.

6 (4

4–85

)I:

56.6

±8.

6 (4

2–74

)

Mea

n ±

SD(r

ange

) dur

atio

n of

diab

etes

inye

ars:

C: 1

8.5

±8.

6 (1

2–30

)I:

15.6

±8.

6 (1

–46)

Num

ber (

%) o

f pat

ient

s with

Wag

ner

grad

e 3/

4:C

: 14

(70)

/6 (3

0)I:

13 (6

5)/7

(35)

Num

ber (

%) o

f pat

ient

s with

neur

opat

hic/

ischa

emic/

mix

ed le

sions

:C

: 14

(70)

/ 0

/ 6 (3

0)I:

13 (6

5) /

2 (1

0) /

5 (2

5)

Mea

n ±

SDan

kle–

brac

hial

bloo

d pr

essu

rein

dex:

C: 1

.29

±0.

50I:

0.96

±0.

34

Mea

n ±

SDvib

rato

r per

cept

ion

thre

shol

d:C

: 43.

2 ±

0.47

I: 35

.8 ±

14.6

0

Num

ber (

%) o

f pat

ient

s with

whi

te c

ell

coun

t >10

,000

/mm

3 :C

: 5/2

0 (2

5)I:

1/20

(5)

Mea

n ±

SDne

utro

phil

coun

t (m

m)3 :

C: 8

300

±35

00I:

7800

±35

00

Num

ber (

%) o

f pat

ient

s with

ES

R >

70m

m/h

:C

: 13/

20 (6

5)I:

11/2

0 (5

5)

C: C

onve

ntio

nal

trea

tmen

t alo

ne (l

ocal

trea

tmen

t plu

s sys

tem

ican

tibio

tic th

erap

y)

(n=

20)

I: C

onve

ntio

nal t

reat

men

t(lo

cal t

reat

men

t plu

ssy

stem

ic an

tibio

ticth

erap

y) p

lus G

-CSF

26

3 µg

dail

y s.c

. for

21da

ys. T

he d

ose

of G

-C

SF w

as te

mpo

raril

yre

duce

d to

175

µg

if th

ene

utro

phil

coun

tex

ceed

ed 3

5,00

0ce

lls/m

m3 . G

-CSF

was

disc

ontin

ued

if th

ene

utro

phil

coun

t was

ove

r50

,000

cel

ls/m

m3

and

was

re-c

omm

ence

d on

ly if

the

coun

t fel

l to

less

than

35,0

00 c

ells/

mm

3(n

= 2

0)

All p

atie

nts:

Loca

l tre

atm

ent c

onsis

ted

of d

ebrid

emen

t of s

oft

tissu

e an

d bo

ne a

ten

rolm

ent a

nd th

erea

fter

of d

aily

insp

ectio

n,cle

ansin

g w

ith st

erile

wat

er, d

isinf

ectio

n w

ithpo

vidon

e io

dine

, sur

gical

rem

oval

of n

ecro

tic ti

ssue

as re

quire

d an

d oc

clusiv

edr

essin

g of

foot

lesio

ns.

Empi

rical

antib

iotic

ther

apy

was

bas

ed o

n th

eco

mbi

natio

n of

cipro

floxa

cin a

ndcli

ndam

ycin

. I.v.

ther

apy

Stat

istica

l met

hods

:O

ne-s

ampl

e t-

test

for

com

paris

on o

f con

tinuo

usva

riabl

es a

nd M

ann–

Whi

tney

U-

test

for c

ateg

orica

l var

iable

s.

Num

ber (

%) u

nder

goin

gam

puta

tion

at 2

1 da

ys:

C: 5

/20

(25)

I: 1/

20 (5

)p

= 0

.08

Num

ber (

%) u

nder

goin

gam

puta

tion

at 9

-wee

k fo

llow

-up:

C: 9

/20

(45)

I: 3/

20 (1

5)p

= 0

.038

Num

ber u

nder

goin

g m

ajor

ampu

tatio

n:C

: 2 (a

t 21

and

30da

ys)

I: 0

Num

ber u

nder

goin

g am

puta

tion

of m

etat

arsa

l bon

es:

C: 1

(at d

ay 2

5)I:

1 (a

t day

45)

Adve

rse

even

ts:

No

adve

rse

even

ts a

ssoc

iated

with

G-C

SF w

ere

obse

rved

.D

osag

e ha

d to

be

redu

ced

in 2

patie

nts o

win

g to

neu

trop

hil

coun

t high

er th

an 3

5,00

0ce

lls/m

m3 . T

he n

eutr

ophi

l cou

ntdi

d no

t exc

eed

50,0

00 c

ells/

mm

3

in a

ny p

atie

nt

Ther

e w

ere

now

ithdr

awals

durin

g th

e 21

-day

trial

or a

t the

9-

wee

k fo

llow

-up

At 6

mon

ths,

4pa

tient

s fro

mIw

ere

lost

tofo

llow

-up

Stud

y sp

onso

rshi

p:N

ot st

ated

cont

inue

d

Appendix 4

144

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

cont

ainin

g so

lid m

ediu

msu

itabl

e fo

r bot

h ae

robi

can

d an

aero

bic

micr

oorg

anism

s and

deliv

ered

to th

elab

orat

ory

for i

mm

ediat

epr

oces

sing.

The

foot

lesio

ns w

ere

evalu

ated

at

wee

ks 3

and

9 a

ndcla

ssifi

ed a

s one

of t

hefo

llow

ing:

cur

e(c

ompl

ete

closu

re o

f the

ulce

r with

out s

igns o

fun

derly

ing

bone

infe

ctio

n); i

mpr

ovem

ent

(era

dica

tion

of p

atho

gens

indi

cate

d by

neg

ative

swab

or t

issue

cul

ture

,co

uple

d w

ith m

arke

d or

com

plet

e re

duct

ion

ofce

llulit

is bu

t inc

ompl

ete

closu

re o

f the

ulce

r or

closu

re o

f the

ulce

r but

pers

isten

t sign

s of a

ctive

unde

rlyin

g bo

ne in

fect

ion

such

as l

ocal

pain

,er

ythe

ma

and

swel

ling)

;or

failu

re (a

bsen

ce o

fcli

nica

l im

prov

emen

tirr

espe

ctive

of c

ultu

rere

sults

). Am

puta

tion,

defin

ed a

s any

exc

ision

of b

one

segm

ent,

was

cons

ider

ed fa

ilure

whe

nits

indi

catio

n w

as d

ue to

pers

isten

t inf

ectio

n af

ter

15da

ys o

f app

ropr

iate

antib

iotic

ther

apy

and

loca

l tre

atm

ent.

Indi

catio

n fo

r am

puta

tion

ankl

e/br

achi

al bl

ood

pres

sure

inde

x<

0.5)

; any

crit

ical

cond

ition

with

imm

ediat

e ris

k of

deat

h; re

nal

impa

irmen

t; hi

stor

yof

alle

rgic

reac

tion

to c

ipro

floxa

cin o

rcli

ndam

ycin

; any

cont

ra-in

dica

tion

toG

-CSF

adm

inist

ratio

n

Num

ber (

%) o

f pat

ient

s with

pos

itive

bloo

d cu

lture

s:C

: 2/2

0 (1

0)I:

0

Det

ectio

n of

ost

eom

yelit

is:Al

l pat

ient

s had

ost

eom

yelit

is at

bas

elin

e,de

tect

ed b

y po

sitive

bon

e pr

obe.

15

patie

nts (

6 in

C a

nd 9

in I)

had

diag

nosis

conf

irmed

by

indi

um-la

belle

d le

ukoc

yte

scan

com

bine

d w

ith te

chne

tium

-99m

bone

scan

Num

ber (

%) o

f pat

ient

s with

exp

osed

bone

:C

: 4/2

0 (2

0)I:

6/20

(30)

Num

ber (

%) o

f pat

ient

s with

life

-th

reat

enin

g in

fect

ion:

C: 2

/20

(10)

I: 0

Mea

n ±

SDnu

mbe

r of u

lcers

per

pat

ient

:C

: 1.4

±1.

0I:

1.4±

0.6

Num

ber (

%) o

f pat

ient

s with

mor

e th

anon

e ul

cer:

C: 5

/20

(25)

I: 6/

20 (3

0)

Mea

n ±

SDnu

mbe

r of i

solat

es p

erpa

tient

:C

: 2.3

0 ±

1.6

I: 2.

05 ±

1.2

Num

ber (

%) o

f pat

ient

s with

polym

icrob

ial in

fect

ion:

C: 1

0/20

(50)

I: 14

/20

(70)

(cip

roflo

xacin

400

mg

b.i.d

. plu

s clin

dam

ycin

90

0 m

g t.i

.d.)

was

adm

inist

ered

in th

e ca

seof

mor

e se

rious

infe

ctio

n(fe

brile

dise

ase,

ext

ende

dce

llulit

is w

ith ly

mph

angit

is,in

com

plet

e de

brid

emen

tof

nec

rotic

tiss

ue, o

rex

tens

ive b

one

invo

lvem

ent)

and

the

ther

apy

was

switc

hed

toth

e or

al ro

ute

whe

nap

prop

riate

. The

ora

lre

gimen

(cip

roflo

xacin

at

750

mg

b.i.d

. plu

scli

ndam

ycin

300

mg

q.d.

s.)w

as c

onsid

ered

appr

opria

te fo

r les

s crit

ical

patie

nts.

Adju

stm

ents

totr

eatm

ent w

ere

mad

e on

the

basis

of w

ound

cultu

res a

nd se

nsiti

vitie

s

Insu

lin w

as g

iven

eith

er b

yco

ntin

uous

i.v.

infu

sion

ora

mul

tiple

-dos

e re

gimen

.

Mea

n ±

SDne

utro

phil

coun

ts(c

ells/

mm

3):

C: 6

,500

±4,

400

I: 25

,200

±3,

500

p=

0.0

02

Trea

tmen

t out

com

es fo

r num

ber

(%) o

f pat

ient

s 3 w

eeks

afte

rst

art o

f tre

atm

ent C

/I:C

ure:

0/0

Impr

ovem

ent:

9 (4

5)/1

2 (6

0) (n

s)Fa

ilure

: 11

(55)

/8 (4

0) (n

s)

Trea

tmen

t out

com

es fo

r num

ber

(%) o

f pat

ient

s 9 w

eeks

afte

rst

art o

f tre

atm

ent C

/I:C

ure:

7 (3

5)/7

(35)

(ns)

Impr

ovem

ent:

8 (4

0)/4

(20)

(ns)

Failu

re: 5

(25)

/9 (4

5) (n

s)

Both

pat

ient

s with

life

-th

reat

enin

g in

fect

ion

at ti

me

ofra

ndom

isatio

n (b

oth

in C

) wer

ecla

ssifi

ed a

s im

prov

ed a

t wee

k 9

Trea

tmen

t out

com

es fo

r num

ber

(%) o

f pat

ient

s at 6

-mon

thfo

llow

-up

C/I

(eva

luat

ed in

20

patie

nts i

n C

and

16

in I,

as 4

wer

e lo

st to

follo

w-u

p):

Cur

e or

stab

le: 1

5/20

(75)

/13/

16(8

1)W

orse

ned:

5/2

0 (2

5)/3

/16

(19)

ns Num

ber o

f pat

ient

s with

bact

erial

isol

ates

C/I

afte

r3

wee

ks o

f tre

atm

ent:

Gra

m-p

ositi

ve a

erob

es:

CN

S-M

R 3/

5SA

-MS

0/1

SA-M

R 1/

2

cont

inue

d


145


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

was

ass

esse

d by

orth

opae

dic

staf

f at t

heho

spita

l who

wer

e no

tin

volve

d in

the

stud

y, an

dha

d no

t bee

n bl

inde

d to

trea

tmen

t allo

catio

n

Setti

ng a

nd le

ngth

of

trea

tmen

t:H

ospi

tal.

Leng

th o

f tria

l21

days

. Fol

low

-up

at9

wee

ks a

nd 6

mon

ths.

Num

ber (

%) o

f pat

ient

s with

cel

lulit

isdi

amet

er >

2 cm

:C

: 15/

20 (7

5)I:

10/2

0 (5

0)

Num

ber (

%) o

f pat

ient

s with

visi

ble

infe

cted

wet

gan

gren

e of

the

toes

:C

: 4/2

0 (2

0)I:

4/20

(20)

Num

ber (

%) p

atie

nts w

ith a

n ab

sces

s:C

: 3/2

0 (1

5)I:

1/20

(5)

Num

ber (

%) p

atie

nts w

ith u

lcer d

iamet

er>

2cm

:C

: 11/

20 (5

5)I:

13/2

0 (6

5)

Num

ber o

f pat

ient

s with

bac

teria

l iso

lates

C/I:

Gra

m-p

ositi

ve a

erob

es:

CN

S-M

S 5/

1SA

-MS

8/8

SA-M

R 2/

2Co

ryne

bact

eriu

msp

ecie

s 2/2

Ente

roco

ccus

spec

ies 3

/7St

rept

ococ

cusa

galac

tiae

4/4

Stre

ptoc

occu

spyo

gene

s 0/2

Gra

m-n

egat

ive a

erob

es:

Esch

erich

ia c

oli1

/4Pr

oteu

s mira

bilis

2/0

Ente

roba

cter

aer

ogen

es1/

0Kl

ebsie

lla p

neum

onia

e1/

0An

aero

bes:

n2/

5Fu

soba

cter

ium

spec

ies 1

/2Pe

ptos

trept

ococ

cuss

pecie

s 1/4

Prev

otel

la b

ivia

0/1

Tota

l 33

(34%

)/41

(55%

)

Cory

neba

cter

ium

spec

ies 1

/2G

ram

-neg

ative

aer

obes

:Ps

eudo

mon

as a

erug

inos

a1/

1Es

cher

ichia

col

i2/0

Tota

l 8 (4

2%)/1

1 (5

8%)

Mea

n nu

mbe

r of i

solat

es p

erpa

tient

at d

ay 7

:C

: 1.0

5I:

0.95

Mea

n nu

mbe

r of i

solat

es p

erpa

tient

at d

ay 2

1:C

: 0.5

5I:

0.55

Num

ber (

%) o

f pat

ient

sre

quiri

ng a

djus

tmen

t of e

mpi

rical

antib

iotic

ther

apy

durin

g th

est

udy

perio

d:C

: 12/

20 (6

0)I:

12/2

0 (6

0)

Mea

n ±

SD/m

edian

(ran

ge)

dura

tion

of a

ntib

iotic

ther

apy

(day

s):

C: 5

8.7

±23

.7/6

0 (3

0–11

9)I:

68.9

±29

.2/6

2.5

(30–

163)

Num

ber (

%) o

f pat

ient

sun

derg

oing

ora

l/i.v.

ant

ibio

ticth

erap

y du

ring

the

stud

y pe

riod:

C: 1

1/20

(55)

/9/2

0 (4

5)I:

13/2

0 (6

5)/7

/20

(35)

ns Vasc

ular

reco

nstr

uctio

n w

as n

otun

dert

aken

in a

ny p

atie

nt d

urin

gth

e st

udy

perio

d

Glu

cose

met

abol

ism w

asad

equa

tely

cont

rolle

d in

all

patie

nts

CN

S-M

R, m

ethi

cillin

-res

istan

t, co

agul

ase

nega

tive

stap

hylo

cocc

i; C

NS-

MS,

met

hicil

lin-s

ensit

ive, c

oagu

lase

nega

tive

stap

hylo

cocc

i; SA

-MR,

met

hicil

lin-r

esist

ant,

Stap

hylo

cocc

us a

ureu

s; SA

-MS,

met

hicil

lin-

sens

itive

, Sta

phylo

cocc

us a

ureu

s.

Appendix 4

146

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Dw

ivedi

(200

0),12

7In

dia

Stud

y de

sign:

RCT

Met

hod

ofra

ndom

isatio

n:

Not

spec

ified

Uni

t of a

lloca

tion:

Pa

tient

Calc

ulat

ion

of st

atist

ical

pow

er: N

ot re

port

ed

Out

com

e as

sess

men

t:Am

puta

tion

rate

Mea

sure

men

t of u

lcer

mar

gins (

cent

imet

re ta

peby

Sm

elo’

s dev

ice),

pres

ence

of g

ranu

latio

ntis

sue,

abs

ence

of

puru

lent

disc

harg

e (v

iana

ked

eye

exam

inat

ion)

hist

olog

ical c

hang

es (v

iatis

sue

biop

sies)

,ro

entg

enog

ram

of

affe

cted

par

t, ar

teria

lcir

culat

ion

(ultr

asou

ndD

oppl

er/A

B in

dex)

,im

mun

olog

ical c

hang

es(Ig

G, I

gA, I

gM v

ia sin

glera

dial

diffu

sion

(Fah

ey19

65)33

1 ), to

tal p

rote

ins

Gra

ding

of r

esul

ts b

ym

ild, m

oder

ate,

goo

dre

cove

ry

Setti

ng a

nd le

ngth

of

trea

tmen

t: D

iabet

iccli

nic/

5ye

ars

Inclu

sion

crite

ria:

100

patie

nts w

ithno

n-he

aling

diab

etic

foot

ulce

r of

6–12

mon

ths

dura

tion

Exclu

sion

crite

ria:

Non

e st

ated

Gen

der m

ale/fe

male

:70

/30

50 p

atie

nts e

ach

in 1

1 an

d 12

;ge

nder

split

not

give

n

Age

rang

e: 3

1–70

yea

rsAg

e-m

atch

ed g

roup

s (no

t sta

ted

how

don

e)

Dur

atio

n of

dia

bete

s:30

% 0

–5 y

ears

; 40%

6–1

0 ye

ars;

40%

>10

yea

rs

Diab

etic

cont

rol b

oth

grou

ps b

ysu

itabl

e hy

pogly

caem

ic ag

ents

or

insu

lin

Die

tary

hab

it:

Both

gro

ups 1

500–

2000

cal

per d

ay

Socia

l sta

tes:

60%

rura

l; 40

% u

rban

I1: 5

0 pa

tient

s rec

eive

d su

itabl

esy

stem

ic an

tibio

tics (

acco

rdin

gto

ant

ibio

tic se

nsiti

vity)

plu

sm

etro

nida

zole

, loc

al an

tisep

tics

and

perip

hera

l vas

cular

dila

tor

(Pen

toxi

fyllin

e).

I2: 5

0 pa

tient

s rec

eive

d a

wat

er-s

olub

le so

lid e

xtra

ct to

Man

jisht

ha (R

ubia

cor

difo

lia) a

ndAs

hvag

andh

a (W

ithan

iaso

mni

fera

) eac

h 50

0m

g or

ally,

3 ×

day.

Patie

nts a

lso re

quire

dto

kee

p af

fect

ed p

art d

ippe

d in

luke

war

m d

ecoc

tion

of ro

ots

of b

oth

plan

ts m

ixed

toge

ther

for 3

0m

inut

es d

aily.

Wou

nds

dres

sed

with

out a

nyco

nven

tiona

l loc

al an

tisep

tic

Both

gro

ups r

ecei

ved

regu

larsu

rgica

l tre

atm

ent c

onsis

ting

ofin

cisio

n, d

rain

age

of a

bsce

sses

and

wou

nd d

ebrid

emen

t (as

and

whe

n re

quire

d)

Con

trol

gro

up d

ata

avail

able

for i

mm

unog

lobu

lins a

nd to

tal

prot

eins

. Valu

es ta

ken

from

stan

dard

read

ings

of a

ge-

mat

ched

non

-diab

etics

of

imm

unop

atho

logy

labo

rato

ry(In

stitu

te o

f Med

ical S

cienc

es,

Bana

ras H

indu

Uni

vers

ity)

Resu

lts ta

bles

ava

ilabl

e on

ly fo

rim

mun

oglo

bulin

s, to

tal p

rote

ins

and

arte

rial c

ircul

atio

n

I1: A

mpu

tatio

n: 3

0% o

f gro

upun

derw

ent t

otal

or p

artia

lam

puta

tion

(per

sona

lco

mm

unica

tion)

(50%

inab

stra

ct.12

7 )

IgG

leve

ls ra

ised

signi

fican

tlybe

fore

and

afte

r tre

atm

ent

(t-va

lue:

0.1

60; p

< 0

.05)

. Whe

naf

ter t

reat

men

t com

pare

d to

cont

rol d

ata,

t-va

lue:

7.3

2;

p <

0.0

01Pa

tient

s sho

wed

mild

tom

oder

ate

reco

very

I2: A

mpu

tatio

n: 1

6% o

f pat

ient

sun

derw

ent p

artia

l am

puta

tion

(per

sona

l com

mun

icatio

n) (2

0%in

abs

trac

t.127 )

Stat

istica

lly si

gnifi

cant

cha

nges

note

d in

IgG

(t-v

alue:

0.1

63;

p<

0.0

5), I

gA (t

-valu

e: 1

.985

; p

< 0

.05)

, IgM

(t-v

alue:

1.7

34;

p<

0.0

1) a

nd to

tal p

rote

in le

vels

(t-va

lue:

0.9

79; p

<0.

01) w

hen

com

pare

d be

fore

and

afte

rtr

eatm

ent.

Com

pare

d w

ithco

ntro

l dat

a, o

nly

IgG

(t v

alue:

7.44

; p<

0.0

01),

IgA

(1.4

988;

p

< 0

.05)

and

tota

l pro

tein

(0.8

785;

p<

0.0

5) sh

owed

signi

fican

t im

prov

emen

tPa

tient

s sho

wed

mod

erat

e to

good

reco

very

and

dem

onst

rabl

ehi

stol

ogica

l cha

nges

in re

duce

dsu

bepi

thel

ial o

edem

a, re

duce

dex

udat

es, v

ascu

lar c

hann

el

No

deta

ilsRa

tiona

le fo

rde

finin

g th

e st

udy

agen

t as a

nan

timicr

obial

agen

t: au

thor

sju

stify

effe

ctive

ness

of M

anjis

htha

on

basis

of a

bilit

y of

rem

ove

micr

oang

iopa

thic

and

athe

rosc

lero

ticch

ange

s ins

ide

the

arte

ries/c

apilla

ries

in w

ound

are

a,th

us fa

cilita

ting

bloo

d su

pply,

nutr

ition

and

rem

oval

ofm

icrob

es. A

lsoth

at A

shva

gand

haim

prov

edim

mun

olog

ical

stat

us o

f pat

ient

s

cont

inue

d


147


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

prof

ilera

tion

and

appe

aran

ce o

fhe

alth

gran

ulat

ion

tissu

e. G

ood

impr

ovem

ent i

n ar

teria

lcir

culat

ion

of a

ffect

ed p

art a

lsono

ted.

Con

trol

of p

urul

ent

disc

harg

e (m

aggo

tssp

onta

neou

sly d

ischa

rged

afte

r4–

6 di

ppin

gs)

At 3

mon

ths:

both

gro

ups

show

ed st

atist

ically

sign

ifica

ntch

ange

s (p

< 0

.01)

in a

nkle

brac

hial

pres

sure

inde

x(A

Bin

dex)

Appendix 4

148

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Erst

ad (1

997)

,107

USA

Stud

y de

sign:

RC

T (D

B)

Met

hod

ofra

ndom

isatio

n:N

ot st

ated

Uni

t of a

lloca

tion:

Patie

nt

Calc

ulat

ion

of st

atist

ical

pow

er:

Not

men

tione

d

Out

com

e as

sess

men

t:Ti

ssue

isch

aem

iaas

sess

ed u

sing

Dop

pler

-de

rived

ank

le–b

rach

ialin

dex

and

palp

atio

n of

pulse

s (fe

mor

al,po

plite

al, p

oste

rior t

ibial

,an

d do

rsali

s ped

is).

Clin

ical r

espo

nse

class

ified

as:

cure

(com

plet

e re

solu

tion

ofpr

esen

ting

signs

and

sym

ptom

s);

impr

ovem

ent (

part

ialim

prov

emen

t of

pres

entin

g sig

ns a

ndsy

mpt

oms)

; fail

ure

(no

impr

ovem

ent o

rw

orse

ning

of p

rese

ntin

gsig

ns a

nd sy

mpt

oms)

.Pa

tient

s who

requ

ired

surg

ery

wer

e co

nsid

ered

evalu

able

if th

ean

timicr

obial

was

give

nfo

r at l

east

5da

ys p

rior

to su

rger

y or

if th

ean

timicr

obial

was

requ

ired

post

oper

ative

ly

Popu

latio

n:Ag

e at

leas

t18

year

s, w

ithin

sulin

or n

on-in

sulin

depe

nden

t diab

etes

atte

ndin

g th

eVa

scul

ar S

urge

rySe

rvice

at a

300

-bed

unive

rsity

med

ical

cent

re in

Sou

ther

nAr

izona

Inclu

sion

crite

ria:

At le

ast g

rade

I fo

otin

fect

ion

(see

belo

w);

not

rece

ived

succ

essfu

lan

timicr

obial

ther

apy

with

in th

epr

evio

us 4

days

,as

sess

ed b

y cli

nica

lim

prov

emen

t

Exclu

sion

crite

ria:

Know

nhy

pers

ensit

ivity

tope

nicil

lins o

rce

phalo

spor

ins;

crea

tinin

e cle

aran

cele

ss th

an15

ml/m

inut

e;re

cent

hist

ory

ofdr

ug o

r alco

hol

abus

e; c

onco

mita

ntin

fect

ion

at a

site

othe

r tha

n th

e fo

otth

at re

quire

dad

ditio

nal

antim

icrob

ials;

term

inal

illnes

s;ne

utro

peni

c;

Gen

der

Not

repo

rted

Mea

n (r

ange

) age

(yea

rs):

I1: 6

0.7

(31–

77)

I2: 5

7.8

(34–

93)

Num

ber (

%) w

ith ty

pe 1

/type

2di

abet

es:

I1: 1

3/18

(72)

/5/1

8 (2

8)I2

: 12/

18 (6

7)/6

/18

(33)

Mea

n du

ratio

n of

diab

etes

(yea

rs):

I1: 1

2.8

I2: 1

3.3

Num

ber (

%) w

ith g

rade

of w

ound

infe

ctio

n I1

/I2:

Gra

de I:

2/1

8 (1

1%)/1

/18

(6%

)G

rade

II: 8

/18

(44%

)/12/

18 (6

7%)

Gra

de II

I: 6/

18 (3

3%)/5

/18

(28%

)G

rade

IV: 2

/18

(11%

)/0

The

degr

ee o

f tiss

ue is

chae

mia

asde

term

ined

by

pulse

palp

atio

n an

dan

kle–

brac

hial

inde

x w

asco

mpa

rabl

e be

twee

n th

e 2

grou

ps(d

etail

s pro

vided

in th

e pa

per)

Num

ber (

%) w

ho h

ad e

xper

ienc

edfa

iled

outp

atie

nt a

ntim

icrob

ialth

erap

y pr

ior t

o ad

miss

ion:

I1: 1

0/18

(56%

) (6

patie

nts r

ecei

ved

cipro

floxa

cin)

I2: 7

/18

(39%

) (re

ceive

d a

varie

ty o

fan

timicr

obial

age

nts)

Mea

n an

kle–

brac

hial

pres

sure

inde

xof

righ

t leg

:I1

: 0.9

3I2

: 0.9

0

I1: A

/S 3

g q.

d.s.

if cr

eatin

ine

clear

ance

mor

e th

an50

ml/m

inut

e. S

ame

dose

was

given

t.d.

s. or

b.d

. if c

reat

inin

ecle

aran

ce 3

0–50

or

15–3

0 m

l/min

ute,

resp

ectiv

ely.

Dur

atio

n of

ther

apy

at le

ast

5da

ys (n

= 1

8)

I2: C

efox

itin

2g

q.d.

s. if

crea

tinin

e cle

aran

ce m

ore

than

50m

l/min

ute.

Sam

e do

se w

asgiv

en t.

d.s.

or b

.d, i

f cre

atin

ine

clear

ance

30–

50 o

r 15

–30

ml/m

inut

e re

spec

tivel

y.D

urat

ion

of th

erap

y at

leas

t5

days

(n=

18)

All p

atie

nts:

No

addi

tiona

l ant

imicr

obial

sw

ere

adm

inist

ered

dur

ing

hosp

italis

atio

n un

less

a p

atie

ntfa

iled

to re

spon

d to

the

stud

yan

timicr

obial

ther

apy

with

in48

hour

s, in

whi

ch c

ase

the

patie

nt w

as w

ithdr

awn.

Surg

ical i

nter

vent

ions

wer

epe

rform

ed a

s req

uire

d

Stat

istica

l met

hods

:�

2te

st u

sed

for c

linica

l and

bact

erio

logic

al ev

aluat

ions

and

Wilc

oxon

rank

sum

test

use

d to

com

pare

gro

ups f

or m

ean

dura

tion

of h

ospi

talis

atio

n an

dm

ean

chan

ges i

n cli

nica

l sign

s and

sym

ptom

s fro

m st

udy

entr

y to

end

of th

erap

y. Fi

sher

’s ex

act

test

(tw

o-ta

iled)

use

d to

com

pare

the

trea

tmen

tou

tcom

es (s

ucce

sses

and

failu

res)

of th

e 2

grou

ps. A

nalys

is w

asba

sed

on in

tent

ion-

to-tr

eat.

Num

ber (

%) w

ith c

linica

lre

spon

se to

trea

tmen

t I1/

I2:

Cur

ed: 1

/18

(6)/7

/18

(39)

Impr

oved

: 14/

18 (7

8)/9

/18

(50)

Faile

d: 2

/18

(11)

/1/1

8 (6

)In

dete

rmin

ate

resu

lt: 1

/18

(6)/1

/18

(6)

p=

0.0

3 fo

r pat

ient

s clas

sifie

d as

cure

d, b

ut n

o sig

nific

ant

diffe

renc

e w

hen

cure

and

impr

ovem

ent c

onsid

ered

toge

ther

Ther

e w

as n

o sig

nific

ant

diffe

renc

e be

twee

n gr

oups

in th

epr

opor

tion

of p

atie

nts w

ho h

adch

ange

s in

clini

cal s

igns a

ndsy

mpt

oms f

rom

bas

elin

e to

end

of th

erap

y

Num

ber (

%) w

ith b

acte

riolo

gical

resp

onse

to th

erap

y I1

/I2:

Erad

icatio

n: 6

/6 (1

00%

)/8/1

1(7

3%)

Part

ial e

radi

catio

n: 0

/2/1

1 (1

8%)

Pers

isten

ce: 0

/1/1

1 (9

%)

Num

ber o

fpa

tient

s not

com

plet

ing

5-da

yco

urse

of

trea

tmen

t:I1

: 1 (d

ue to

adve

rse

even

tun

relat

ed to

stud

ym

edica

tion)

I2: 2

(1 d

ue to

inad

equa

tere

spon

se to

ther

apy,

1 du

e to

requ

irem

ent f

orco

ncom

itant

ther

apy

for a

vagin

al in

fect

ion)

Num

ber o

fpa

tient

s eva

luab

lefo

r bac

terio

logic

alou

tcom

e (i.

e.cu

ltura

ble

mat

erial

ava

ilabl

efro

m in

fect

ed si

teat

bas

elin

e):

I1: 6

I2: 1

1

Revie

wer

’sco

mm

ent:

mos

t,bu

t not

all

of th

epa

tient

s in

this

stud

y ha

d a

DFU

(33/

36)

The

trial

aut

hors

com

men

ted

that

“the

unc

ontr

olle

din

fect

ious

pro

cess

had

ofte

n le

d to

loss

of f

oot

arch

itect

ure

befo

reho

spita

lisat

ion

and

i.v. a

ntim

icrob

ialth

erap

y w

asin

dica

ted

topr

otec

t aga

inst

sept

icaem

iabe

fore

, dur

ing

and

afte

rde

brid

emen

t”

Stud

y sp

onso

rshi

p:N

ot st

ated

cont

inue

d


149


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

to c

ontr

ol re

sidua

l sign

sof

infe

ctio

n at

the

affe

cted

site

(equ

atin

g to

at le

ast 5

tota

l day

s of

ther

apy)

. Pat

ient

s who

wer

e th

ough

t not

tore

quire

an

ampu

tatio

nba

sed

on th

e ad

miss

ion

inve

stiga

tions

, but

subs

eque

ntly

requ

ired

one

due

to d

iseas

epr

ogre

ssio

n, w

ere

class

ified

as c

linica

lfa

ilure

s.Ba

cter

ial e

radi

catio

n(a

sses

sed

by n

eedl

eas

pira

tion,

or d

eep

tissu

eor

bon

e sa

mpl

ing

durin

gop

erat

ive d

ebrid

emen

t)w

as d

efin

ed a

s the

disa

ppea

ranc

e of

cultu

rabl

e m

ater

ial o

rel

imin

atio

n of

pat

hoge

nsat

the

end

of th

erap

y an

dat

2-w

eek

follo

w-u

p. If

the

path

ogen

was

elim

inat

ed b

ut a

diff

eren

tpa

thog

en e

mer

ged

durin

g or

afte

r the

rapy

,th

e ev

aluat

ion

was

term

ed e

radi

catio

n/su

perin

fect

ion.

Par

tial

erad

icatio

n w

as d

efin

edas

disa

ppea

ranc

e of

som

e, b

ut n

ot a

ll of

the

path

ogen

s. Pe

rsist

ence

was

def

ined

as p

rese

nce

of in

itial

path

ogen

s at t

heen

d of

ther

apy.

Inde

term

inat

e: re

sults

preg

nant

;br

east

feed

ing

Seve

rity

scale

for

diab

etic

foot

infe

ctio

n us

ed in

the

trial

:G

rade

I: c

ellu

litis,

no

skin

bre

akG

rade

II: c

ellu

litis,

supe

rficia

l ulce

ran

d/or

pun

ctur

ew

ound

pre

sent

Gra

de II

I: ce

llulit

is,de

ep u

lcer a

nd/o

rpu

nctu

re w

ound

with

susp

ecte

dos

teom

yelit

isG

rade

IV: c

ellu

litis,

deep

ulce

r, an

dos

teom

yelit

is w

ithde

stru

ctio

n of

foot

arch

itect

ure

and/

orw

et g

angr

ene

Mea

n an

kle–

brac

hial

pres

sure

inde

xof

left

leg:

I1: 0

.90

I2

: 0.8

3

No

signi

fican

t diff

eren

ces w

ere

foun

d be

twee

n gr

oups

The

over

all m

ean

±SD

num

ber

of is

olat

es p

er p

atie

nt w

as3.

4±1.

1 (n

ot re

port

ed p

ergr

oup)

. At l

east

one

spec

ies o

fSt

aphy

loco

ccus

was

isol

ated

from

all p

atie

nts,

and

all b

ut o

nepa

tient

had

at l

east

one

spec

ies

of S

trept

ococ

cuso

r Ent

eroc

occu

s.Al

l of t

he S

taph

yloco

ccus

and

Stre

ptoc

occu

siso

lates

wer

esu

scep

tible

to b

oth

stud

yan

tibio

tic re

gimen

s, bu

t the

Ente

roco

ccus

isolat

es (2

5% o

fpa

tient

s, all

in I1

) wer

esu

scep

tible

onl

y to

A/S

. Eac

hpa

tient

with

isol

ates

susc

eptib

leto

the

pres

crib

ed a

ntim

icrob

ialag

ent h

ad c

linica

l im

prov

emen

tor

cur

e, e

xcep

t for

one

pat

ient

inI1

who

requ

ired

are

vasc

ular

isatio

n pr

oced

ure

shor

tly a

fter a

dmiss

ion.

Of t

hepa

tient

s with

one

or m

ore

orga

nism

s res

istan

t to

the

stud

yan

timicr

obial

(25%

of p

atie

nts i

nea

ch g

roup

), all

had

clin

ical

impr

ovem

ent d

urin

g th

erap

y

Num

ber o

f pat

ient

s und

ergo

ing

ampu

tatio

ns I1

/I2:

Toe

only

3/6

Toe

and

ray

4/1

Belo

w k

nee

1/1

Num

ber o

f pat

ient

s und

ergo

ing

reva

scul

arisa

tion

proc

edur

es:

I1: f

emor

otib

ial b

ypas

s 1Ao

rtob

ifem

oral

bypa

ss a

nd to

eam

puta

tion

1

cont

inue

d

Appendix 4

150

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

wer

e th

ose

that

did

not

fit in

to a

ny c

ateg

ory

for

both

clin

ical a

ndba

cter

iolo

gical

asse

ssm

ent.

Spec

imen

sw

ere

plac

ed in

ster

ileco

ntain

ers a

ndtr

ansp

orte

d to

the

labor

ator

y. Sp

ecim

ens

wer

e te

sted

for a

erob

ican

d an

aero

bic

orga

nism

sw

ith su

bseq

uent

susc

eptib

ility

test

ing

that

inclu

ded

dete

rmin

atio

nof

min

imum

inhi

bito

ryco

ncen

trat

ion

of is

olat

es.

In a

dditi

on, t

he n

umbe

rof

isol

ates

iden

tifie

d,su

rgica

l pro

cedu

res

requ

ired,

dur

atio

n of

hosp

italis

atio

n, a

ndad

vers

e ev

ents

wer

ere

cord

ed

Setti

ng/le

ngth

of

trea

tmen

t:H

ospi

tal.

Initi

al fo

llow

-up

was

2w

eeks

pos

t-ho

spita

l disc

harg

e. L

ater

follo

w-u

p w

as 1

yea

r

I2: p

oplit

eal–

tibial

byp

ass a

ndbe

low

-kne

e am

puta

tion

1Be

low

kne

e fe

mor

opop

litea

lby

pass

1Ili

ac a

ngio

plas

ty 1

Popl

iteal

angio

plas

ty 1

Mea

n (r

ange

) dur

atio

n of

hosp

italis

atio

n (d

ays)

:I1

: 21.

1 (6

.0–5

8.0)

I2: 1

2.1

(4.0

–39.

0)p

= 0

.06

Prop

ortio

n of

pat

ient

sex

perie

ncin

g ga

stro

inte

stin

alad

vers

e ev

ents

:I1

: 39%

I2: 3

3%

Thre

e pa

tient

s in

grou

p I1

suffe

red

a se

rious

adv

erse

eve

nt(w

orse

ning

of c

onge

stive

car

diac

failu

re) w

hich

the

auth

ors

cons

ider

ed to

be

unre

lated

to th

est

udy

trea

tmen

t


151


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Gou

gh (1

997)

,100

UK

Dup

licat

e pu

blica

tion:

Gou

gh (1

998)

174

Stud

y de

sign:

RC

T (D

B)

Met

hod

ofra

ndom

isatio

n:Ra

ndom

num

ber l

ist

Uni

t of a

lloca

tion:

Patie

nt

Calc

ulat

ion

of st

atist

ical

pow

er:

A sa

mpl

e siz

e of

40

patie

nts w

as e

stim

ated

base

d on

evid

ence

of a

mea

n tim

e to

reso

lutio

nof

infe

ctio

n of

13.

0(S

D6.

5) d

ays i

n sim

ilar

patie

nts.

A re

duct

ion

of6

days

was

take

n as

clini

cally

sign

ifica

nt w

ith�

= 0

.05

and

pow

er o

f0.

8

Out

com

es a

sses

sed:

Tim

e to

hos

pita

ldi

scha

rge

(elig

ibilit

ycr

iteria

for d

ischa

rge

wer

e re

solu

tion

ofce

llulit

is, i.

e.di

sapp

eara

nce

clini

cally

of so

ft-tis

sue

eryt

hem

a,no

furt

her e

xuda

te fr

omth

e ul

cer,

skin

tem

pera

ture

diff

eren

cew

ithin

nor

mal

limits

, and

nega

tive

foot

ulce

rcu

lture

s)

Popu

latio

n:Pa

tient

s adm

itted

from

a sp

ecial

istdi

abet

ic fo

ot c

linic

Inclu

sion

crite

ria:

Adul

t (>

18ye

ars)

diab

etic

patie

nts

with

ext

ensiv

ece

llulit

is, d

efin

ed a

san

acu

te sp

read

ing

infe

ctio

n of

the

skin

with

invo

lvem

ent o

fth

e su

bcut

aneo

ustis

sues

, clin

ically

char

acte

rised

by

eryt

hem

a (>

2cm

indi

amet

er) i

nas

socia

tion

with

puru

lent

disc

harg

e,w

ith o

r with

out

lymph

angit

is

If a

patie

nt h

adse

vera

l ulce

rs, t

hem

ost s

ever

ely

affe

cted

one

was

stud

ied

Exclu

sion

crite

ria:

Abso

lute

neu

trop

hil

coun

t of <

1.0

×10

9 /l or

>50

×10

9 /l;hi

stor

y of

mali

gnan

tdi

sord

er; b

lood

dysc

rasia

; HIV

infe

ctio

n; se

rum

crea

tinin

e>

250

µmol

/l or

rena

l rep

lacem

ent

ther

apy;

hep

atic

dise

ase;

pre

vious

Num

ber m

ale/fe

male

:C

: 15/

5I:

14/6

Num

ber w

hite

/Afro

-Car

ibbe

an:

C: 1

5/5

I: 18

/2

Med

ian (r

ange

) age

in (y

ears

):C

: 66

(58–

81)

I: 65

(30–

86)

Med

ian (r

ange

) dur

atio

n of

diab

etes

in (y

ears

):C

: 19

(1–4

4)I:

18.5

(0.1

–50)

Num

ber i

nsul

in d

epen

dent

/non

-in

sulin

dep

ende

nt:

C: 4

/16

I: 6/

14

Num

ber t

reat

ed w

ith in

sulin

:C

: 15

I: 13

Med

ian (r

ange

) glyc

ated

haem

oglo

bin

(%):

C: 8

.70

(5.5

–12.

9)I:

9.25

(5.5

–13.

7)

Med

ian (r

ange

) bod

y m

ass i

ndex

in(k

g/m

2 ):C

: 24.

9 (2

1.1–

40.7

)I:

28.4

(21.

0–40

.8)

Num

ber w

ith n

ephr

opat

hy:

C: 5

I: 5

Med

ian (r

ange

) vib

ratio

n pe

rcep

tion

thre

shol

d (v

olts

):C

: 37.

4 (8

.3–5

0.0)

I: 35

.7 (1

8.3–

50.0

)

I: G

-CSF

give

n at

an

initi

al do

seof

5µg

/k/d

ay, r

educ

ed to

2.5

µg/k

g/da

y, if,

afte

r 2 d

oses

,th

e ab

solu

te n

eutr

ophi

l cou

ntw

as h

igher

than

25

×10

9 /l. If

the

abso

lute

neu

trop

hil c

ount

rem

ained

abo

ve th

is va

lue

afte

ra

furt

her 2

dos

es, 2

.5µg

/kg

was

give

n on

alte

rnat

e da

ys. I

fat

any

poi

nt th

e ab

solu

tene

utro

phil

coun

t was

>50

×10

9 /l or

the

tota

l whi

te c

ell

coun

t was

>75

×10

9 /l, G

-CSF

was

stop

ped

until

the

abso

lute

neut

roph

il co

unt f

ell b

elow

10

×10

9 /l. G

-CSF

was

adm

inist

ered

as a

dail

ysu

bcut

aneo

us in

ject

ion

for

7da

ys (n

= 2

0)

C: P

laceb

o, c

onsis

ting

of a

salin

e so

lutio

n, id

entic

al in

appe

aran

ce w

ith a

ctive

prep

arat

ion,

adm

inist

ered

as a

daily

subc

utan

eous

inje

ctio

n fo

r7

days

(n=

20)

All p

atie

nts:

A co

mbi

natio

n of

4 a

ntib

iotic

s(c

efta

zidim

e, a

mox

icillin

,flu

cloxa

cillin

and

met

roni

dazo

le) w

as g

iven

i.v.

until

cel

lulit

is an

d ul

cer

disc

harg

e re

solve

d. M

ost

patie

nts r

ecei

ved

the

follo

win

gre

spec

tive

dose

s dail

y: 3

, 1.5

, 2an

d 1.

5g.

Alte

rnat

ively,

vanc

omyc

in i.

v. w

as u

sed

ifth

ere

was

kno

wn

peni

cillin

hype

rsen

sitivi

ty o

r if t

he p

atie

ntw

as o

r had

bee

n co

loni

sed

or

Stat

istica

l met

hods

:�

2te

st w

ith Y

ate’

s cor

rect

ion

for

small

num

bers

was

use

d fo

rca

tego

rical

data

, and

log-

rank

test

used

for t

ime

to e

vent

dat

a

The

med

ian (r

ange

) dos

e of

G

-CSF

ove

r the

7da

ys w

as 3

02(2

00–4

40) µ

g/da

y, w

ith 9

pat

ient

sre

quiri

ng a

redu

ctio

n in

dos

e

Num

ber o

f pat

ient

s who

rece

ived

antib

iotic

regim

enco

nsist

ing

of c

efta

zidim

e,am

oxici

llin, f

luclo

xacil

lin, a

ndm

etro

nida

zole

(give

n i.v

. the

n by

mou

th if

app

ropr

iate)

:C

: 15

I: 17

Num

ber o

f pat

ient

s who

rece

ived

vanc

omyc

in:

C: 4

(3 h

ad M

RSA,

1 h

adpe

nicil

lin a

llerg

y)I:

3 (2

had

MRS

A, 1

had

pen

icillin

aller

gy)

Num

ber o

f pat

ient

s with

evid

ence

of o

steo

mye

litis:

C: 1

2I:

12

Patie

nts w

ith o

steo

mye

litis

rece

ived

com

bine

d or

al an

d i.v

.th

erap

y fo

r at l

east

10

wee

ks

Med

ian (r

ange

) tim

e to

hos

pita

ldi

scha

rge

in d

ays:

C: 1

7.5

(9–1

00)

I: 10

(7–3

1)p

= 0

.02

Med

ian (r

ange

) tim

e to

reso

lutio

n

Ther

e w

ere

now

ithdr

awals

Auth

ors’

note

:G

-CSF

ther

apy

was

ass

ociat

edw

ith th

ede

velo

pmen

t of

leuc

ocyt

osis,

due

almos

t ent

irely

toan

incr

ease

inne

utro

phil

coun

t

Nor

mal

rang

es fo

rha

emat

olog

yan

alyse

s, as

sugg

este

d by

trial

auth

ors:

Tota

l whi

te c

ells

(4.0

–10.

0) ×

109 /l

Neu

trop

hils

(2.5

–7.5

) ×10

9 /lLy

mph

ocyt

es(1

.3–4

.0) ×

109 /L

Mon

ocyt

es(0

.2–1

.5) ×

109 /L

Ratio

nale

for

defin

ing

the

stud

yag

ent a

s an

antim

icrob

ialag

ent:

Endo

geno

us

G-C

SFco

ncen

trat

ions

rise

durin

g ba

cter

ialse

psis

in b

oth

neut

rope

nic

and

non-

neut

rope

nic

stat

es, s

ugge

stin

gth

at G

-CSF

may

have

a c

entr

al ro

lein

the

neut

roph

ilre

spon

se to

cont

inue

d

Appendix 4

152

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Tim

e to

reso

lutio

n of

cellu

litis

(ass

esse

d by

skin

tem

pera

ture

usin

gin

frare

d th

erm

omet

eran

d co

mpa

ring

aver

age

of3

read

ings

with

in a

rea

ofce

llulit

is w

ith th

ose

take

nfro

m th

e co

rres

pond

ing

site

on th

e no

n-in

fect

edfo

ot, a

diff

eren

ce o

f mor

eth

an 2

°C b

eing

def

ined

as

abno

rmal)

Tim

e to

with

draw

al of

antib

iotic

s

Tim

e to

neg

ative

swab

cultu

re (a

sses

sed

usin

gda

ily sw

abs t

aken

from

the

deep

est p

art o

f the

wou

nd a

fter c

lean

sing

the

ulce

r with

ster

ilesa

line

and

rem

ovin

gsu

perfi

cial d

ebris

;sp

ecim

ens w

ere

analy

sed

for a

erob

ic an

dan

aero

bic

cultu

re, a

ndsa

mpl

ing

was

repe

ated

until

cul

ture

s wer

ene

gativ

e on

2co

nsec

utive

day

s)

Requ

irem

ent f

or su

rger

y

Ulce

r hea

ling

Requ

irem

ent f

oran

giogr

aphy

and

asso

ciate

d pr

oced

ures

Diag

nosis

of

oste

omye

litis

(usin

g pl

ainra

diog

raph

y an

d pr

obe

orga

ntr

ansp

lanta

tion;

imm

unos

uppr

essiv

eth

erap

y in

cludi

ngco

rtico

ster

iods

;pr

egna

ncy;

lact

atio

n;m

ultip

le o

rgan

failu

re; s

econ

dary

tose

ptica

emia;

crit

ical

leg

ischa

emia

(ank

lesy

stol

ic pr

essu

re<

50m

mH

g or

ankl

e/br

achi

al bl

ood

pres

sure

inde

x<

0.5)

; dor

sal

tran

scut

aneo

usox

ygen

pre

ssur

e<

30m

mH

g

Neu

trop

hils

from

10

healt

hy v

olun

teer

s,m

atch

ed b

y ag

e an

dge

nder

to th

edi

abet

ic pa

tient

s,w

ere

used

as

cont

rols

for

neut

roph

il fu

nctio

nas

says

Med

ian (r

ange

) Dop

pler

inde

x fo

ran

kle/

brac

hial

bloo

d pr

essu

re ra

tio:

C: 0

.99

(0.6

5–1.

50)

I: 1.

00 (0

.53–

1.28

)

Num

ber w

ith re

tinop

athy

:C

: 13

I: 12

Num

ber r

ecei

ving

antib

iotic

s on

recr

uitm

ent t

o th

e tr

ial:

C: 3

I: 3

Num

ber c

urre

ntly

smok

ing:

C: 2

I: 3

Num

ber w

ith h

istor

y of

cor

onar

y or

cere

brov

ascu

lar d

iseas

e:C

: 10

I: 7

Num

ber w

ith p

revio

us m

inor

ampu

tatio

n or

deb

ridem

ent:

C: 1

3I:

9

Num

ber w

ith u

lcers

in th

efo

refo

ot/m

idfo

ot/h

indf

oot:

C: 1

7/2/

1I:

15/2

/2In

add

ition

, one

pat

ient

in g

roup

Iha

d ex

tens

ive c

ellu

litis

seco

ndar

y to

a pa

rony

chia

with

out u

lcera

tion

Num

ber w

ith m

ultip

le u

lcers

:C

: 9I:

7

Med

ian (r

ange

) dur

atio

n of

foot

ulce

r (da

ys):

C: 3

9.5

(2–1

825)

I: 21

.0 (2

–127

8)

infe

cted

dur

ing

the

past

yea

rw

ith M

RSA.

If a

n in

fect

ing

path

ogen

was

iden

tifie

d be

fore

adm

issio

n an

d en

rolm

ent,

the

appr

opria

te a

ntib

iotic

s wer

eus

ed a

s firs

t-lin

e th

erap

y.Su

bseq

uent

cha

nges

toan

tibio

tic tr

eatm

ent w

ere

guid

ed b

y m

icrob

iolo

gical

cultu

res a

nd se

nsiti

vitie

s.G

lycae

mic

cont

rol w

asop

timise

d w

ith in

sulin

in a

llpa

rtici

pant

s, us

ing

a co

ntin

uous

i.v. i

nfus

ion

or a

mul

tiple

-dos

ere

gimen

. Onl

y st

anda

rd fo

amdr

essin

gs w

ere

used

. All

rece

ived

appr

opria

te p

odiat

rictr

eatm

ent.

Dec

ision

s abo

utsu

rgica

l deb

ridem

ent o

ram

puta

tion

wer

e ba

sed

oncli

nica

l sign

s, in

cludi

ng th

epr

esen

ce o

f non

-viab

le ti

ssue

,th

e de

velo

pmen

t of g

angr

ene,

absc

ess f

orm

atio

n an

d lac

k of

impr

ovem

ent d

espi

te o

ptim

uman

timicr

obial

ther

apy

of c

ellu

litis

in d

ays:

C: 1

2 (5

–93)

I: 7

(5–2

0)p

= 0

.03

Med

ian (r

ange

) tim

e to

with

draw

al of

i.v.

antib

iotic

s in

(day

s):

C: 1

4.5

(8–6

3)I:

8.5

(5–3

0)p

= 0

.02

Med

ian (r

ange

) tim

e to

neg

ative

swab

cul

ture

in (d

ays)

:C

: 8 (2

–79)

(pos

itive

swab

beca

me

ster

ile in

15

patie

nts)

I: 4

(2–1

0) (p

ositi

ve sw

ab b

ecam

est

erile

in 1

6 pa

tient

s)p

= 0

.02

Med

ian (r

ange

) foo

t tem

pera

ture

diffe

renc

e in

(ºC

) at d

ay 7

:C

: 2.1

(0.1

–5.8

)I:

1.1

(0.1

–2.8

)p

= 0

.011

Num

ber r

equi

ring

surg

ery

(deb

ridem

ent u

nder

gen

eral

anae

sthe

sia a

nd/o

r ray

ampu

tatio

n):

C: 4

pat

ient

s (1

durin

g fir

st7

days

, 3 a

fter f

irst 7

days

; 2 h

adto

e am

puta

tion,

2 h

ad e

xten

sive

debr

idem

ent u

nder

ana

esth

esia)

I: no

nep

= 0

.114

Num

ber (

%) o

f pat

ient

s with

reso

lutio

n of

cel

lulit

is at

day

7:

C: 4

(20%

)I:

11 (5

5%)

p=

0.0

5

infe

ctio

n. E

xter

nal

adm

inist

ratio

n of

G-C

SF is

thou

ght

to in

crea

se th

ere

leas

e of

neut

roph

ils fr

omth

e bo

ne m

arro

wan

d im

prov

ene

utro

phil

func

tion

Stud

y sp

onso

rshi

p:Th

e le

ad a

utho

rw

as su

ppor

ted

bya

gran

t fro

mAm

gen

CA,

USA

cont

inue

d


153


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

to b

one)

Hae

mat

olog

y (s

ampl

esta

ken

by st

aff n

otin

volve

d in

clin

ical

asse

ssm

ent o

f the

patie

nts;

resu

lts g

iven

toth

e ph

arm

acist

, who

unde

rtoo

k ch

ange

s in

dose

s of G

-CSF

, whi

chw

ere

conc

eale

d fro

m th

ein

vest

igato

rs)

Effe

cts o

f G-C

SF o

n th

ege

nera

tion

of n

eutr

ophi

lsu

pero

xide

: mea

sure

d by

a sp

ectr

opho

tom

etric

assa

y

Adve

rse

effe

cts

Patie

nts w

ere

revie

wed

daily

by

3 in

depe

nden

tcli

nicia

ns. A

ll cli

nica

lde

cisio

ns (r

egar

ding

need

for s

urge

ry o

rel

igibi

lity

for h

ospi

tal

disc

harg

e) w

ere

mad

ein

depe

nden

tly o

f stu

dytr

eatm

ent a

nd w

hite

-cel

lco

unt

Setti

ng a

nd le

ngth

of

trea

tmen

t:H

ospi

tal;

7da

ys

Med

ian (r

ange

) dur

atio

n of

cel

lulit

is(d

ays)

:C

: 4 (2

–21)

I: 5

(1–1

4)

Med

ian (r

ange

) foo

t tem

pera

ture

diffe

renc

e (º

C):

C: 3

.1 (0

–9.1

)I:

4.3

(1.4

–11.

2)

Med

ian (r

ange

) tot

al w

hite

cel

lco

unt (

×10

9 /l):

C: 7

.8 (3

.7–1

1.1)

I: 7.

6 (4

.8–1

7.1)

Med

ian (r

ange

) neu

trop

hil c

ount

(×

109 /l)

:C

: 5.5

(1.4

–7.9

)I:

5.6

(2.6

–15.

9)

Med

ian (r

ange

) lym

phoc

yte

coun

t (×

109 /l)

:C

: 1.9

(0.8

–3.3

)I:

1.8

(0.9

–3.3

)

Med

ian (r

ange

) mon

ocyt

e co

unt

(×10

9 /l):

C: 0

.47

(0.1

–1.1

)I:

0.39

(0.1

–0.9

)

Micr

obio

logy

resu

lts (n

umbe

r of

patie

nts i

n C

/I):

Posit

ive w

ound

cul

ture

15/

16

Gra

m-p

ositi

ve a

erob

es:

Stap

hylo

cocc

us a

ureu

s5/1

1St

rept

ococ

cus a

gala

ctia

e0/

1St

rept

ococ

cusC

0/1

Stre

ptoc

occu

sG 0

/2Es

cher

ichia

col

i3/0

MRS

A 3/

2

Num

ber (

%) o

f pat

ient

with

ulce

r hea

led

at d

ay 7

:C

: 0I:

4 (2

1%)

p=

0.0

9

In p

atie

nts w

ith m

ultip

le u

lcers

,th

ere

was

no

dete

riora

tion

in a

nyse

cond

ary

ulce

rs

Med

ian (r

ange

) blo

od g

luco

se(m

mol

/l):

C: 1

1.5

(2.7

–24.

4)I:

12.4

(3.0

–27.

2)p

= 0

.42

Med

ian (r

ange

) ins

ulin

dos

e in

(U/k

g/da

y):

C: 0

.48

(0.1

5–1.

01)

I: 0.

58 (0

.11–

1.12

)p

= 0

.38

Num

ber o

f pat

ient

s und

ergo

ing

angio

grap

hy:

C: 7

I: 4

p=

0.5

Num

ber o

f pat

ient

s und

ergo

ing

perc

utan

eous

tran

slum

inal

ballo

on a

ngio

plas

ty/v

ascu

larsu

rger

y/no

inte

rven

tion:

C: 3

/3/1

– p

atie

nt re

fuse

d fu

rthe

rin

terv

entio

nI:

2/1/

1 –

had

vasc

ular

dise

ase

unsu

itabl

e fo

r int

erve

ntio

np

= 0

.449

for b

etw

een-

grou

pdi

ffere

nce

for p

ropo

rtio

ns o

fpa

tient

s und

ergo

ing

angio

plas

tyor

surg

ery

Ther

e w

ere

no si

gnifi

cant

chan

ges i

n ha

emog

lobi

n or

in

cont

inue

d

Appendix 4

154

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Gra

m-n

egat

ive a

erob

es:

Ente

roba

cter

spec

ies 2

/3Ac

inet

obac

ters

pecie

s 0/1

Serra

tiasp

ecie

s 2/0

Kleb

siella

spec

ies 3

/0Pr

oteu

sspe

cies 2

/0Es

cher

ichia

col

i2/0

Oth

er 4

/1

Anae

robe

s:Ba

cter

iode

s fra

gilis

1/1

Oth

er 2

/2

Polym

icrob

ial in

fect

ion

9/6

plat

elet

cou

nts i

n ei

ther

gro

updu

ring

the

stud

y pe

riod

Med

ian (r

ange

) tot

al w

hite

cel

lco

unt (

×10

9 /l) a

t day

3:

C: 6

.9 (3

.8–1

1.5)

I: 25

.8 (1

7.6–

45.5

)p

< 0

.000

1

Med

ian (r

ange

) neu

trop

hil c

ount

(x 1

09 /l) a

t day

3:

C: 4

.5 (2

.5–8

.5)

I: 19

.9 (1

5.5–

41.9

)p

< 0

.000

1

Med

ian (r

ange

) lym

phoc

yte

coun

t(×

109 /l)

at d

ay 3

:C

: 1.8

(1.0

–2.9

)I:

2.3

(0.7

–4.5

)p

= 0

.07

Med

ian (r

ange

) mon

ocyt

e co

unt

(×10

9 /l) a

t day

3:

C: 0

.44

(0–1

.5)

I: 0.

48 (0

–3.9

)p

= 0

.201

Med

ian (r

ange

) tot

al w

hite

cel

lco

unt (

×10

9 /l) a

t day

7:

C: 6

.1 (4

.1–1

2.3)

I: 27

.8 (1

0.8–

41.0

)p

< 0

.000

1

Med

ian (r

ange

) neu

trop

hil c

ount

(×10

9 /l) a

t day

7:

C: 3

.8 (1

.0–6

.7)

I: 22

.4 (7

.9–3

7.1)

p<

0.0

001

Med

ian (r

ange

) lym

phoc

yte

coun

t(×

109 /l)

at d

ay 7

:C

: 1.8

(1.0

–5.1

)I:

2.6

(1.5

–4.9

)p

= 0

.012

cont

inue

d


155


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Med

ian (r

ange

) mon

ocyt

e co

unt

(×10

9 /l) a

t day

7:

C: 0

.54

(0.2

–1.1

)I:

0.69

(0.2

–3.7

)p

= 0

.044

Med

ian (r

ange

) neu

trop

hil

supe

roxi

de p

rodu

ctio

n in

nmol

/106

neut

roph

il in

30m

inut

es:

C: 7

.3 (2

.1–1

1.5)

I: 16

.1 (4

.2–2

4.2)

Num

ber o

f pat

ient

s with

tran

sient

rise

in se

rum

alk

aline

phos

phat

ase:

C: 1

I: 7

p<

0.0

5

Num

ber o

f pat

ient

s with

tran

sient

bon

e pa

in n

ot re

quiri

ngan

alges

ia:C

: not

repo

rted

I: 3

Appendix 4

156

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Gra

yson

(199

4),44

USA

Stud

y de

sign:

RC

T (D

B)

Met

hod

ofra

ndom

isatio

n:C

ompu

ter-

gene

rate

dco

de

Uni

t of a

lloca

tion:

Patie

nts,

but m

ost

outc

omes

are

repo

rted

in te

rms o

f the

num

ber

of in

fect

ions

per

stud

yar

m

Calc

ulat

ion

of st

atist

ical

pow

er:

Assu

min

g re

crui

tmen

t of

40 p

atie

nts p

er st

udy

arm

, it w

as e

stim

ated

that

, with

an

expe

cted

clini

cal r

espo

nse

rate

of

80%

for I

/C, t

he p

ower

of th

e st

udy

to d

etec

tth

at A

/S w

as n

ot m

ore

than

20%

less

effe

ctive

than

I/C

wou

ld b

e 0.

7

Out

com

e as

sess

men

t:

Clin

ical a

ndm

icrob

iolo

gical

end-

poin

ts w

ere

asse

ssed

afte

r 5 d

ays o

f em

piric

altr

eatm

ent a

nd a

tco

mpl

etio

n of

i.v.

ther

apy

Blin

d cli

nica

l ass

essm

ent

of si

gns a

nd sy

mpt

oms

was

con

duct

ed b

y 2

phys

ician

s dail

y fo

r the

first

6da

ys, t

hen

atre

gular

inte

rvals

unt

il th

e

Popu

latio

n:D

iabet

ic pa

tient

sw

ith li

mb-

thre

aten

ing

infe

ctio

nof

the

feet

or l

egs

iden

tifie

d by

Vasc

ular

and

Podi

atry

Ser

vices

at

the

New

Eng

land

Dea

cone

ss H

ospi

tal,

Bost

on, M

A, U

SA

Inclu

sion

crite

ria:

Requ

irem

ent f

orho

spita

lisat

ion;

age

at le

ast 1

8ye

ars;

and

pres

ence

of

diab

etes

and

lim

b-th

reat

enin

g in

fect

ion

invo

lving

the

low

erex

trem

ity. L

imb-

thre

aten

ing

infe

ctio

nw

as d

efin

ed b

y at

leas

t the

pre

senc

eof

cel

lulit

is, w

ith o

rw

ithou

t ulce

ratio

nor

pur

ulen

tdi

scha

rge

Exclu

sion

crite

ria:

Know

nhy

pers

ensit

ivity

to�

-lact

am a

ntib

iotic

s;re

quire

men

t for

othe

r con

com

itant

antib

iotic

trea

tmen

t;se

rum

cre

atin

ine

leve

l of 3

.5m

g/dl

or

grea

ter;

preg

nanc

y;ex

pect

ed d

eath

with

in 4

8ho

urs;

Num

ber m

ale/fe

male

:I1

: 30/

17I2

: 37/

9

Mea

n ag

e (y

ear)

:I1

: 59

I2: 6

1

Mea

n du

ratio

n of

diab

etes

(yea

rs):

I1: 2

0I2

: 19

Num

ber (

%) o

f inf

ectio

ns w

ithin

sulin

-dep

ende

nt d

iabet

es:

I1: 3

8 (7

9)I2

: 38

(79)

Num

ber (

%) o

f inf

ectio

ns w

ithse

nsor

y ne

urop

athy

:I1

: 43

(90)

I2: 4

6 (9

6)

Num

ber (

%) o

f inf

ectio

ns w

ithim

paire

d re

nal f

unct

ion

(def

ined

as

crea

tinin

e le

vel >

1.3

mg/

dl):

I1:

9 (1

9)I2

: 14

(29)

Num

ber (

%) o

f inf

ectio

ns w

ithte

mpe

ratu

re o

f >37

.8°C

:I1

: 21

(44)

I2: 1

3 (2

7)

Num

ber (

%) o

f inf

ectio

ns w

ith u

lcer

pres

ent:

I1: 4

2 (9

2)I2

: 46

(96)

Num

ber (

%) o

f inf

ectio

ns w

ithce

llulit

is pr

esen

t:I1

: 48

(100

)I2

: 47

(98)

I1: A

/S re

gimen

. Usu

al do

se(w

hen

crea

tinin

e cle

aran

ce w

asat

leas

t 30

ml/m

inut

e) 2

gam

picil

lin/1

g su

lbac

tam

(tot

al3

g) i.

v. q.

d.s.

In c

ases

of

impa

ired

rena

l fun

ctio

n(c

reat

inin

e cle

aran

ce15

–29

ml/m

inut

e) to

tal d

ose

was

redu

ced

to 1

.5–3

g b.

d.W

hen

crea

tinin

e cle

aran

ce w

asle

ss th

an 1

5 m

l/min

ute,

the

patie

nt w

as e

xclu

ded

from

the

stud

y (n

= 4

7 pa

tient

s with

48

infe

ctio

ns)

I2: I

/C re

gimen

. Usu

al do

se(w

hen

crea

tinin

e cle

aran

cegr

eate

r tha

n 30

ml/m

inut

e)50

0m

g i.v

. q.d

.s. In

cas

es o

fim

paire

d re

nal f

unct

ion

(cre

atin

ine

clear

ance

21–3

0m

l/min

ute)

dos

e w

asre

duce

d to

500

mg

t.d.s.

Whe

ncr

eatin

ine

clear

ance

was

20m

l/min

ute

or le

ss, t

hepa

tient

was

exc

lude

d fro

m th

est

udy

(n=

46

patie

nts w

ith 4

8in

fect

ions

).

All p

atie

nts:

Stud

y m

edica

tion

was

com

men

ced

with

in 1

2ho

urs o

fba

selin

e w

ound

cul

ture

s. Th

efir

st 5

days

of t

reat

men

t wer

ede

fined

as a

per

iod

of e

mpi

rical

ther

apy

as c

ultu

res a

ndse

nsiti

vitie

s wer

e no

t ava

ilabl

ebe

fore

this

time

All p

atie

nts u

nder

wen

t bed

rest

, sur

gical

drain

age

and

debr

idem

ent o

f inf

ecte

d ul

cers

Stat

istica

l met

hods

:�

2te

st fo

r cat

egor

ical d

ata;

Stud

ent’s

t-te

st fo

r con

tinuo

usda

ta

Mea

n ±

SD/m

edian

(ran

ge)

num

ber o

f dos

es o

f ant

ibio

ticth

erap

y:I1

: 47

±26

/41

(10–

121)

I2: 5

5 ±

35/4

8 (1

3–17

8)p

= 0

.20

Mea

n ±

SD/m

edian

(ran

ge)

dura

tion

of a

ntib

iotic

ther

apy

inda

ys:

I1: 1

3 ±

6.5/

12 (4

–32)

I2: 1

5 ±

8.6/

13 (5

–45)

p=

0.2

5

Num

ber o

f inf

ectio

ns w

ithem

piric

al tr

eatm

ent c

ompl

eted

(20

dose

s):

I1: 4

5I2

: 45

Num

ber o

f inf

ectio

ns w

ithsig

nific

ant s

tudy

vio

latio

ns(m

issin

g m

edica

tion

dose

s):

I1: 3

I2: 6

p=

0.4

8

Num

ber o

f inf

ectio

ns re

quiri

ngdo

se re

duct

ion:

I1: 2

I2: 3

Num

ber o

f inf

ectio

ns w

here

non

-pr

otoc

ol i.

v. an

tibio

tics w

ere

given

due

to fa

ilure

of s

tudy

agen

t/oth

er re

ason

:I1

: 8/3

I2: 6

/3

All p

atie

nts w

ere

inclu

ded

in th

eev

aluat

ion

at th

een

d of

ther

apy

Num

ber (

%) o

fpa

tient

s los

t to

follo

w-u

p:I1

: 8/4

7 (1

7)I2

: 5/4

6 (1

1)

Trial

aut

hors

’co

mm

ent:

I/C h

asan

ant

imicr

obial

activ

ity a

gain

st a

broa

d sp

ectr

um o

for

gani

sms.

A/S

has

activ

ity si

mila

r to,

but l

ess b

road

than

, tha

t of I

/C

Trial

aut

hors

’co

mm

ent:

in tr

ials

of th

is ty

pe th

ere

are

majo

rdi

ffere

nces

betw

een

evalu

atio

ns in

term

s of t

he ro

leof

surg

ery

intr

eatin

gos

teom

yelit

is as

wel

l as t

hede

finiti

ons o

fsu

cces

s and

failu

re.

Thes

e di

ffere

nces

limit

the

relia

bilit

yof

com

paris

ons o

fou

tcom

e of

antib

iotic

ther

apy

for f

oot i

nfec

tion

in d

iabet

ic pa

tient

sst

udie

d in

var

ious

trial

s

Trial

aut

hors

’co

mm

ent:

the

resu

lts c

anno

t be

gene

ralis

ed to

diab

etic

patie

nts

with

a li

fe-

thre

aten

ing co

ntin

ued


157


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

com

plet

ion

of th

erap

y.Th

e as

sess

men

t inc

lude

ddo

cum

enta

tion

of th

edi

amet

er a

nd d

epth

of

ulce

rs, a

nd th

e ex

tent

of

cellu

litis,

lym

phan

gitis,

tissu

e ne

cros

is an

dpu

rule

nt d

ischa

rge.

Dail

yin

sulin

dos

ages

and

surg

ical p

roce

dure

s wer

ere

cord

ed

Aero

bic

and

anae

robi

ccu

lture

s of t

he d

eep

wou

nd (f

ollo

win

g sh

arp

debr

idem

ent)

orde

brid

ed ti

ssue

wer

epe

rform

ed o

n da

ys 0

, 3,

5 an

d on

the

final

day

ofi.v

. ant

ibio

tic tr

eatm

ent.

Whe

n pr

esen

t, pu

s was

aspi

rate

d an

d su

bmitt

edfo

r cul

ture

in a

cap

ped

syrin

ge. A

ll id

entif

ied

path

ogen

s wer

e te

sted

for s

usce

ptib

ility

to th

est

udy

drug

s

The

diag

nosis

of

oste

omye

litis

was

mad

eus

ing

hist

opat

holo

gy,

radi

olog

y an

d cli

nica

lsig

ns

Clin

ical e

nd-p

oint

s wer

e:cu

re (r

esol

utio

n of

soft

tissu

e in

fect

ion)

;im

prov

emen

t (all

eviat

ion

of a

t lea

st 2

pre

sent

ing

signs

or s

ympt

oms o

fin

fect

ion)

; fail

ure

(inad

equa

te

seve

re u

nder

lying

dise

ase

that

migh

tin

terfe

re w

ithev

aluat

ion

of th

eth

erap

eutic

resp

onse

; im

mun

ede

pres

sion

due

toun

derly

ing

dise

ase;

prio

r org

antr

ansp

lanta

tion

orim

mun

osup

pres

sive

drug

ther

apy;

curr

ent i

nvol

vem

ent

in a

clin

ical s

tudy

of

an in

vest

igatio

nal

drug

; rec

ent

trea

tmen

t fail

ure

usin

g an

tibio

tics

with

sim

ilar

antim

icrob

ialsp

ectr

um to

the

stud

y ag

ents

Cre

atin

ine

clear

ance

less

than

15

ml/m

in

Num

ber (

%) o

f inf

ectio

ns w

ithlym

phan

gitis

pres

ent:

I1: 1

4 (2

9)I2

: 19

(40)

Num

ber (

%) o

f inf

ectio

ns w

ithpu

rule

nt d

ischa

rge

pres

ent:

I1: 3

7 (7

7)I2

: 37

(77)

Num

ber (

%) o

f inf

ectio

ns o

nfo

refo

ot:

I1: 4

4 (9

2)I2

: 43

(90)

Num

ber (

%) o

f inf

ectio

ns o

nm

idfo

ot:

I1: 3

(6)

I2: 3

(6)

Num

ber (

%) o

f inf

ectio

ns o

nhi

ndfo

ot:

I1: 1

(2)

I2: 2

(4)

Num

ber (

%) o

f inf

ectio

ns w

ithle

ucoc

ytos

is (>

10,0

00le

ucoc

ytes

/mm

3 ):I1

: 24/

48 (5

0)I2

: 27/

48 (5

6)

Num

ber (

%) o

f inf

ectio

ns w

ithpo

sitive

blo

od c

ultu

re:

I1: 2

/48

(4)

I2: 1

/45

(2)

Num

ber (

%) o

f inf

ectio

ns w

ithos

teom

yelit

is pr

esen

t on

plain

radi

ogra

ph:

I1: 1

3/44

(30)

I2: 1

1/44

(25)

and

necr

otic

tissu

e, v

igoro

usco

ntro

l of d

iabet

es m

ellit

us,

and

use

of st

erile

wou

nddr

essin

gs (g

auze

soak

ed in

norm

al sa

line

or o

ne-q

uart

erst

reng

th p

ovid

one

iodi

ne).

Whe

n ap

prop

riate

, art

erial

circu

latio

n of

the

low

er li

mb

was

eva

luat

ed b

y no

n-in

vasiv

ean

d ar

terio

grap

hic

tech

niqu

es,

and

surg

ery

was

per

form

ed a

sre

quire

d

Antib

iotic

ther

apy

was

revis

edin

cas

es w

here

the

clini

cal

resp

onse

was

uns

atisf

acto

ry(b

lindi

ng w

as m

ainta

ined

).Re

visio

n co

uld

inclu

de u

se o

fre

plac

emen

t or a

dditi

onal

agen

ts. F

ollo

win

g co

mpl

etio

nof

stud

y th

erap

y, pa

tient

sre

ceive

d a

shor

t cou

rse

of o

ral

antib

iotic

s if n

eces

sary

Trea

tmen

t was

with

draw

n if

anur

ticar

ial o

r mor

billif

orm

rash

deve

lope

d

Num

ber (

%) o

f inf

ectio

ns w

houn

derw

ent s

urgic

al de

brid

emen

ton

ly:I1

: 9 (1

9)I2

: 15

(31)

p=

0.2

4

Num

ber (

%) o

f inf

ectio

ns w

houn

derw

ent a

mpu

tatio

n:I1

: 33

(69)

I2: 2

8 (5

8)p

= 0

.25

Num

ber (

%) o

f am

puta

tions

invo

lving

exc

ision

of d

igits

and

dist

al m

etat

arsa

l bon

es:

I1: 3

0/33

(91)

I2: 2

7/28

(96)

p=

0.7

3

Num

ber (

%) o

f inf

ectio

ns w

houn

derw

ent v

ascu

larre

cons

truc

tion:

I1: 7

(15)

I2: 1

5 (3

1)p

= 0

.09

Num

ber w

ith c

linica

l out

com

e at

day

5/en

d of

ther

apy:

Cur

e:I1

: 28/

48 (5

8%)/3

9/48

(81%

)I2

: 29/

48 (6

0%)/4

1/48

(85%

)p

= 0

.78

Impr

ovem

ent:

I1: 1

7/48

(35%

)/0I2

: 18/

48 (3

8%)/0

Failu

re:

I1: 3

/48

(6%

)/8/4

8 (1

7%)

I2: 1

/48

(2%

)/6/4

8 (1

3%)

Inde

term

inat

e:I1

: 0/1

/48

(2%

)I2

: 0/1

/48

(2%

)

infe

ctio

n as

such

patie

nts w

ere

exclu

ded

Stud

y sp

onso

rshi

p:G

rant

supp

ort

prov

ided

by

Pfize

rPh

arm

aceu

ticals

,Ro

erig

Divi

sion,

New

Yor

k, U

SA

cont

inue

d

Appendix 4

158

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

impr

ovem

ent,

nece

ssita

ting

a ch

ange

inan

tibio

tic th

erap

y); a

ndin

dete

rmin

ate

(clin

ical

asse

ssm

ent n

ot p

ossib

ledu

e to

am

puta

tion)

Micr

obio

logic

al en

d-po

ints

wer

e: e

radi

catio

n(c

lear

ance

of p

rincip

alpa

thog

ens f

rom

the

wou

nd; p

artia

l era

dica

tion

(cle

aran

ce o

f som

e bu

tno

t all

path

ogen

s);

pers

isten

ce (p

ersis

tenc

eof

prin

cipal

path

ogen

s);

and

supe

rinfe

ctio

n(e

limin

atio

n of

prin

ciple

path

ogen

s but

em

erge

nce

of a

new

pat

hoge

n du

ring

trea

tmen

t)

Adve

rse

even

ts w

ere

grad

ed a

s: sig

nific

ant

(sev

ere

reac

tion

nece

ssita

ting

with

draw

alof

stud

y ag

ent o

r spe

cific

trea

tmen

t);m

oder

ate/

poss

ible

(are

actio

n th

at d

id n

otne

cess

itate

with

draw

al of

stud

y ag

ent o

r spe

cific

trea

tmen

t); a

ndm

ild/u

nlik

ely

(an

even

tun

cert

ainly

asso

ciate

dw

ith th

e st

udy

drug

)

Setti

ng a

nd le

ngth

of

trea

tmen

t:H

ospi

tal,

single

-cen

tre.

Aver

age

trea

tmen

tdu

ratio

n 14

days

.

Num

ber (

%) o

f inf

ectio

ns w

ithos

teom

yelit

is pr

esen

t on

tech

netiu

mbo

ne sc

an:

I1: 0

/2I2

: 1/1

(100

)

Num

ber (

%) o

f inf

ectio

ns w

ithos

teom

yelit

is pr

esen

t on

hist

olog

ical

asse

ssm

ent o

f bon

e:I1

: 28/

31 (9

0)I2

: 25/

32 (7

8)

Num

ber (

%) o

f inf

ectio

ns w

ithpo

sitive

bon

e cu

lture

:I1

: 11/

12 (9

7)I2

: 7/8

(88)

Num

ber (

%) o

f inf

ectio

ns w

ithpr

esen

ce o

f ost

eom

yelit

is co

nfirm

edby

bon

e hi

stol

ogy,

bone

cul

ture

or

clini

cal p

rese

nce

of p

urul

ent,

non-

viabl

e bo

ne:

I1: 3

2/47

(68)

I2: 2

7/48

(56)

Num

ber (

%) o

f inf

ectio

ns w

ithpe

riphe

ral v

ascu

lar d

iseas

e (d

efin

edby

dim

inish

ed o

r abs

ent p

ulse

s):

I1: 3

9 (8

1)I2

: 38

(79)

Num

ber o

f bac

teria

l iso

lates

per

grou

p (I1

/I2):

Gra

m-p

ositi

ve a

erob

es:

Stap

hylo

cocc

us a

ureu

s29/

25C

oagu

lase-

nega

tive

stap

hylo

cocc

i4/

8St

rept

ococ

ci9/

26En

tero

cocc

i15/

13O

ther

2/1

Gra

m-n

egat

ive a

erob

es:

Pseu

dom

onas

aer

ugin

osa

4/3

Num

ber w

ith m

icrob

iolo

gical

outc

ome

at d

ay 5

/end

of t

hera

py:

Erad

icatio

n:I1

: 17/

48 (3

5%)/3

2/48

(67%

)I2

: 20/

48 (4

2%)/3

6/48

(75%

)p

= 0

.5Pa

rtial

era

dica

tion:

I1: 1

8/48

(38%

)/8/4

8 (1

7%)

I2: 1

5/48

(31%

)/5/4

8 (1

0%)

Pers

isten

ce:

I1: 7

/48

(15%

)/2/4

8 (4

%)

I2: 6

/48

(13%

)/3/4

8 (6

%)

Supe

rinfe

ctio

n:I1

: 0 /

2/48

(4%

)I2

: 0 /

3/48

(6%

)In

dete

rmin

ate:

I1: 6

/48

(13%

)/4/4

8 (8

%)

I2: 7

/48

(15%

)/1/4

8 (2

%)

Num

ber (

%) o

f fail

ures

of

ther

apy

per n

umbe

r of i

nfec

tions

in p

atie

nts w

ith o

steo

mye

litis:

I1: 6

/32

(19%

)I2

: 5/2

7 (1

9%)

Num

ber o

f fail

ures

of t

hera

pype

r num

ber o

f epi

sode

sas

socia

ted

with

resis

tant

path

ogen

s:I1

: 7/1

6 (4

4%)

I2: 4

/5 (8

0%)

Num

ber o

f pat

ient

s ass

essa

ble

atfo

llow

-up:

I1: 3

9I2

: 41

Mea

n ±

SD/m

edian

(ran

ge)

dura

tion

of fo

llow

-up

(wee

ks):

I1: 4

9 ±

36 /

36 (0

-113

)I2

: 53

±35

/ 57

(1-1

08)

p=

0.6

for m

eans

cont

inue

d


159


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Aver

age

dura

tion

offo

llow

-up

1ye

arN

on-a

erug

inos

a Ps

eudo

mon

assp

ecie

s1/

0Xa

ntho

mon

as m

alto

philia

1/1

Ente

roba

cter

spec

ies 3

/6Ac

inet

obac

ters

pecie

s 3 /

4M

orga

nella

spec

ies 2

/1Se

rratia

spec

ies 3

/2Kl

ebsie

llasp

ecie

s 3/2

Prot

euss

pecie

s 6/1

Esch

erich

ia c

oli4

/2O

ther

3/6

Anae

robe

s:Ba

cter

oide

s fra

gilis

3/3

Non

-frag

ilis b

acte

roid

essp

ecie

s 9/1

5Pe

ptoc

occu

sspe

cies 3

/9O

ther

8/6

Cand

ida

spec

ies:

1/2

Num

ber (

%) o

f ide

ntifi

ed p

atho

gens

and

thei

r res

istan

ce to

stud

y ag

ents

:To

tal i

solat

es:

I1: 4

5/48

(94)

I2: 4

7/48

(98)

Mul

tiple

pat

hoge

ns:

I1: 3

7/45

(82)

I2: 4

0/47

(85)

Gra

m-p

ositi

ve a

erob

es a

lone

:I1

: 21/

45 (4

7)I2

: 14/

47 (3

0)G

ram

-neg

ative

aer

obes

alo

ne:

I1: 0

/45

I2: 0

/47

Mix

ed G

ram

-pos

itive

and

Gra

m-

nega

tive

aero

bes a

lone

:I1

: 7/4

5 (9

)I2

: 11/

47 (2

3)M

ixed

aer

obes

and

ana

erob

es:

I1: 1

6/45

(36)

I2: 2

1/47

(45)

Anae

robe

s alo

ne:

I1: 1

/45

(2)

Num

ber w

ith c

linica

l out

com

e at

follo

w-u

p (b

ased

on

39as

sess

able

pat

ient

s in

I1 a

nd 4

1as

sess

able

pat

ient

s in

I2):

Cur

e:I1

: 27/

39 (6

9%)

I2: 3

3/41

(80%

)In

dete

rmin

ate:

I1: 3

/39

(8%

)I2

: 0/4

1Fa

ilure

:I1

: 9/3

9 (2

3%)

I2: 8

/41

(20%

)Re

lapse

:I1

: 6I2

: 9

Num

ber (

%) o

f adv

erse

eve

nts

(den

omin

ator

is n

umbe

r of

infe

ctio

ns):

Sign

ifica

nt:

I1: 7

/48

(15%

)I2

: 9/4

8 (1

9%)

Mod

erat

e/po

ssib

le:

I1: 8

/48

(17%

)I2

: 6/4

8 (1

3%)

Mild

/unl

ikel

y:I1

: 1/4

8 (2

%)

I2: 2

/48

(4%

)To

tal:

I1: 1

6/48

(33%

)I2

: 17/

48 (3

5%)

cont

inue

d

Appendix 4

160

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

I2: 1

/47

(2)

Num

ber o

f iso

latio

ns o

f res

istan

tpa

thog

ens i

n I1

/I2:

A/S-

resis

tant

aer

obes

12/

10O

ther

aer

obes

with

pro

babl

ere

sista

nce

4/5

A/S-

resis

tant

ana

erob

es 0

/0A/

S-su

scep

tibilit

y un

know

n 0/

3I/C

-res

istan

t aer

obes

2/4

I/C-r

esist

ant a

naer

obes

0/0

I/C-s

usce

ptib

ility

unkn

own

3/2

Num

ber o

f pat

ient

s with

pat

hoge

nspo

tent

ially

resis

tant

to th

e as

signe

dst

udy

drug

:I1

: 16

I2: 4

Base

line

ulce

r cha

ract

erist

ics su

ch a

sar

ea o

r dur

atio

n w

ere

not r

epor

ted


161


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Kast

enba

uer (

2003

),118

Aust

ria

Stud

y de

sign:

RC

T(s

ingle

-blin

d: p

atie

ntbl

inde

d)

Met

hod

ofra

ndom

isatio

n:

Not

stat

ed

Uni

t of a

lloca

tion:

Pa

tient

Out

com

e as

sess

men

t:Re

solu

tion

of c

ellu

litis,

spec

ified

clin

ically

and

by a

n in

fect

ion

sum

mar

y sc

ore

(ISS)

.I1

: G-C

SF (F

ilgra

stim

)vs

I2: p

laceb

o

Setti

ng: I

npat

ient

s

Leng

th o

f tre

atm

ent:

10da

ys

Popu

latio

n:

Diab

etic

patie

nts w

ithin

fect

ed fo

otul

cers

Inclu

sion

crite

ria:

Diab

etic

patie

nts w

ithm

oder

ate-

sized

(diam

eter

0.5–

3cm

)in

fect

edne

urop

athi

c(a

bnor

mal

10g

mon

ofila

men

tte

st) f

oot u

lcer

of W

agne

r’sgr

ade

2 or

3

Exclu

sion

crite

ria:

pres

ence

of

gang

rene

,ha

emat

olog

ical

dise

ases

,pa

ncyt

open

ia,ne

oplas

ia,im

paire

dki

dney

/live

rfu

nctio

n, re

cent

trea

tmen

t with

cyto

kine

s or

imm

unoa

ctive

drug

s

n=

37

I1I2

(n=

20)

(n=

17)

Male

(%)

n=

15

(75)

n=

12

(77)

Type

II D

iabet

esn

= 1

9 (9

5)n

= 8

(94)

(%)

Age

(yea

rs)

60.8

±11

.158

.2 ±

8.1

Diab

etes

Dur

atio

n (y

ears

)14

.7 ±

8.5

15.5

±10

.6H

bA1 C

(%)

8.9

±1.

79.

2 ±

2.6

I1: (

n=

20)

pat

ient

sre

ceive

d an

initi

al do

se o

f5

�g/

kg b

ody

wei

ght G

-C

SF (F

ilgra

stim

: Am

gen,

Vien

na, A

ustr

ia) in

ject

edsu

bcut

aneo

usly

I2: (

n=

17)

pat

ient

sre

ceive

d 5

�g/

kg b

ody

wei

ght p

laceb

o (0

.9%

ster

ile sa

line

solu

tion)

inje

cted

s.c.

All p

atie

nts h

ad to

main

tain

stric

t bed

rest

and

rece

ived

the

sam

e st

anda

rd o

fw

ound

car

e, in

cludi

ngde

brid

emen

t. Al

l pat

ient

str

eate

d w

ith i.

v. an

tibio

tics

(clin

dam

ycin

and

cipro

floxa

cin) u

ntil

infla

mm

atio

n vis

ibly

impr

oved

. Ora

l ant

ibio

tics

adm

inist

ered

ther

eafte

r if

nece

ssar

y

Abso

lute

neu

trop

hil a

ndle

ukoc

yte

coun

ts m

easu

red

daily

. Tre

atm

ent w

asom

itted

if th

e ab

solu

tene

utro

phil

coun

t was

grea

ter t

han

50,0

00/l

and

the

abso

lute

leuk

ocyt

eco

unt g

reat

er th

an75

,000

/l, a

nd w

as re

-in

stall

ed w

hen

neut

roph

ilsdr

oppe

d be

low

30,

000

and

the

leuk

ocyt

e co

unt b

elow

50,0

00.

Clin

ical f

oot i

nspe

ctio

n:ce

llulit

is (e

ryth

ema,

Stat

istica

l met

hods

: mea

ns ±

SD;

Shap

iro–W

ilk W

-test

. Man

n–W

hitn

eyU-

test

, sign

test

, �2

test

s. Ka

plan

-M

eier

ana

lysis

(log-

rank

test

). Pr

imar

yen

d-po

int (

by IS

S) a

nalys

ed b

y IT

Tan

d pe

r pro

toco

l I1I2

Leuk

ocyt

e co

unt (

× 109 /1

):D

ay 1

8.1

±2.

67.

7 ±

1.9

Day

10

40.8

±16

.39.

3 ±

8.3

CRP

(mg/

dl):

Day

11.

73 ±

2.2

1.71

±2.

31

Day

s 2–1

0 (m

ean)

2.14

±2.

271.

04 ±

0.63

Wag

ner g

rade

1/2

/3 (%

):D

ay 1

0/75

/25

0/82

/18

Day

10

13/8

7/0

7/93

/0

Ulce

r vol

ume

(µl):

Day

120

3 ±

203

358

±39

5D

ay 1

083

±14

023

3 ±

235

Prop

ortio

n of

pat

ient

s ach

ievin

gco

mpl

ete

heali

ng (d

ay 1

0):

I1: 0

/20

(0%

)I2

: 2/1

7 (1

1%)

Prop

ortio

n of

pat

ient

s with

unre

solve

d ce

llulit

is (d

ay 1

0):

I1: 2

7%I2

: 17%

(from

surv

ival c

urve

pro

vided

by

the

auth

or)

Mea

n re

duct

ion

afte

r RX

:

Abso

lute

: I1

: 120

µl

I2: 1

25 �

l

Num

bers

of

with

draw

als p

ertr

eatm

ent g

roup

:

I1: 2

(see

adv

erse

even

ts)

I2: 1

(ost

eom

yelit

is)

Stud

y sp

onso

rshi

p:Am

gen,

Aus

tria

(man

ufac

ture

rs o

fFi

lgras

tim)

The

auth

ors

desc

ribe

prim

ary

end-

poin

t as I

SSbu

t thi

s has

not

been

vali

date

d as

am

easu

re o

fin

fect

ion.

Hea

ling

data

wer

e als

oco

llect

ed a

nd th

isis

a cli

nica

llyim

port

ant

outc

ome

cont

inue

d

Appendix 4

162

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

oede

ma,

pus

form

atio

n an

dlym

phan

gitis)

, ISS

, ulce

rvo

lum

e, a

nd W

agne

r’sgr

ade

carr

ied

out d

aily

Pres

ence

of e

ryth

ema

(10

poin

ts fo

r pre

senc

e in

each

sect

ion,

loca

l, do

rsal,

low

er le

g)Ly

mph

angit

is (2

0 po

ints

)D

iffer

ence

incir

cum

fere

nce:

fore

foot

/ank

le/lo

wer

leg

Relat

ive (t

his i

s bias

ed b

y th

em

ismat

ch in

ulce

r vol

ume

at th

e st

art

of th

e tr

ial):

I1: 1

20/2

03 (5

9%)

I2: 1

25/3

58 (3

5%)

Adve

rse

even

ts: w

orse

ned

liver

func

tion,

skin

effl

ores

cenc

e (li

kely

tobe

attr

ibut

ed to

G-C

SF) i

n 2

(I1)

patie

nts

CRP

, C-r

eact

ive

prot

ein;

ESR

, ery

thro

cyte

sed

imen

tatio

n ra

te; I

SS, i

nfec

tion

sum

mar

y sc

ore.


163


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Lips

ky (2

004)

,109

USA

(stu

dy p

opul

atio

nta

ken

from

8co

untr

ies:

Belgi

um,

Ger

man

y, Ita

ly,Po

rtug

al, S

witz

erlan

d,Sp

ain, U

K, U

SA)

Stud

y de

sign:

RC

T (o

pen-

label

,m

ultic

entr

e –

45 si

tes)

Met

hod

ofra

ndom

isatio

n:

Not

stat

ed

Uni

t of a

lloca

tion:

Pa

tient

Out

com

e as

sess

men

t:C

linica

l cur

e ra

tear

ising

from

the

adm

inist

ratio

n of

Line

zolid

(I1)

vs A

/Cor

A/C

(I2)

. Out

com

ecla

ssifi

ed a

s (1)

cur

ed,

(2) i

mpr

oved

or (

3)fa

iled

Test

of c

ure

evalu

atio

nco

nduc

ted

15–2

1 da

ysaf

ter t

reat

men

t was

com

plet

ed

Setti

ng:

Inpa

tient

/out

patie

nt

Leng

th o

f tre

atm

ent:

Betw

een

7–28

day

s

Inclu

sion

crite

ria:

Con

sent

ing

men

and

wom

en a

ged

18ye

ars o

r ove

r;w

ith d

iabet

esm

ellit

us a

nd a

foot

infe

ctio

n. In

fect

ions

defin

ed b

y cli

nica

lsig

ns a

nd sy

mpt

oms

(dra

inag

e, e

ryth

ema,

fluct

uanc

e, w

arm

th,

pain

, ten

dern

ess,

indu

ratio

n) a

ndca

tego

rised

as o

neor

mor

e of

the

follo

win

g: c

ellu

litis,

paro

nych

ia, in

fect

edul

cer,

deep

soft

tissu

e in

fect

ion,

sept

ic ar

thrit

is,ab

sces

s,os

teom

yelit

is.Pa

tient

s cou

ldun

derg

o an

yne

cess

ary

debr

idem

ent o

rot

her s

urgic

alpr

oced

ures

as l

ong

as th

e en

tire

infe

cted

are

a w

asno

t res

ecte

d or

ampu

tate

d

Exclu

sion

crite

ria:

Crit

ical i

scha

emia

ofth

e af

fect

ed li

mb

(def

ined

as a

bsen

ceof

ped

al pu

lses,

abse

nt o

r abn

orm

alD

oppl

er w

avef

orm

s,

371

patie

nts e

nrol

led:

10

rece

ived

notr

eatm

ent

I1: n

= 2

41I2

: n=

120

Gen

der:

I1I2

Male

:17

1 (7

1%)

86 (7

2%)

Fem

ale:

70 (2

9%)

34 (2

8%)

Ethn

icity

: W

hite

206

(85%

)10

0 (8

3%)

Blac

k27

(11%

)16

(13%

)O

ther

8 (3

%)

4 (3

%)

Mea

n ±

SD63

±12

62 ±

13ag

e (y

ears

)

Type

II d

iabet

es (%

)61

52

Type

of i

nfec

tion:

Infe

cted

ulce

r19

0 (7

9%)

93 (7

8%)

Cel

lulit

is10

1 (4

2%)

60 (5

0%)

Dee

p so

ft tis

sue

37 (1

5%)

16 (1

3%)

tissu

ePa

rony

chia

12 (5

%)

11 (9

%)

Ost

eom

yelit

is57

(24%

)20

(17%

)O

ther

8 (3

%)

5 (4

%)

Foot

isch

aem

ia:n

= 9

8 (4

9%)

Wou

nd a

rea:

“mos

t wer

e ≤2

cm2

in a

rea”

Wou

nd d

epth

:“m

ost w

ere

≤9 m

m d

eep”

Wou

nd d

urat

ion:

“mos

t wer

e <

8 w

eeks

dur

atio

n”

No

data

by

grou

p to

allo

w c

ompa

rison

I1: n

= 2

41 p

atie

nts

rece

ived

linez

olid

(600

mg

ever

y 12

hour

sei

ther

i.v.

or o

rally

)

I2: n

= 1

20 p

atie

nts

rece

ived

A/S

(1.5

–3g

ever

y 6

hour

s i.v.

) or

A/C

(500

–875

mg

ever

y8–

12 h

ours

ora

lly)

Ther

apy

given

on

inpa

tient

or o

utpa

tient

basis

, ini

tiate

d by

eith

eri.v

. or o

ral r

oute

and

coul

d sw

itch

from

i.v.

toor

al at

the

inve

stiga

tor’s

disc

retio

n. T

reat

men

t for

at le

ast 7

but f

or n

om

ore

than

28

days

Vanc

omyc

in (1

g ev

ery

12ho

urs i

.v., a

djus

ted

for

rena

l dys

func

tion,

adva

nced

age

or o

besit

y)ad

ded

to th

eam

inop

enici

llin/�

-lac

tam

ase

inhi

bito

rre

gimen

if in

fect

ion

with

MRS

A su

spec

ted

orco

nfirm

ed.

Inve

stiga

tor c

ould

choo

se to

give

aztr

eona

m (1

–2g

i.v.

ever

y 8–

12ho

urs)

for

patie

nts s

uspe

cted

or

docu

men

ted

to h

ave

Gra

m-n

egat

ivepa

thog

ens r

esist

ant t

ost

udy

med

icatio

n

Stat

istica

l met

hods

: In

tent

ion-

to-tr

eat;

one-

way

AN

OVA

;W

ilcox

on ra

nk su

m te

st; �

2 ; Fi

sher

’s ex

act t

est;

CIs;

frequ

encie

s/per

cent

ages

Def

initi

ons o

f clin

ical r

espo

nse

totr

eatm

ent:

Cur

ed: r

esol

utio

n of

all

clini

cal s

igns

and

sym

ptom

s of i

nfec

tion

and

ahe

aling

wou

nd a

fter ≥

5da

ys o

fth

erap

y. Im

prov

ed: r

esol

utio

n of

at

leas

t tw

o, b

ut n

ot a

ll, c

linica

l sign

s or

sym

ptom

s of i

nfec

tion

afte

r ≥5

days

of th

erap

y (o

nly

used

at e

nd o

ftr

eatm

ent).

Fail

ed: p

ersis

tenc

e or

prog

ress

ion

of b

asel

ine

clini

cal s

igns

and

sym

ptom

s of i

nfec

tion

afte

r≥2

days

of t

hera

py. M

issin

g: p

atie

nts

rece

ived

<2

days

of t

hera

pyIn

dete

rmin

ate:

circ

umst

ance

spr

eclu

ded

class

ifica

tion

Clin

ically

eva

luab

le p

atie

nts (

met

entr

y cr

iteria

, too

k 80

% o

fpr

escr

ibed

med

icatio

n, h

ad a

dequ

ate

follo

w-u

p):

I1: 2

03/2

41 (8

4%)

I2: 1

03/1

20 (8

6%)

Ove

rall

clini

cal c

ure:

I1: 1

65/2

03 (8

1%)

I2: 7

7/10

8 (7

1%)

I1: 1

8I2

: 4D

iscon

tinua

tion

due

to a

dver

seev

ent

Stud

y sp

onso

rshi

p:Ph

aram

acia

Cor

pora

tion;

Dep

artm

ent o

fVe

tera

ns A

ffairs

.

They

des

crib

e th

eIT

T po

pulat

ion

asall

peo

ple

who

had

rece

ived

at le

ast

one

dose

of s

tudy

med

icatio

n. It

shou

ld in

clude

all

who

wer

era

ndom

ised,

rega

rdle

ss o

fw

heth

er th

eyre

ceive

d th

e st

udy

med

icatio

ns

Issue

s wor

thy

ofno

te re

gard

ing

bioa

vaila

bilit

y of

A/B

(i.v./

oral)

and

the

pote

ntial

for

early

out

patie

nttr

eatm

ent i

f apo

tent

, ora

l age

ntis

avail

able

, e.g

.flu

oroq

uino

lone

s/lin

ezol

id

cont

inue

d

Appendix 4

164

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

toe

bloo

d pr

essu

re<

45m

mH

g), u

nles

sap

prov

ed b

y a

vasc

ular

surg

eon.

Aw

ound

with

pros

thet

ic m

ater

ials

or d

evice

s; an

infe

ctio

n re

quiri

ngm

ore

than

28

days

of a

ntib

iotic

trea

tmen

t; a

wou

ndw

ith e

xten

sive

gang

rene

. Pat

ient

sals

o ex

clude

d if

they

had

rece

ived

>72

hour

s of

pote

ntial

ly ef

fect

ivean

tibio

tic th

erap

y in

wee

k pr

ior t

oen

rolm

ent;

need

edad

ditio

nal n

on-s

tudy

antib

iotic

; abs

olut

ene

utro

phil

coun

t<

500

cells

/mm

3 ;pr

egna

ncy

orlac

tatin

g; h

istor

y of

hype

rsen

sitivi

ty to

linez

olid

, pen

icillin

or v

anco

myc

in

Use

of t

opica

lan

timicr

obial

age

nts n

otpe

rmitt

ed

Patie

nts r

ecei

ved

twice

-da

ily d

ress

ing

chan

ges

(any

ster

ile n

on-a

dher

ent

type

sele

cted

by

the

inve

stiga

tor)

and

per

iodi

cde

brid

emen

t as r

equi

red.

Pres

sure

on

the

wou

ndav

oide

d by

a m

etho

dse

lect

ed b

y th

ein

vest

igato

r

Resu

lts fo

r inf

ecte

d ul

cers

:(c

linica

l cur

e)I1

: 131

/190

(69%

)I2

: 57/

93 (6

1%)

Mea

n du

ratio

n of

ther

apy

(day

s ±SD

)I1

: 17.

2 ±

7.9

I2: 1

6.5

±7.

9

Clin

ical c

ure

rate

s for

mos

t fre

quen

tlyiso

lated

bas

elin

e pa

thog

ens (

base

d on

am

odifi

ed in

tent

ion-

to-tr

eat p

opul

atio

n, i.

e.th

ose

patie

nts w

ith a

Gra

m-p

ositi

veba

selin

e pa

thog

en):

I1 (%

)I2

(%)

Stap

hylo

cocc

us a

ureu

s:M

ethi

cillin

sens

itive

50/6

7 (7

5)28

/39

(72)

Met

hicil

lin re

sista

nt13

/18

(72)

4/7

(57)

Coa

gulas

e-ne

gativ

eSt

aphy

loco

cci:

31/3

5 (8

9)17

/19

(90)

Stre

ptoc

occu

sag

alac

tiae

26/3

1 (8

4)9/

18 (5

0)En

tero

cocc

ussp

p.23

/34

(68)

13/1

7 (7

6)Ps

eudo

mon

assp

p.13

/16

(81)

7/11

(64)

Ente

roba

cter

iacea

52/6

5 (8

0)16

/23

(70)

Adve

rse

even

ts n

(%):

I1I2

Any

even

ta64

(26.

6)12

(10)

Diar

rhoe

a18

(7.5

)4

(3.3

)N

ause

a14

(5.8

)0

(0)

Anae

mia

11 (4

.6)

0 (0

)Th

rom

bocy

tope

nia

9 (3

.7)

0 (0

)Vo

miti

ng4

(1.7

)1

(0.8

)D

ecre

ased

app

etite

3 (1

.2)

0 (0

)D

yspe

psia

3 (1

.2)

1 (0

.8)

a (Sta

tistic

ally

signi

fican

t mor

e ev

ents

with

I1).

cont

inue

d


165


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Disc

ontin

uatio

n du

e to

adv

erse

eve

nt:

I1: 1

8I2

: 4

Use

of v

anco

myc

in:

I1: 1

I2

: 5

Use

of a

ztre

onam

:I1

: 12

I2: 3

Appendix 4

166

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Lips

ky (u

npub

lishe

d)B,

114

USA

Stud

y 30

4Fu

ll pa

pers

not

ava

ilabl

e.D

ata

extr

acte

d fro

mab

stra

ct p

rese

nted

at

37th

ICAA

C

(Sep

t. 28

–Oct

. 1 1

997)

and

CD

-Rom

slid

espr

esen

ted

at th

e FD

AAd

visor

y C

omm

ittee

(Mar

ch 1

999)

Stud

y de

sign:

RC

T(d

oubl

e-bl

ind)

I1: P

exiga

nan

I2: O

floxa

cin

Met

hod

ofra

ndom

isatio

n:

Not

stat

ed

Uni

t of a

lloca

tion:

Pa

tient

Calc

ulat

ion

of st

atist

ical

pow

er:

Not

stat

ed

Out

com

e as

sess

men

t:Pr

imar

y: (1

) clin

ical

outc

ome

(cur

ed: n

ofu

rthe

r sign

s or

sym

ptom

s of i

nfec

tion;

impr

oved

: sign

ifica

ntim

prov

emen

t but

inco

mpl

etel

y re

solve

d;fa

iled:

no

appa

rent

resp

onse

to th

erap

y);

(2) m

icrob

iolo

gical

outc

ome,

(3) t

hera

peut

icre

spon

se

Popu

latio

n:

39 c

entr

es, 3

42 (I

117

1; I2

171

) DFU

outp

atie

nts

Inclu

sion

crite

ria:

Clin

ical d

iagno

sisof

DFU

with

out

exte

nsive

cel

lulit

is,os

teom

yelit

is,ex

posu

re o

f bon

eor

tend

on o

r fev

er

Exclu

sion

crite

ria:

Ost

eom

yelit

is,ex

tens

ive c

ellu

litis,

gang

rene

, sys

tem

icto

xicit

y, in

patie

nttr

eatm

ent

Gen

der:

(M/F

)I1

: 118

/53

(69/

31%

)I2

: 109

/62

(64/

36%

)

Ethn

icity

:W

hite

I1: 1

42 (8

3%)

I2: 1

38 (8

1%)

Afric

an/A

mer

ican

I1:

20 (1

2%)

I2:

24 (1

4%)

Oth

erI1

: 9

(5%

)I2

: 9

(5%

)

Mea

n ±

SDag

e (y

ears

):I1

: 60.

8 (1

1.8)

I2: 5

9.5

(12.

4)

Trea

ted

with

ora

l ant

idiab

etic

med

icatio

n/in

sulin

dep

ende

nt:

I1:

Any

med

icatio

n:17

0 (9

9%)

Insu

lin:

118

(69%

)O

ral a

gent

s:56

(33%

)I2

:An

y m

edica

tion:

169

(99%

)In

sulin

:11

2 (6

5%)

Ora

l age

nts:

66 (3

9%)

Body

wei

ght m

ean

±SD

(lb)

:

I1: 2

07.1

(46.

0)I2

: 209

.2 (4

7.0)

Evid

ence

of n

euro

path

y an

d ty

pe:

Non

-palp

able

pul

ses i

n af

fect

ed fo

ot:

I1I2

Dor

sal p

edis:

22 (1

3%)

17 (1

0%)

Post

erial

tibi

al:

29 (1

7%)

22 (1

3%)

Dop

pler

pul

ses:

1 (<

1%)

2 (<

1%)

<40

mm

Hg

Neu

ropa

thy:

I1I2

Righ

t:13

7 (8

0%)1

42 (8

3%)

Left:

40 (8

2%)

138

(81%

)

I1: 1

71 p

atie

nts

rece

ived

twice

a d

ayap

plica

tion

of p

exiga

nan

crea

m (1

%) –

a b

road

-sp

ectr

um to

pica

lan

timicr

obial

age

nt

I2: 1

71 p

atie

nts

rece

ived

twice

dail

ydo

se o

f oflo

xacin

(400

mg

b.d.

)

Deb

ridem

ent a

nd o

ff-lo

adin

g of

ulce

rspe

rform

ed in

add

ition

to a

ntim

icrob

ialth

erap

y. St

anda

rddr

essin

gs u

sed

Stat

istica

l met

hods

:

For c

linica

l out

com

e:

Inte

ntio

n-to

-trea

t (IT

T): a

ll ra

ndom

ised

patie

nts;

per-

prot

ocol

2 (P

P2):

ITT

patie

nts w

ith n

one

ofth

e ni

ne p

roto

col v

iolat

ions

For m

icrob

iolo

gical

outc

ome

and

ther

apeu

ticre

spon

se:

Inte

ntio

n-to

-trea

t micr

obio

logic

al (IT

TM):

ITT

patie

nts w

ith a

t lea

st o

ne b

asel

ine

path

ogen

; per

-pr

otoc

ol m

icrob

iolo

gical

(PP2

M):

PP2

patie

nts

with

at l

east

one

bas

elin

e pa

thog

en

Deb

ridem

ent p

erfo

rmed

:I1

I2Ba

selin

e93

.694

.2D

ay 3

81.9

77.6

Day

10

79.7

75.6

EOT

65.8

63.0

Follo

w-u

p59

.854

.2

Clin

ical o

utco

meb

Ove

rall

clini

cal o

utco

me

at d

ay 1

0:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

T15

2/17

189

151/

171

88–6

.16

to 7

.33

PP2

96/1

0889

106/

120

88–7

.71

to 8

.82

Ove

rall

clini

cal o

utco

me

at e

nd o

f tre

atm

ent:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

T15

3/17

189

153/

171

89–6

.51

to 6

.51

PP

298

/108

9110

9/12

091

–7.6

2 to

7.4

4

Ove

rall

clini

cal o

utco

me

at fo

llow

-up:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

T13

4/16

3 82

137/

163

84–9

.97

to 6

.29

PP2

87/1

05 8

310

1/11

786

–13.

00 to

6.0

7

Num

bers

of

with

draw

als p

ertr

eatm

ent

grou

p:I1

: 16

I2: 1

5

Reas

ons f

orw

ithdr

awal:

Dat

a no

tav

ailab

le b

yst

udy

303/

304

Relat

edst

udie

s:Li

psky

(unp

ublis

hed

B) –

see

sepa

rate

dat

aex

trac

tion)

cont

inue

d


167


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Seco

ndar

y: (1

) wou

ndsc

ores

and

mea

sure

men

ts;

(2)b

asel

ine

path

ogen

erad

icatio

n

Setti

ng: O

utpa

tient

s

Leng

th o

f tre

atm

ent:

14–2

8 da

ysAs

sess

men

t: Ba

selin

eda

ys 3

, 10a , 1

4, 2

1, e

ndof

trea

tmen

t (EO

T)a

(14–

28 d

ays)

, fol

low

-up

(FU

)a(2

wee

ks a

fter e

ndof

trea

tmen

t visi

t)a

Prin

cipal

time

poin

ts o

fin

tere

st

Foot

ulce

r, os

teom

yelit

is an

dam

puta

tion/

foot

surg

ery

hist

ory:

I1I2

Foot

ulce

rs11

3 (6

6%)1

09 (6

4%)

Ost

eom

yelit

is34

(20%

)40

(23%

)Am

puta

tion/

78 (4

6%)

64 (3

7%)

foot

surg

ery

Ampu

tatio

n49

(29%

)49

(29%

)

Base

line

wou

nd a

rea

(med

ian, m

m2 )

(min

.–m

ax.): I1

I214

6.9

160.

8(6

.2–2

628.

0)(3

2.9–

1738

.0)

Base

line

wou

nd d

epth

(med

ian, m

m2 )

(min

.–m

ax.) I1

I23.

03.

0(0

–14)

(0–2

0)

b %

resp

onse

= %

cur

ed +

% im

prov

edD

iffer

ence

(Diff

) = p

exiga

nan

% –

oflo

xacin

%

Cur

ed a

t day

10

(%):

I1I2

ITT

2020

ITTM

1919

PP2

2219

PP2M

2120

Cur

ed a

t end

of t

reat

men

t (%

):IT

T49

47IT

TM49

46PP

253

51PP

2M52

51

Cur

ed a

t fol

low

-up

(%):

ITT

5153

ITTM

5151

PP2

5055

PP2M

4954

Micr

obio

logic

al ou

tcom

ec

Ove

rall

micr

obio

logic

al ou

tcom

e at

day

10:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

TM44

/138

3230

/140

210.

12 to

20.

79PP

2M31

/89

3520

/96

211.

18 to

26.

81

Ove

rall

micr

obio

logic

al ou

tcom

e at

end

of

trea

tmen

t:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

TM63

/138

4666

/140

47–1

3.22

to 1

0.24

PP2M

45/8

951

50/9

652

–15.

95 to

12.

90

Ove

rall

micr

obio

logic

al ou

tcom

e at

follo

w-u

p:

I1I2

95%

CI

n/N

%n/

N%

Diff

.TT

M63

/138

4666

/140

47–1

3.22

to 1

0.24

PP2M

45/8

951

50/9

652

–15.

95 to

12.

90

cont

inue

d

Appendix 4

168

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

c %

resp

onse

= %

reso

lved

+ %

impr

oved

Diff

.= p

exiga

nan%

– o

floxa

cin%

Micr

obio

logic

al ou

tcom

e ‘re

solve

d’ a

t end

of

trea

tmen

t:I1

I2IT

TM53

(38%

)59

(42%

)

Micr

obio

logic

al ou

tcom

e ‘re

solve

d’ a

t fol

low

-up:

I1I2

ITTM

50 (3

8%)

61 (4

6%)

Ther

apeu

tic re

spon

sed

Ther

apeu

tic re

spon

se a

t end

of t

reat

men

t:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

TM46

/138

3853

/140

38–1

5.77

to 6

.73

PP2M

32/8

936

36

/96

41–1

8.68

to 9

.34

Ther

apeu

tic re

spon

se a

t fol

low

-up:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

TM48

/130

3760

/134

45–1

9.68

to 3

.97

PP2M

32/8

637

44/9

447

–23.

97 to

4.7

7d

% re

spon

se =

% c

linica

lly c

ured

+m

icrob

iolo

gicall

y re

solve

dD

iffer

ence

= p

exiga

nan

% –

oflo

xacin

%Re

duct

ion

in w

ound

are

a (m

m2 ) f

rom

bas

elin

e by

EOT

(FU

) clin

ical r

espo

nse

(ITT)

:

EOT

FUI1

I2I1

I2C

ured

:M

edian

–72.

8–1

13.6

–91.

8–1

23.7

Mea

n–9

0.3

–183

.6–1

09.2

–184

.4M

edian

(%)

–67.

1–7

7.8

–78.

9–9

3.9

Mea

n (%

)–5

6.0

–65.

8–5

7.1

–76.

5

Impr

oved

:M

edian

–69.

4–6

9.2

–60.

7–6

0.5

Mea

n–1

20.6

–80.

9–9

8.6

–109

.6

cont

inue

d


169


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Med

ian (%

)–4

6.5

–45.

1–3

7.9

–38.

8M

ean

(%)

–38.

8–3

5.7

–14.

3–3

2.6

Faile

d:M

edian

22.1

–38.

3–0

.9–4

4.3

Mea

n39

.9–8

3.4

24.4

–90.

0M

edian

(%)

10.8

–20.

8–1

.3–4

9.4

Mea

n (%

)21

.0–1

8.3

19.9

–22.

7

Mos

t fre

quen

t bas

elin

e pa

thog

ens e

radi

cate

d at

follo

w-u

p (IT

TM):

I1I2

n/N

%n/

N%

Stap

hylo

cocc

us a

ureu

s29

/55

5342

/70

60En

tero

cocc

us fa

ecal

is25

/49

5132

/47

68St

rept

ococ

cus a

gala

ctia

e13

/25

5213

/23

57St

aphy

loco

ccus

epi

derm

is8/

1362

7/11

64Ps

eudo

mon

as a

erug

inos

a7/

1164

11/1

669

Ente

roco

ccus

spec

ies

4/9

441/

425

Stre

ptoc

occu

s can

is3/

933

5/10

50Es

cher

ichia

col

i7/

710

07/

888

Prev

otel

la b

ivia

7/7

100

4/4

100

Prot

eus m

irabl

is3/

743

6/10

60

Ampu

tatio

n (in

ciden

ce a

nd ty

pe, e

.g. m

ajor/m

inor

)I1

: 7I2

: 3

Num

ber/d

urat

ion

of h

ospi

tal a

dmiss

ions

for D

FUpr

oble

ms (

by E

OT

and

FU fa

ilure

s):

EOT

failu

res

FU fa

ilure

sI1

:3

4I2

:6

7

Adve

rse

even

ts le

adin

g to

pat

ient

with

draw

al:

I1I2

n%

n%

At le

ast o

ne a

dver

se e

vent

lead

ing

to w

ithdr

awal

169

159

cont

inue

d

Appendix 4

170

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Mos

t fre

quen

t adv

erse

eve

nt (c

ombi

ned

stud

ies

303/

304)

:D

iarrh

oea

Nau

sea

Pain

Serio

us a

dver

se e

vent

s:I1

: 22

(13%

)I2

: 19

(11%

)


171


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Lips

ky (

unpu

blish

ed)

A,11

4U

SA

Stud

y 30

3Fu

ll pa

pers

not

ava

ilabl

e.D

ata

extr

acte

d fro

mab

stra

ct p

rese

nted

at

37th

ICAA

C (S

ept.

28–O

ct. 1

, 199

7) a

ndC

D-R

om sl

ides

pres

ente

d at

the

FDA

Advis

ory

Com

mitt

ee(M

arch

199

9)

Stud

y de

sign:

RC

T(d

oubl

e-bl

ind)

I1: P

exiga

nan

I2: O

floxa

cin

Met

hod

ofra

ndom

isatio

n:

Not

stat

ed

Uni

t of a

lloca

tion:

Pa

tient

Calc

ulat

ion

of st

atist

ical

pow

er:

Not

stat

ed

Out

com

e as

sess

men

t:Pr

imar

y: (1

) clin

ical

outc

ome

(cur

ed: n

ofu

rthe

r sign

s or

sym

ptom

s of i

nfec

tion;

impr

oved

: sign

ifica

ntim

prov

emen

t but

inco

mpl

etel

y re

solve

d;fa

iled:

no

appa

rent

resp

onse

to th

erap

y);

(2) m

icrob

iolo

gical

outc

ome;

(3) t

hera

peut

icre

spon

se

Popu

latio

n:

42 c

ente

rs, 4

93(I1

247

; I2

246)

DFU

out

patie

nts

Inclu

sion

crite

ria:

Clin

ical d

iagno

sisof

diab

etic

foot

ulce

r with

out

exte

nsive

cellu

litis,

oste

omye

litis,

expo

sure

of b

one

or te

ndon

or

feve

r

Exclu

sion

crite

ria:

Ost

eom

yelit

is,ex

tens

ivece

llulit

is,ga

ngre

ne,

syst

emic

toxi

city,

inpa

tient

trea

tmen

t

Gen

der:

(M/F

)I1

: 185

/62

(75/

25%

)I2

: 180

/66

(73/

27%

)

Ethn

icity

:W

hite

I1: 1

84 (7

4%)

I2: 1

92 (7

8%)

Afric

an/A

mer

ican

I1:

22 (9

%)

I2:

20 (8

%)

Oth

erI1

: 41

(17%

)I2

: 34

(14%

)

Mea

n ±

SDag

e (y

ears

):I1

: 58.

3 (1

2.2)

I2: 5

8.7

(12.

1)

Trea

ted

with

ora

l ant

idiab

etic

med

icatio

n/in

sulin

dep

ende

nt:

I1:

Any

med

icatio

n:24

6 (1

00%

)In

sulin

:17

1 (6

9%)

Ora

l age

nts:

82 (3

3%)

I2:

Any

med

icatio

n:24

3 (9

9%)

Insu

lin:

151

(61%

)O

ral a

gent

s:97

(39%

)

Body

wei

ght m

ean

±SD

(lb):

I1: 2

07.8

(48.

5)I2

: 211

.3 (4

4.7)

Evid

ence

of n

euro

path

y, an

d ty

pe:

Non

-palp

able

pul

ses i

n af

fect

ed fo

ot:

I1I2

Dor

sal p

edis:

23 (9

%)

24 (1

0%)

Post

erial

tibi

al:31

(13%

)30

(12%

)D

oppl

er p

ulse

s:5

(2%

)3

(1%

)<

40m

mH

g

Neu

ropa

thy:

I1I2

Righ

t:21

4 (8

7%)

216

(88%

)Le

ft:21

9 (8

9%)

213

(87%

)

I1: 2

47 p

atie

nts

rece

ived

twice

a d

ayap

plica

tion

ofpe

xiga

nan

crea

m (1

%)

– a

broa

d-sp

ectr

umto

pica

l ant

imicr

obial

agen

t

I2: 2

46 p

atie

nts

rece

ived

twice

dail

ydo

se o

f oflo

xacin

(400

mg

b.d.

)

Deb

ridem

ent a

nd o

ff-lo

adin

g of

ulce

rspe

rform

ed in

add

ition

to a

ntim

icrob

ialth

erap

y. St

anda

rddr

essin

gs u

sed

Stat

istica

l met

hods

:

For c

linica

l out

com

e:

Inte

ntio

n-to

-trea

t (IT

T): a

ll ra

ndom

ised

patie

nts;

per p

roto

col 2

(PP2

) (ju

dged

to h

ave

com

plet

ed a

tle

ast 7

5% o

f dos

es):

ITT

patie

nts w

ith n

one

of th

eni

ne p

roto

col v

iolat

ions

For m

icrob

iolo

gical

outc

ome

and

ther

apeu

ticre

spon

se:

Inte

ntio

n-to

-trea

t micr

obio

logic

al (IT

TM):

ITT

patie

nts w

ith a

t lea

st o

ne b

asel

ine

path

ogen

; per

prot

ocol

micr

obio

logic

al (P

P2M

): PP

2 pa

tient

s with

at le

ast o

ne b

asel

ine

path

ogen

Deb

ridem

ent p

erfo

rmed

(ITT

):I1

I2Ba

selin

e96

.893

.1D

ay 3

82.5

79.7

Day

10

86.1

83.9

End

of tr

eatm

ent

71.7

63.9

Follo

w-u

p68

.463

.1

Clin

ical o

utco

meb

Ove

rall

clini

cal o

utco

me

at d

ay 1

0:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

T20

8/24

784

220/

246

89–1

1.18

to 0

.74

PP2

105/

125

8412

7/14

190

–14.

18 to

2.0

4

Ove

rall

clini

cal o

utco

me

at e

nd o

f tre

atm

ent:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

T21

0/24

785

224/

246

91–1

1.74

to –

0.33

PP2

106/

125

8512

9/14

191

–14.

50 to

1.1

2

Ove

rall

clini

cal o

utco

me

at fo

llow

-up:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

T18

6/24

377

201/

240

84–1

4.29

to –

0.12

PP

292

/123

7511

8/14

084

–19.

25 to

0.2

8

Num

bers

of

with

draw

als p

ertr

eatm

ent

grou

p:

I1: 2

8I2

: 23

Reas

ons f

orw

ithdr

awal:

Dat

a no

tav

ailab

le b

yst

udy

303/

304

Ove

rall:

I1

I2C

ellu

litis

157

Infe

ctio

n4

4O

steo

M4

31+

AE

4438

Relat

edst

udie

s:Li

psky

et a

l.(u

npub

lishe

d)A

see

sepa

rate

dat

aex

trac

tion)

cont

inue

d

Appendix 4

172

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Seco

ndar

y: (1

) wou

ndsc

ores

and

mea

sure

men

ts,

(2) b

asel

ine

path

ogen

erad

icatio

n

Setti

ng: O

utpa

tient

s

Leng

th o

f tre

atm

ent:

14–2

8 da

ysAs

sess

men

t: Ba

selin

e,da

ys 3

, 10a , 1

4, 2

1, e

ndof

trea

tmen

t (EO

T)a

(14–

28 d

ays)

, Fol

low

-up

(FU

)a(2

wee

ks a

fter e

ndof

trea

tmen

t visi

t)a

Prin

cipal

time

poin

ts o

fin

tere

st

Foot

ulce

r, os

teom

yelit

is an

dam

puta

tion/

foot

surg

ery

hist

ory:

I1I2

Foot

ulce

rs16

4 (6

6%)

145

(59%

)O

steo

mye

litis

80 (3

2%)

59 (2

4%)

Ampu

tatio

n/12

1 (4

9%)

85 (3

5%)

foot

surg

ery

Ampu

tatio

n94

(38%

)64

(26%

)

Base

line

wou

nd a

rea

(med

ian m

m2 ):

(min

–max

.)I1

I213

1.5

117.

3(0

–223

7.0)

(6.2

–199

1.0)

Base

line

wou

nd d

epth

(med

ian m

m)

(min

.–m

ax.)

I1I2

3.0

(0.1

–13)

3.0

(0–1

4)

b %

resp

onse

= %

cur

ed +

% im

prov

edD

iffer

ence

= p

exiga

nan

% –

oflo

xacin

%

Cur

ed a

t day

10

(%):

I1I2

ITT

2628

ITTM

2226

PP2

2428

PP2M

2224

Cur

ed a

t end

of t

reat

men

t (%

):IT

T54

61IT

TM52

56PP

253

62PP

2M55

55

Cur

ed a

t fol

low

-up

(%):

ITT

5665

ITTM

5560

PP2

5663

PP2M

5559

Micr

obio

logic

al ou

tcom

ec

Ove

rall

micr

obio

logic

al ou

tcom

e at

day

10:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

TM73

/189

3966

/198

33–4

.27

to 1

4.85

PP2M

40/9

542

45/1

2137

–8.2

4 to

18.

07

Ove

rall

micr

obio

logic

al ou

tcom

e at

end

of

trea

tmen

t:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

TM91

/189

4894

/198

47–9

.29

to 1

0.63

PP2M

50/9

553

58/1

2148

–8.7

3 to

18.

13

Ove

rall

micr

obio

logic

al ou

tcom

e at

follo

w-u

p:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

TM78

/185

4290

/194

46–1

4.23

to 5

.77

PP2M

42/9

345

55/1

2145

–13.

76 to

13.

17

cont

inue

d


173


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

c %

resp

onse

= %

reso

lved

+ %

impr

oved

Diff

. = p

exiga

nan

% –

oflo

xacin

%

Micr

obio

logic

al ou

tcom

e ‘re

solve

d’ a

t end

of

trea

tmen

t:I1

I2IT

TM74

(39%

)82

(41%

)

Micr

obio

logic

al ‘re

solve

d’ a

t fol

low

-up:

ITTM

75 (4

1%)

84 (4

3%)

Ther

apeu

tic re

spon

sed

Ther

apeu

tic re

spon

se a

t end

of t

reat

men

t:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

TM67

/189

3575

/198

38–1

2.03

to 7

.18

PP2M

38/9

540

48/1

2140

–12.

83 to

13.

49

Ther

apeu

tic re

spon

se a

t fol

low

-up:

I1I2

95%

CI

n/N

%n/

N%

Diff

.IT

TM73

/185

3982

/193

42–1

2.94

to 6

.89

PP2M

38/9

341

50/1

2042

–14.

14 to

12.

53

d %

resp

onse

= %

clin

ically

cur

ed +

micr

obio

logic

ally

reso

lved

Diff

. = p

exiga

nan

% –

oflo

xacin

%

Redu

ctio

n in

wou

nd a

rea

(mm

2 ) fro

m b

asel

ine

byEO

T (F

U) c

linica

l res

pons

e (IT

T):

EOT

FUI1

I2I1

I2C

ured

:M

edian

–67.

7–6

4.6

–74.

9–6

9.2

Mea

n–1

23.2

–99.

6–1

20.0

–114

.4M

edian

(%)

–75.

2–7

6.5

–84.

6–8

7.1

Mea

n (%

)–6

2.8

–63.

2–6

2.0

–68.

9

Impr

oved

:M

edian

–54.

3–4

7.9

–51.

8–5

0.9

Mea

n–7

0.2

–81.

3–8

6.2

–87.

9M

edian

(%)

–35.

7–3

7.8

–26.

1–3

5.2

Mea

n(%

)–2

9.6

–25.

2–3

0.9

–28.

4co

ntin

ued

Appendix 4

174

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Faile

d:M

edian

2.6

–30.

1–4

3.1

–59.

7M

ean

36.4

–117

.8–3

3.8

–168

.3M

edian

(%)

0.9

–24.

1–2

9.7

–27.

2M

ean(

%)

21.3

–19.

0–1

3.4

–30.

2

Mos

t fre

quen

t bas

elin

e pa

thog

ens e

radi

cate

d at

follo

w-u

p (IT

TM):

I1I2

n/N

%n/

N%

Stap

hylo

cocc

us a

ureu

s43

/87

4955

/91

60En

tero

cocc

us fa

ecal

is33

/56

5935

/58

60St

rept

ococ

cus a

gala

ctia

e18

/34

5326

/43

60En

tero

cocc

us sp

ecie

s12

/17

716/

875

Prot

eus m

irabl

is9/

1369

9/11

82St

rept

ococ

cuss

pecie

s11

/13

856/

967

Eche

richi

a co

li8/

1267

7/8

88Ps

eudo

mon

as a

erug

inos

a4/

1136

10/2

050

Stap

hylo

cocc

us e

pide

rmid

is7/

1164

9/12

75

Ampu

tatio

n:

I1: 4

I2: 6

Num

ber/d

urat

ion

of h

ospi

tal a

dmiss

ions

for D

FUpr

oble

ms (

by E

OT

and

FU fa

ilure

s):

EOT

failu

res

FU fa

ilure

sI1

:11

14I2

:4

9

Adve

rse

even

ts le

adin

g to

pat

ient

with

draw

al:

I1I2

n%

n%

At le

ast o

ne a

dver

se e

vent

lead

ing

to w

ithdr

awal

2811

239

Mos

t fre

quen

t adv

erse

eve

nt (c

ombi

ned

stud

ies

303/

304)

:I1

I2D

iarrh

oea

42

Nau

sea

22

Pain

21

cont

inue

d


175


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Prob

ably

relat

ed a

dver

se e

vent

s:41

841

7

Serio

us a

dver

se e

vent

s: (n=

28)

(n=

20)

11%

8%

Appendix 4

176

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Lips

ky (1

990)

,75U

SA

Stud

y de

sign:

RC

T

Met

hod

ofra

ndom

isatio

n:N

ot sp

ecifi

ed

Uni

t of a

lloca

tion:

Pa

tient

Calc

ulat

ion

of st

atist

ical

pow

er:

See

Com

men

ts se

ctio

n

Out

com

e as

sess

men

t(b

linde

d):

Wou

nd h

ealin

g/siz

e of

ulce

r (cli

nica

lcla

ssifi

catio

n); p

atho

gen

prof

ile (m

icrob

iolo

gical

class

ifica

tion)

Setti

ng a

nd le

ngth

of

trea

tmen

t: O

utpa

tient

clini

c/2

wee

ks

(+ 3

mon

ths f

ollo

w-u

p)

Recr

uitm

ent:

Oct

ober

1985

–Mar

ch 1

988

Writ

ten

info

rmed

cons

ent:

Loca

l Com

mitt

ee e

thica

lap

prov

al

Popu

latio

n:

Diab

etic

outp

atie

nts –

Seat

tle (W

A)Ve

tera

ns A

ffairs

Med

ical C

ente

r

Inclu

sion

crite

ria:

Patie

nts w

ithcli

nica

lly in

fect

edle

sion

(low

erex

trem

ity).

No

antim

icrob

ialth

erap

y pr

eced

ing

2w

eeks

(les

ions

wer

e ±

brea

k in

skin

)

Exclu

sion

crite

ria:

Pres

ence

of

syst

emic

toxi

city

(e.g

. high

feve

r,hy

pote

nsio

n),

pres

ence

of

imm

ediat

e lif

e or

limb

thre

at,

inab

ility

tope

rform

dail

yw

ound

car

e,hi

stor

y of

pat

ient

non-

com

plian

cew

ith o

utpa

tient

trea

tmen

t,un

willi

ngne

ss to

retu

rn fo

rou

tpat

ient

visi

ts,

aller

gy to

stud

ydr

ugs

Def

initi

on o

fin

fect

ion:

rece

ntde

velo

pmen

t of

All m

ale (n

= 6

0)I1

: n=

27

I2: n

= 2

9

Mea

n ±

SEM

age

(yea

rs):

I1: 5

9.4

±2.

3I2

: 62.

7 ±

2.4

Non

-insu

lin-d

epen

dent

diab

etes

:I1

: 23

(85%

)I2

: 28

(97%

)

Insu

lin-tr

eate

d:I1

: 19

(70%

)I2

: 18

(62%

)

Lesio

n ul

cera

ted:

I1: 2

4 (8

9%)

I2: 2

7 (9

3%)

Infe

ctio

n pr

esen

t <1

mon

th:

I1: 2

6 (9

6%)

I2: 2

8 (9

7%)

Lesio

n fo

ul sm

ellin

g:I1

: 2 (7

%)

I2: 2

(7%

)

Anae

robe

s iso

lated

:I1

: 4 (1

5%)

I2: 3

(10%

)

Aero

bic

Gra

m-n

egat

ive b

acilli

isol

ated

:I1

: 7 (2

6%)

I2: 5

(17%

)

No

use

of a

ntim

icrob

ial a

gent

s in

prec

edin

g 2

wee

ks

Auth

ors r

epor

t no

stat

istica

llysig

nific

ant d

iffer

ence

s bet

wee

n gr

oups

on d

emog

raph

ic, c

linica

l or

micr

obio

logic

al ch

arac

teris

tics

60 p

atie

nts r

ando

mise

d, b

ut d

ata

on

I1: n

= 2

7 re

ceive

d or

alcli

ndam

ycin

hyd

roch

lorid

e(C

leoc

in) 3

00m

g,

4×da

ily fo

r 2w

eeks

I2: n

= 2

9 re

ceive

d or

alce

phale

xin

(Kef

lex)

50

0 m

g, 4

×da

ily fo

r2

wee

ks

Patie

nts w

ere

seen

inou

tpat

ient

clin

ic ev

ery

3–7

days

, dep

endi

ng o

nse

verit

y of

infe

ctio

n

Wou

nd c

are:

Al

l les

ions

cle

anse

d,dr

esse

d an

d de

brid

emen

tad

min

ister

ed (w

here

nece

ssar

y) a

t ini

tial

evalu

atio

n. P

atie

nts

advis

ed to

per

form

twice

-da

ily c

lean

sing

and

dres

sing

regim

en, a

void

unne

cess

ary

ambu

latio

n,se

lf-ev

aluat

ion/

call

rese

arch

nur

se if

nece

ssar

y

Thos

e w

hose

infe

ctio

nsfa

iled

to im

prov

e, o

rw

orse

ned,

wer

ew

ithdr

awn

from

the

stud

yan

d ho

spita

lised

. Tho

sew

hose

cul

ture

s yie

lded

one

or m

ore

isolat

esre

sista

nt to

the

stud

yan

tibio

tic w

ere

asse

ssed

.Th

erap

y co

ntin

ued

ifin

fect

ion

impr

ovin

g,ot

herw

ise o

ther

appr

opria

te tr

eatm

ent

Infe

ctio

n re

spon

se: (

n=

56) I1

I2C

ured

21 (7

8%)

21 (7

2%)

Impr

oved

5 (1

9%)

4 (1

4%)

Faile

d1

(4%

)4

(14%

)

Bact

erio

logic

al re

spon

se: (

n=

52)

I1 (n

= 2

6)I2

(n=

26)

Cur

ed20

(77%

)20

(77%

)Im

prov

ed4

(15%

)2

(8%

)Fa

iled

2 (8

%)

2 (8

%)

Supe

rinfe

ctio

n3

(12%

)1

(4%

)

Wou

nd h

ealin

g: (n

= 5

2) I1 (n

= 2

5)I2

(n=

27)

Hea

led

10 (4

0%)

9 (3

3%)

Prog

ress

14 (5

6%)

18 (6

7%)

Uni

mpr

oved

1 (4

%)

0 (0

%)

Recu

rren

ce a

t fol

low

-up

(15

±9

mon

ths)

:8/

51 (1

6%) o

f pat

ient

s with

cur

ed o

rim

prov

ed in

fect

ion

at 2

wee

ks re

quire

dth

erap

y fo

r sub

sequ

ent i

nfec

tion

at sa

me

site

4 pa

tient

s req

uire

d tr

eatm

ent (

>2

wee

ks) (

I2)

Acqu

isitio

n of

resis

tant

org

anism

s: no

ted

in1

patie

nt (I

1) a

nd 4

pat

ient

s (I2

)

Adve

rse

even

ts:

I1:1

pat

ient

with

mild

diar

rhoe

a –

reso

lved

I2:2

pat

ient

s with

mild

nau

sea

and

diar

rhoe

a –

reso

lved

Num

bers

of

with

draw

als: 2

Reas

ons f

orw

ithdr

awal:

hosp

italis

atio

n(1

was

due

tore

ason

sun

relat

ed to

the

infe

ctio

n)

Que

ry th

ese

as‘w

ithdr

awals

’ –th

ere

was

no

crite

ria fo

rde

finin

g a

with

draw

al

Lim

itatio

ns o

fth

e st

udy

(as

note

d by

auth

ors)

:D

iffer

ence

inov

erall

infe

ctio

nre

spon

se ra

tebe

twee

n I1

and

I2 w

asno

tst

atist

ically

signi

fican

t due

to lo

w p

ower

All m

ale

Stud

ysp

onso

rshi

p:Au

thor

sac

know

ledg

e‘g

rant

-in-a

id’

from

Upj

ohn,

Kalam

azoo

,M

I, U

SA

Def

initi

on o

fou

tcom

es:

Cur

ed =

all

signs

and

sym

ptom

s of

infe

ctio

n ha

dre

solve

d

Impr

oved

=m

ost s

igns

and

sym

ptom

sha

d re

solve

d

Faile

d =

no

subs

tant

ial

cont

inue

d


177


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

puru

lenc

e or

atle

ast 2

of t

hefo

llow

ing:

eryt

hem

a,w

arm

th,

tend

erne

ss,

indu

ratio

n,flu

ctua

nce,

drain

age

56 re

port

ed a

s 4 w

ere

exclu

ded

as:

dete

ctio

n of

ost

eom

yelit

is af

ter

rand

omisa

tion

(n=

2);

patie

ntin

siste

nce

on b

eing

hos

pita

lised

(n

= 1

); pa

tient

failu

re to

take

A/B

(n

= 1

)

adm

inist

ered

. Afte

r2

wee

ks o

f the

rapy

, tho

sesh

owin

g im

prov

emen

t but

pers

istin

g cli

nica

l sign

s of

infe

ctio

n w

ere

inst

ruct

edto

con

tinue

pre

scrib

edre

gimen

. On

each

retu

rnvis

it, m

edica

tion

com

plian

ce re

view

ed a

ndad

vers

e dr

ug e

ffect

sas

sess

ed

Loca

l car

e of

ulce

rsin

clude

d co

vera

ge w

ithfin

e m

esh,

non

-adh

eren

tdr

essin

g an

d dr

y ga

uze

onto

p of

that

. Cle

ansin

g of

ulce

r (by

pat

ient

) was

with

hyd

roge

n pe

roxi

de(tw

ice/d

aily)

impr

ovem

ent

in in

fect

ion

AND

ach

ange

in A

/Btr

eatm

ent O

Rsu

rgica

lin

terv

entio

nbe

lieve

dne

cess

ary

Appendix 4

178

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Mar

chin

a (1

997)

,123

Italy

Stud

y de

sign:

RCT

(sin

gle-b

lind)

Met

hod

ofra

ndom

isatio

n:N

ot st

ated

Uni

t of a

lloca

tion:

Patie

nts

Calc

ulat

ion

of st

atist

ical

pow

er:

No

a pr

iori

pow

erca

lculat

ion

repo

rted

Out

com

e as

sess

men

t:H

ealin

g pr

ogre

ssas

sess

ed a

t 5, 1

0 an

d15

days

. Wou

nds w

ere

grad

ed a

s one

of t

hefo

llow

ing:

3: c

ompl

ete

heali

ng2:

>50

% w

ound

are

ahe

aled,

relat

ive to

base

line

1: 2

5–50

% h

eale

dU

nsat

isfac

tory

<25

%he

aled

No

info

rmat

ion

given

abou

t met

hods

of

mea

sure

men

t or h

owm

any

asse

ssor

s inv

olve

d

Trea

tmen

t dur

atio

n:

15-d

ay tr

ial. S

ettin

g no

tst

ated

Inclu

sion

crite

ria:

Patie

nts a

ged

65ye

ars a

nd o

ver,

with

DFU

s, ve

nous

leg

ulce

rs a

ndpr

essu

re so

res.

Wou

nds h

ad to

be

class

ified

as 1

st o

r2n

d de

gree

(not

defin

ed)

Exclu

sion

crite

ria:

Sens

itivit

y to

test

med

icatio

n,re

ceivi

ng o

ther

trea

tmen

t

Gen

der (

M/F

):I 6

/14

C 8

/12

Mea

n ±

SD(r

ange

) age

(yea

rs):

I 76.

7 ±

5.2

(66–

86)

C 7

9.1

±6.

4 (6

7–89

)

Wou

nd ty

pe:

Pres

sure

ulce

r/diab

etic

foot

I 9/1

1C

10/

10

Wou

nd c

ondi

tion:

Goo

d/m

oder

ate/

poor

Pres

sure

ulce

rsI 0

/3/6

C 0

/3/7

DFU

sI 4

/6/1

C 3

/7/0

No

info

rmat

ion

given

on

base

line

wou

nd a

rea

38 p

atie

nts p

rese

nted

oth

er c

o-m

orbi

ditie

s (e.

g. d

iabet

es m

ellit

us,

hype

rten

sion)

and

con

tinue

d w

ithus

ual m

edica

tion

durin

g th

e st

udy

perio

d

I: W

ound

s wer

e cle

aned

with

norm

al sa

line

and

drie

d w

ithga

uze.

An

antis

eptic

spra

y (2

%eo

sin a

nd 0

.3%

chl

orox

yleno

lin

hyd

rogly

colic

solu

tion)

was

appl

ied

to th

e w

ound

surfa

ceus

ing

gauz

e. W

ound

was

then

cove

red

with

gau

ze. T

hedr

essin

g w

as c

hang

ed2–

3tim

es p

er d

ay. T

here

wer

eno

det

ails o

f the

use

of o

ther

inte

rven

tions

(e.g

. pre

ssur

ere

lief)

Patie

nts w

ho w

ere

bein

gtr

eate

d w

ith a

n an

tisep

tic p

rior

to th

e st

udy

had

a 1

day

‘was

h-ou

t’ pe

riod,

dur

ing

whi

ch th

ew

ound

was

cle

aned

2–3

tim

esw

ith n

orm

al sa

line.

Dur

ing

the

stud

y pe

riod,

trea

tmen

t with

othe

r ant

isept

ics, h

ealin

gm

edica

tions

, ant

ibio

tics,

analg

esics

, abs

orbi

ng a

gent

san

d an

ti-in

flam

mat

ory

agen

tsw

as d

iscon

tinue

d.(n

= 2

0)

C: A

s abo

ve, e

xcep

t tha

t an

alter

nativ

e sp

ray

was

use

d (n

otde

scrib

ed).

(n=

20)

At 1

5da

ys

Hea

ling

(3/2

/1/u

nsat

isfac

tory

)Al

l wou

nds

I 58%

/12%

/30%

/0C

30%

/40%

/18%

/12%

Figu

res t

aken

from

gra

ph

Hea

ling

(3/2

/1/u

nsat

isfac

tory

)Fo

r DFU

s onl

yI 8

2%/1

8%/0

/0C

50%

/50%

/0/0

Figu

res t

aken

from

gra

ph

Hea

ling

(3/2

/1/u

nsat

isfac

tory

)Fo

r pre

ssur

e ul

cers

onl

yI 2

0%/1

0%/7

0%/0

C 1

0%/3

0%/3

0%/3

0%Fi

gure

s tak

en fr

om g

raph

Adve

rse

effe

cts (

loca

l bur

ning

sens

atio

n)I 3

pat

ient

sC

1 p

atie

nt

No

with

draw

alsTh

is is

a sm

allst

udy.

Larg

ernu

mbe

rs m

ay b

ere

quire

d to

det

ect

the

true

trea

tmen

tef

fect

The

base

line

and

end-

poin

tas

sess

men

ts o

fw

ound

con

ditio

nap

pear

to b

e ba

sed

on a

subj

ectiv

eas

sess

men

t. Th

ere

are

no d

etail

s of

inde

pend

ent

asse

ssm

ents

by

mor

e th

an o

neex

amin

er, a

ndbl

indi

ng p

roce

dure

sar

e als

o un

clear

.Th

e re

liabi

lity

ofth

e re

sults

may

ther

efor

e be

ques

tiona

ble

C, c

ontr

ol g

roup

; I, i

nter

vent

ion

grou

p.


179


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Mar

kevic

h (2

000)

,105

Ukr

aine

RCT

Met

hod

of ra

ndom

isatio

nN

ot st

ated

Uni

t of a

lloca

tion:

Patie

nt

No

pres

enta

tion

ofpo

wer

calc

ulat

ion

Out

com

e as

sess

men

t:N

umbe

r of u

lcers

heale

d, p

ropo

rtio

n of

ulce

rs w

ith a

t lea

st 5

0%gr

anul

atio

n tis

sue,

prop

ortio

n of

pat

ient

sw

ith a

t lea

st 5

0%re

duct

ion

in w

ound

are

a,w

ound

dep

th a

ndvo

lum

e, e

valu

atio

n of

surr

ound

ing

skin

, tiss

uequ

ality

(nec

rotic

, slo

ugh,

fibro

tic o

r gra

nulat

ion)

,ex

udat

e, o

dour

and

gluco

se le

vels

Setti

ng:

Inpa

tient

s in

Lviv

Med

ical

Uni

vers

ity H

ospi

tal

Popu

latio

n:

140

peop

le w

ithne

urop

athi

c fo

otw

ound

s req

uirin

gde

brid

emen

t

Inclu

sion

crite

ria:

Non

e st

ated

insh

ort a

bstr

act b

utan

othe

r con

fere

nce

repo

rt st

ates

diab

etes

mel

litus

,ne

urop

athy

, gra

de 2

or 3

ulce

rs w

ithslo

ugh,

palp

able

foot

pulse

s

Exclu

sion

crite

ria:

Non

e st

ated

insh

ort a

bstr

act b

utan

othe

r con

fere

nce

repo

rt st

ates

perip

hera

l vas

cular

dise

ase,

isch

aem

iche

art d

iseas

e, re

nal

failu

re, h

epat

icdi

seas

e, rh

eum

atoi

dar

thrit

is, im

mun

o-co

mpr

omise

d an

dco

ncur

rent

ster

oid

ther

apy

Mea

n ag

e: 5

3.6

year

s (±

15.4

year

s)(u

ncle

ar w

hat f

igure

±re

pres

ents

)

Mea

n du

ratio

n of

diab

etes

: 15.

8±

10.7

year

s (un

clear

if ±

is SD

/SE

or ra

nge)

Mea

n ±

SDul

cer a

rea:

I1: L

arva

l the

rapy

gro

up –

14.

9cm

2

I2: H

ydro

gel g

roup

– 1

5.14

cm2

Auth

ors s

tate

: “w

ound

surfa

ce a

rea,

dept

h an

d vo

lum

e, e

valu

atio

n of

surr

ound

ing

skin

, tiss

ue q

ualit

y(n

ecro

tic, s

loug

h, fi

brot

ic or

gran

ulat

ion)

and

hea

ling

rate

s,ex

udat

e, o

dour

and

glu

cose

leve

lsw

ere

com

para

ble

at b

asel

ine”

but

no d

ata

prov

ided

oth

er th

an o

nw

ound

are

a

No

data

on

gend

er, e

thni

city

or ty

peof

diab

etes

for a

ll 14

0 pa

rtici

pant

s,bu

t dat

a av

ailab

le fo

r 22

patie

nts

repo

rted

at a

con

fere

nce:

Male

/fem

ale: 4

5%/5

5%Ty

pe I/

II di

abet

es: 2

7%/7

3%U

lcer g

rade

2/3

: 86%

/14%

I1: L

arva

l the

rapy

(ste

rile

larva

eof

the

gree

n bo

ttle

fly, L

ucilia

serri

cata

) 6–1

0 lar

vae

per

1cm

2w

ound

are

a, re

mov

edaf

ter 7

2 ho

urs.

Dre

ssin

gs ly

ing

abov

e lar

vae

wer

e ch

ange

d as

requ

ired.

Up

to th

ree

appl

icatio

ns o

f lar

vae

wer

eus

ed. n

= 7

0

I2: H

ydro

gel d

ress

ing

(unn

amed

). D

ress

ing

rem

oved

at le

ast e

very

thre

e da

ys.

n=

70

No

info

rmat

ion

on c

oncu

rren

ttr

eatm

ents

(suc

h as

bed

rest

).Al

l par

ticip

ants

wer

e ho

spita

lin

patie

nts

Stat

istica

l met

hods

: 3-

way

AN

OVA

, ind

epen

dent

t-

test

, �2

test

Prop

ortio

n of

pat

ient

s ach

ievin

gco

mpl

ete

heali

ng in

10

days

: I1

: 5/7

0 (7

.1%

)I2

: 2/7

0 (2

.9%

)

Prop

ortio

n of

pat

ient

s with

at

leas

t 50%

gra

nulat

ion

tissu

e in

wou

nd:

I1: 6

0% (?

42/7

0)I2

: 34.

3% (?

24/7

0)p

< 0

.001

Prop

ortio

n of

pat

ient

s with

at

leas

t 50%

redu

ctio

n in

are

a of

wou

nd:

I1. 5

1.1%

(?36

/70)

I2. 2

7.1%

(?19

/70)

p<

0.0

5

Num

bers

of

with

draw

als p

ertr

eatm

ent

grou

p: n

otst

ated

Abst

ract

ava

ilabl

e on

full

stud

y (n

= 1

40),

but p

rese

ntat

ion

ofre

sults

from

52

patie

nts (

? an

inte

riman

alysis

) obt

ained

from

con

fere

nce

proc

eedi

ngs

No

info

rmat

ion

onfu

ndin

g/sp

onso

rshi

p

10-d

ay fo

llow

-up

isto

o sh

ort t

o ca

ptur

eul

cer h

ealin

g

The

repo

rt d

oes n

otre

port

the

prop

ortio

n of

peo

ple

who

se u

lcer b

ecam

eco

mpl

etel

y de

brid

edin

the

10-d

ay p

erio

din

the

two

grou

ps,

the

num

ber o

f lar

val

ther

apy

trea

tmen

tsre

quire

d or

the

med

ian ti

me

toco

mpl

ete

debr

idem

ent

The

ulce

rs in

this

stud

y ar

e lar

ge (a

rea

of 1

5cm

2 ) in

com

paris

on w

ithot

her D

FU st

udie

san

d th

is m

ay a

ffect

its g

ener

alisa

bilit

y

Appendix 4

180

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Pete

rson

(198

9),10

1U

SA

Stud

y de

sign:

RC

T

Met

hod

ofra

ndom

isatio

n: P

harm

acy

Serv

ice ra

ndom

lyas

signe

d pa

tient

scip

roflo

xacin

at a

dos

e of

eith

er 7

50 o

r 100

0m

gor

ally

twice

dail

y. Al

lot

hers

wer

e bl

inde

d to

the

rand

omisa

tion

by th

eus

e of

plac

ebo

to m

ake

the

num

ber o

f dail

ydo

ses i

dent

ical i

n bo

thgr

oups

Uni

t of a

lloca

tion:

Pa

tient

Out

com

e as

sess

men

t:Re

spon

se to

two

diffe

rent

dos

es o

fcip

roflo

xacin

(I1,

750

mg

twice

dail

y; I2

, 100

0m

gtw

ice d

aily)

: ful

lysu

cces

sful o

utco

me

defin

ed a

s not

requ

iring

eith

er re

peat

antim

icrob

ial th

erap

y fo

rin

itial

infe

ctio

n or

ampu

tatio

n of

the

invo

lved

extr

emity

Popu

latio

n:

Adul

ts w

ithpe

riphe

ral v

ascu

lardi

seas

e(b

ut u

ncle

arw

heth

er w

ound

sar

e di

abet

ic or

vasc

ular

in o

rigin

)

Inclu

sion

crite

ria:

(1) H

istor

y of

clini

cal e

viden

ce o

fpe

riphe

ral v

ascu

lardi

seas

e or

diab

etes

mel

litus

; (2)

puru

lent

-app

earin

glo

wer

ext

rem

ityle

sion

of su

fficie

ntse

verit

y to

requ

ireho

spita

lisat

ion

for

intr

aven

ous

antim

icrob

ialth

erap

y; (3

) had

two

or m

ore

signs

of

infe

ctio

n in

cludi

nglo

cal h

eat,

oede

ma,

drain

age,

ery

them

a,pa

in, o

rte

mpe

ratu

re g

reat

erth

an 3

7.8°

C

48 p

atie

nts

Gen

der:

M 4

7, F

1

Mea

n ±

SDag

e: 6

4ye

ars

No.

with

diab

etes

mel

litus

: 46/

48(9

6%)

No.

with

ost

eom

yelit

is: 3

1/48

(65%

)N

o. w

ith c

ellu

litis:

16/

48 (3

3%)

I1: (

n= 2

4) re

ceive

dcip

roflo

xacin

at 7

50 m

g or

ally

twice

dail

y. Pa

tient

s diag

nose

das

hav

ing

oste

omye

litis

whe

n co

mpa

tible

cha

nges

wer

eob

serv

ed, e

ither

radi

ogra

phica

lly o

r on

thre

e-ph

ase

bone

scan

. The

sepa

tient

s give

n 3

mon

ths o

fth

erap

y. Pa

tient

s who

had

no

evid

ence

of o

steo

mye

litis

wer

egiv

en 3

wee

ks o

f tre

atm

ent.

No

othe

r ant

imicr

obial

s wer

egiv

en to

pat

ient

s (co

ncur

rent

lyor

follo

win

g cip

roflo

xacin

ther

apy)

unl

ess i

t was

dete

rmin

ed th

at th

e qu

inol

one

trea

tmen

t was

a fa

ilure

I2 (n

= 2

4): A

s abo

ve, b

ut10

00m

g or

al cip

roflo

xacin

given

twice

dail

y

Loca

l wou

nd c

are:

bot

hgr

oups

. (1)

deb

ridem

ent o

fw

ound

to re

mov

e su

rface

esch

ars a

nd n

ecro

tic m

ater

ial;

(2) m

ainte

nanc

e of

a c

lean

wou

nd b

y fo

ot so

akin

g an

d w

etor

dry

gau

ze d

ress

ings

; (3

) avo

idan

ce o

f any

pre

ssur

eon

the

wou

nd it

self;

(4)

ther

apy

of th

e in

fect

ed le

sion

with

syst

emic

rath

er th

anto

pica

l ant

imicr

obial

age

nts

Fully

eva

luab

le p

atie

nts:

I1: 2

3 pa

tient

sI2

: 22

patie

nts

Ampu

tatio

n: (i

n th

ose

for w

hom

ther

apy

faile

d)

I1: 6

/11

(55%

)I2

: 3/7

(43%

)

Long

-term

out

com

e (d

efin

edea

rlier

) in

patie

nts t

reat

ed fo

r (a

) ost

eom

yelit

is an

d (b

) cel

lulit

is(%

):

Tota

l (a)

19

(65)

; (b)

8 (5

0)I1

I2(a

)(b

)(a

)(b

)10

(67)

2 (2

5)9

(64)

6 (7

5)

Adve

rse

even

ts:

I2: 2

pat

ient

s req

uire

d ce

ssat

ion

of tr

eatm

ent.

One

was

due

tona

usea

and

vom

iting

, whi

chbe

gan

follo

win

g ho

spita

ldi

scha

rge

at 2

days

. The

oth

erpa

tient

disc

ontin

ued

at 3

4da

ysdu

e to

seve

re a

nxie

ty, s

imila

r to

that

pre

vious

ly ex

perie

nced

with

othe

r med

icatio

ns

6 pa

tient

s (I2

), 2

patie

nts (

I1)

expe

rienc

ed c

hem

ical

abno

rmali

ties

(incr

ease

d bl

ood

urea

nitr

ogen

or

seru

m c

reat

inin

e le

vels)

Num

bers

of

with

draw

als(a

lthou

ghw

ithdr

awal

not

defin

ed) p

ertr

eatm

ent g

roup

:

I1: 1

rece

ived

ampu

tatio

n w

ithin

24ho

urs o

fen

rolm

ent

I2: 2

pat

ient

s due

to a

dver

se e

vent

s(s

ee p

revio

usno

te)

Stud

y sp

onso

rshi

p:M

iles

Phar

mac

eutic

als,

Wes

t Hav

en, C

T,U

SA

cont

inue

d


181


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Setti

ng a

nd le

ngth

of

trea

tmen

t: in

patie

nts a

tth

e M

inne

apol

is Ve

tera

nsAd

min

istra

tion

Med

ical

Cen

ter.

Trea

tmen

t ove

r72

hour

s/fol

low

-up

at12

mon

ths

Exclu

sion

crite

ria:

(1) F

ailur

e to

give

info

rmed

con

sent

;(2

) alle

rgy

toqu

inol

one

antib

iotic

s; (3

) prio

ran

tibio

tic th

erap

ygiv

en w

ithin

the

prev

ious

72

hour

sth

at w

as e

ffect

ive, i

nviv

oor

invit

ro,

again

st th

eir

path

ogen

ic ba

cter

ialiso

lates

. No

patie

ntw

as e

xclu

ded

for

the

first

two

indi

catio

ns

Swab

cul

ture

s obt

ained

afte

rth

e su

rface

of t

he w

ound

has

been

thor

ough

ly cle

anse

d to

min

imise

surfa

ce c

onta

min

atio

n

Appendix 4

182

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Rhaie

m (1

998)

,124

Tuni

sia

Stud

y de

sign:

RC

T

Met

hod

ofra

ndom

isatio

n:

Not

stat

ed

Uni

t of a

lloca

tion:

Patie

nt

Calc

ulat

ion

of st

atist

ical

pow

er:

Not

des

crib

ed

Out

com

e as

sess

men

t:Th

e m

ain o

utco

mes

repo

rted

per

stud

ygr

oup

wer

e he

aling

rate

and

time

to h

ealin

g.W

here

hea

ling

rate

sw

ere

repo

rted

acc

ordi

ngto

socio

-eco

nom

ic le

vel,

a sc

ore

was

calc

ulat

edac

cord

ing

to th

efo

llow

ing:

leve

l of

educ

atio

n (0

illit

erat

e,

1 pr

imar

y sc

hool

leve

l, 2

seco

ndar

y sc

hool

, 3

furt

her e

duca

tion)

;pr

ofes

sion

(0 u

nem

ploy

ed, 1

low

inco

me,

2 m

oder

ate

inco

me,

3 h

igh in

com

e);

type

of h

ousin

g an

dnu

mbe

r of d

epen

dant

s

Setti

ng a

nd le

ngth

of

trea

tmen

t:H

ospi

tal;

mea

n±sd

(?)

leng

th o

f hos

pita

l sta

y:40

±13

days

Popu

latio

n:D

iabet

ic pa

tient

sw

ith c

utan

eous

wou

nds,

hosp

italis

ed a

t Rab

taH

ospi

tal,

Tuni

sia,

betw

een

1992

and

1995

Inclu

sion

crite

ria:

As a

bove

Exclu

sion

crite

ria:

Not

stat

ed

Base

line

char

acte

ristic

s wer

ere

port

ed fo

r the

sam

ple

over

all,

and

not p

er st

udy

grou

p

Num

ber m

ale/fe

male

:59

/21

Mea

n ±

SD (?

) (ra

nge)

age

(yea

rs):

56 ±

32 (2

6–89

)

Num

ber w

ith in

sulin

-de

pend

ent/n

on-in

sulin

dep

ende

ntdi

abet

es:

61/1

9

Mea

n ±

SD(?)

(ran

ge) d

urat

ion

of d

iabet

es (y

ears

):13

±10

.6 (1

–26)

Num

ber o

f pat

ient

s with

diab

etes

for l

ess t

han/

at le

ast 1

0ye

ars:

22/5

8

Num

ber o

f pat

ient

s with

out

occu

patio

n/illi

tera

te:

61/5

3

Prop

ortio

ns o

f pat

ient

s with

risk

fact

ors:

body

mas

s ind

ex o

f at l

east

25kg

/m2 : 4

0%D

yslip

idae

mia:

28%

Smok

ers:

55%

Alco

hol u

se: 2

1%Pe

riphe

ral n

euro

path

y: 7

4.6%

Vege

tativ

e ne

urop

athy

: 18.

6%Ar

terit

is of

low

er li

mbs

: 46.

6%Ar

teria

l hyp

erte

nsio

n: 3

0.6%

Cor

onar

y in

suffi

cienc

y: 9

.3%

Prop

ortio

n of

pat

ient

s with

diab

etes

-rel

ated

co-

mor

bidi

ty:

Nep

hrop

athy

: 17.

3%

I1: T

he w

ound

was

debr

ided

, cle

aned

with

3%

hydr

ogen

per

oxid

e so

lutio

nan

d dr

ied

with

a c

ompr

ess.

Suga

r was

then

pou

red

into

the

wou

nd c

avity

, tak

ing

care

to e

nsur

e th

at th

e de

epes

tpa

rts o

f the

wou

nd w

ere

fille

d. A

n oc

clusiv

e dr

essin

gan

d ba

ndag

e w

ere

appl

ied

and

chan

ged

daily

(n=

16)

I2: A

s abo

ve, w

ith th

ead

ditio

n of

syst

emic

antib

iotic

s. Th

e ch

oice

of

antib

iotic

was

det

erm

ined

thro

ugh

the

bact

erial

pro

file

of w

ound

sam

ples

and

was

mod

ified

as i

ndica

ted

byfu

rthe

r cul

ture

s (n

= 2

4)

I3: T

he w

ound

was

debr

ided

, cle

aned

with

3%

hydr

ogen

per

oxid

e so

lutio

nan

d dr

ied

with

a c

ompr

ess.

Syst

emic

antib

iotic

s wer

ead

min

ister

ed. A

n oc

clusiv

edr

essin

g an

d ba

ndag

e w

ere

appl

ied

(n=

40)

Stat

istica

l met

hods

:N

ot d

escr

ibed

Hea

ling

rate

(ove

rall)

:I1

: 49.

9%I2

: 45.

8%I1

and

I2 c

ombi

ned:

47.

5%I3

: 40.

0%ns M

ean

time

to h

ealin

g (o

vera

ll):

I1 &

I2: 6

wee

ksI3

: 9 w

eeks

ns Hea

ling

rate

acc

ordi

ng to

site

of

wou

nd:

Foot

:I1

and

I2 c

ombi

ned

30.7

%I3

: 36.

1%ns Si

tes o

ther

than

foot

:I1

and

I2 c

ombi

ned:

100

%I3

: 75%

p<

0.0

01

Ove

rall

heali

ng ra

te fo

rin

fect

ed/n

euro

path

ic/isc

haem

icle

sions

:66

%/3

8.7%

/37.

5%p

< 0

.001

Hea

ling

rate

for

infe

cted

/neu

ropa

thic/

ischa

emic

lesio

ns tr

eate

d w

ith su

gar (

grou

psI1

and

I2 c

ombi

ned)

:66

.6%

/38.

7%/3

1.5%

p<

0.0

01 fo

r inf

ecte

d ve

rsus

neur

opat

hic

wou

nds a

nd fo

rin

fect

ed v

ersu

s isc

haem

ic w

ound

s

Not

repo

rted

Ratio

nale

for u

se o

fsu

gar a

s an

antim

icrob

ial:

in th

eir d

iscus

sion,

the

auth

ors c

ite o

ther

stud

ies t

hat h

ave

used

suga

r as a

topi

cal

antim

icrob

ial a

gent

with

wou

nds,

and

they

also

desc

ribe

the

poss

ible

phys

iolo

gical

mec

hani

sms i

nvol

ved

The

auth

ors p

ropo

sed

that

bet

wee

n-gr

oup

diffe

renc

es m

ay n

ot h

ave

been

det

ecte

d fo

r foo

tw

ound

s bec

ause

of t

hedi

fficu

lty o

f app

lying

suga

r to

the

foot

and

beca

use

of li

kely

conc

urre

nt n

euro

logic

alan

d va

scul

ar c

o-m

orbi

ditie

s

Lim

itatio

ns o

f the

stud

yas

not

ed b

y th

ere

view

er: t

his i

s a w

eak

stud

y in

seve

ral

impo

rtan

t res

pect

s.Ba

selin

e da

ta a

re n

otre

port

ed p

er g

roup

,th

eref

ore

grou

pco

mpa

rabi

lity

cann

ot b

eas

sess

ed. T

here

are

no

base

line

data

on

wou

ndsiz

e or

seve

rity.

Som

ede

tails

of i

nter

vent

ions

are

lacki

ng (e

.g. t

he ty

peof

deb

ridem

ent u

sed,

and

the

type

of s

ugar

).U

neve

n nu

mbe

rs w

ere

cont

inue

d


183


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Diab

etic

retin

opat

hy: 5

3.3%

Prop

ortio

n of

pat

ient

s with

wou

nd o

n fo

ot/le

g/ot

her s

ite:

81.2

5%/5

.00%

/13.

75%

Prop

ortio

n of

pat

ient

s with

infe

cted

/neu

ropa

thic/

ischa

emic

wou

nds:

51.7

%/4

4.6%

/33.

00%

In p

atie

nts w

ith fo

ot w

ound

s,nu

mbe

r (%

) with

mal

perfo

rant

plan

tar l

esio

ns/is

chae

mic

lesio

ns/le

sions

invo

lving

bon

e:55

(68.

75%

)/25

(31.

25%

)/31

(38.

75%

)

Prop

ortio

n of

pat

ient

s with

wou

nds p

rece

ded

by tr

aum

a, n

otim

med

iatel

y no

ticed

due

tose

nsor

y ne

urop

athy

:82

%

Hea

ling

rate

acc

ordi

ng to

dur

atio

nof

diab

etes

:Le

ss th

an 1

0ye

ars:

54.4

%At

leas

t 10

year

s: 36

.6%

p<

0.0

5

Mea

n ±

SD(?)

tim

e to

hea

ling

acco

rdin

g to

dur

atio

n of

diab

etes

:Le

ss th

an 1

0ye

ars:

6.4

±2.

2 w

eeks

At le

ast 1

0ye

ars:

10.7

5 ±

3.1

wee

ksp

< 0

.05

Hea

ling

rate

acc

ordi

ng to

glyc

aem

icco

ntro

l:Bl

ood

suga

r <2

g/l:

48.5

0%Bl

ood

suga

r 2–2

.5g/

l: 31

.25

Bloo

d su

gar >

2.5

g/l:

25.0

0%p

< 0

.05

Hea

ling

rate

acc

ordi

ng to

socio

-ec

onom

ic le

vel:

Goo

d sc

ore

>6:

44.

4%M

oder

ate

3–6:

31.

2%Po

or <

3: 2

3.3%

p<

0.0

5

Mea

n ±

SD(?)

tim

e to

hea

ling

acco

rdin

g to

socio

-eco

nom

ic le

vel:

Goo

d sc

ore

>6:

6 ±

1.6

wee

ksM

oder

ate

3-6:

8.4

±2

wee

ksPo

or <

3: 1

0 ±

3w

eeks

p<

0.0

5

Cos

t of h

ospi

talis

atio

n, n

ot in

cludi

ngtr

eatm

ent (

over

all):

Aver

age

was

800

din

ars (

20 d

inar

spe

r day

)

Cos

t of t

reat

men

t (ov

erall

):Av

erag

e w

as 1

94 d

inar

s per

pat

ient

(sur

gical

proc

edur

es n

ot in

clude

d)

recr

uite

d to

the

stud

ygr

oups

and

this

was

not

expl

ained

in th

e m

etho

dsse

ctio

n. T

he st

udy

perio

d is

not c

lear

. The

mea

n ±

SD(?)

leng

th o

fho

spita

l sta

y w

asre

port

ed a

s 40

±13

days

; how

ever

, an

aver

age

leng

th o

f sta

y of

15–3

0 da

ys is

also

repo

rted

. Pat

ient

s wer

efo

llow

ed u

p fo

r up

to9

wee

ks b

ut it

is n

otst

ated

whe

ther

this

occu

rred

afte

r disc

harg

e,an

d if

so, w

hat

trea

tmen

t was

pro

vided

in th

e in

terim

per

iod.

The

stat

istica

l met

hods

used

are

not

des

crib

ed,

and

it is

not c

lear

whe

ther

the

repo

rted

varia

nces

are

stan

dard

devia

tion

or st

anda

rder

ror.

Hea

ling

rate

s are

repo

rted

, but

hea

ling

isno

t def

ined

. The

re a

refe

w d

etail

s abo

ut h

owou

tcom

es w

ere

asse

ssed

. It i

s not

cle

arin

eve

ry c

ase

exac

tlyw

hat c

ompa

rison

s the

repo

rted

p-v

alues

are

refe

rrin

g to

. Gro

ups 1

and

2 (th

ose

invo

lving

use

of su

gar)

are

som

etim

es c

ombi

ned

for

analy

sis b

ut th

is is

not

expl

ained

in th

e m

etho

ds

cont

inue

d

Appendix 4

184

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

The

auth

ors e

stim

ated

that

by

usin

gsu

gar,

the

aver

age

cost

per

pat

ient

coul

d be

redu

ced

to 2

1 di

nars

as

muc

h of

the

care

cou

ld b

e ca

rrie

dou

t by

the

patie

nt o

r his/

her f

amily

at h

ome.

The

met

hods

of e

stim

atio

nus

ed w

ere

not d

escr

ibed

sect

ion.

Man

y of

the

resu

lts a

re n

ot re

port

edpe

r tre

atm

ent g

roup

. In

thei

r con

clusio

n th

eau

thor

s sta

te th

at u

se o

fsu

gar d

oes n

ot p

rodu

cead

vers

e ef

fect

s, bu

t thi

sw

as n

ot a

sses

sed

durin

gth

e st

udy.

Stud

y sp

onso

rshi

p:N

ot st

ated


185


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Seid

el (1

991)

,110

Ger

man

y

Stud

y de

sign:

CC

T

Met

hod

of a

lloca

tion:

Patie

nts c

hose

thei

r ow

nth

erap

y

Uni

t of a

lloca

tion:

Pa

tient

Calc

ulat

ion

of st

atist

ical

pow

er:

Not

stat

ed

Out

com

e as

sess

men

t:C

linica

l sta

tus o

f ulce

r:(1

) pur

ulen

tm

embr

anes

/no

impr

ovem

ent –

scor

e 0

poin

ts; (

2) p

artia

lva

scul

ar g

ranu

latio

n –

scor

e 1

poin

t; (3

) ful

lva

scul

ar g

ranu

latio

n –

scor

e 2

poin

ts;

(4) d

imin

utio

n of

ulce

r –sc

ore

3 po

ints

; (5)

cur

e –

scor

e 4

poin

ts.

Plan

imet

ric m

easu

res

(pho

togr

aphi

c/X

-ray

).Ba

cter

ial a

nalys

is (n

oda

ta a

vaila

ble)

.Ps

ycho

logic

al ou

tcom

e(q

uest

ionn

aire:

pat

ient

opin

ion

of e

ffect

of

trea

tmen

t)

Setti

ng:

Inpa

tient

s

Leng

th o

f tre

atm

ent:

10da

ys

Popu

latio

n: m

alein

patie

nts w

ithD

NPU

All m

ale (n

= 4

0)

I1: n

= 2

0I2

: n=

20

Age:

45–

70ye

ars

Mea

n ag

e of

initi

al D

NPU

man

ifest

atio

n: 6

2 (±

5 ye

ars)

Type

of d

iabet

es:

Type

I: 8

/40

(20%

)Ty

pe II

a: 1

4/40

(35%

)Ty

pe II

b: 1

8/40

(45%

)

Bact

erio

logy

: N

o da

ta

Clin

ical s

tatu

s of u

lcer (

scor

e):

I1I2

Puru

lent

mem

bran

es9

10Pa

rtial

vas

cular

gran

ulat

ion

98

Full

vasc

ular

gran

ulat

ion

22

Patie

nts w

ith o

steo

mye

litis:

I1: 5

/20

(25%

)I2

: 7/2

0 (3

5%)

I1: (

n=

20)

Pat

ient

s rec

eive

d a

perfu

sion

(onc

e da

ily) o

f RVP

(com

prisi

ng 1

20m

gge

ntam

icin,

50

mg

buflo

med

il,4

mg

dexa

met

haso

ne, 4

mg

ligno

cain

e an

d 25

00IU

of

hepa

rin d

issol

ved

in 1

20m

lsa

line

solu

tion)

. Afte

r ase

ptic

punc

ture

of a

foot

vei

n, th

e le

gis

drain

ed b

y hi

gh e

leva

tion

for

2m

inut

es a

nd th

en m

id/u

pper

leg

com

pres

sed

at 3

0m

m/H

gab

ove

the

syst

olic

arte

rial

pres

sure

. The

‘coc

ktail

’ is t

hen

inje

cted

as a

bol

us. A

dditi

onal

even

ing

med

icatio

n of

60

mg

gent

amici

n i.m

. and

one

reta

rdta

blet

of b

uflo

med

il. F

orre

ason

s of c

ompa

rabi

lity

anad

ditio

nal i

nfus

ion

ther

apy

with

3 ×

4g

pipe

racil

line

also

given

I2: (

n=

20)

Tre

ated

conv

entio

nally

with

3 ×

4g

pipe

racil

lin, 3

×60

mg

gent

amici

n, 3

x 5

0m

gbu

flom

edil,

3 ×

500

ml d

extr

an40

and

3 ×

5000

IU h

epar

inda

ily

Both

gro

ups r

ecei

ved

sam

ere

gimen

of l

ocal

antib

acte

rial

ther

apy

Ulce

r hea

led:

I1: 6

/20

(30%

)I2

: 0/

20 (0

%)

Ulce

r dim

inish

ed in

size

:I1

: 10/

20 (5

0%)

I2:

3/20

(15

%)

% D

imin

utio

n of

ulce

rous

pain

(not

cle

ar w

heth

er th

is is

pain

or

area

?):I1

: 55%

±8

I2:

7.5%

±3.

6

Deb

ridem

ent o

f exu

dativ

ede

tritu

s:I1

: 93%

±3

I2: 4

2% ±

8

Redu

ctio

n in

infe

ctio

us u

lcer

cove

r:I1

: 86%

±3.

7I2

: 38%

±8

Hos

pita

lisat

ion

(ave

rage

day

s):

I1: 1

2 ±

2I2

: 19

±3

Ampu

tatio

n:I1

: 0/2

0 (0

%)

I2: 4

/20

(20%

) (du

e to

unde

rlyin

g os

teom

yelit

is)

Cur

e of

ost

eom

yelit

is (%

):I1

: 4/5

(80%

)I2

: 0/7

(0%

)

HbA

1c (%

):I1

: 8.1

±1.

0I2

: 8.9

±1.

0

Que

stio

nnair

e re

sults

:

Dist

inct

diff

eren

ce b

etw

een

grou

ps w

ith I1

gro

up sh

owin

g

Not

stat

edLi

mita

tions

of t

he st

udy:

Patie

nts c

hose

thei

r ow

nth

erap

y

10%

mor

e ca

ses o

fos

teom

yelit

is in

I2 g

roup

at b

asel

ine?

No

dem

ogra

phic

com

para

bilit

y of

gro

ups

repo

rted

, e.g

. age

data

/type

of d

iabet

es,

area

of u

lcera

tion

Auth

ors s

ay th

eim

prov

emen

t in

patie

ntkn

owle

dge

was

bec

ause

the

30-m

inut

e tr

eatm

ent

time

allow

ed p

atie

nt to

ask

doct

or q

uest

ions

,pa

tient

train

ing

coul

d be

deliv

ered

cont

inue

d

Appendix 4

186

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

grea

ter p

erce

ptio

n of

phys

ical/e

mot

iona

l im

prov

emen

t.C

ompl

iance

and

indi

vidua

lkn

owle

dge

abou

t the

dise

ase

also

high

er in

this

grou

p

Bact

erial

pro

file:

no

resu

lts g

iven

Adve

rse

even

ts (R

VP):

Pete

chiae

: 6/2

0 (3

0%)

Pain

(fro

m a

rter

ial o

cclu

sion)

:5/

20 (2

5%)

Hae

mor

rhag

e: 4

/20

(20%

)St

asis

derm

atiti

s: 3/

20 (1

5%)

Nau

sea:

2/2

0 (8

%)

Reve

rsib

le N

VIII

affe

ctio

n: 1

(5%

)(te

mpo

rary

dec

reas

e in

hea

ring

capa

city)


187


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Seid

el (1

993,

1994

),111,

112

Ger

man

y(G

erm

an tr

ansla

tion

ofpa

per)

Stud

y de

sign:

CC

T

Met

hod

ofra

ndom

isatio

n:

Patie

nts c

hose

thei

r ow

nth

erap

y

Uni

t of a

lloca

tion:

Pa

tient

Calc

ulat

ion

of st

atist

ical

pow

er:

Not

stat

ed

Out

com

e as

sess

men

t:(a

s Sei

del e

t al.,

1991

110 )

Setti

ng a

nd le

ngth

of

trea

tmen

t (in

patie

nts a

sSe

idel

et a

l.,19

9111

0 ).Tr

eatm

ent o

ver 1

0da

ys.

Dat

e of

recr

uitm

ent:

Dec

embe

r 198

9

Popu

latio

n:m

ale in

patie

nts w

ithD

NPU

Male

s: 45

Age:

35–

70 y

ears

Mea

n ±

SDag

e (y

ears

): 60

±4

Type

of d

iabet

es:

Type

I:8

(17%

)Ty

pe II

a:14

(35%

)Ty

pe II

b:23

(48%

)

Clin

ical s

tatu

s of u

lcer: I1

I2Pu

s10

9Pa

rtial

119

Full

33

I1: (

n=

24)

RVP

net

ilmyc

in

Patie

nts g

iven

(10

a.m

.) 20

0m

gne

tilm

ycin

; 50

mg

bufe

dil;

200

IU h

epar

in; 4

mg

dexa

met

haso

ne; 2

mg

lidoc

aine

(all

in 1

00m

l 0.9

% sa

line)

. At

6p.

m.:

100

mg

netil

myc

in(i.

m.);

600

mg

bufe

dil r

etar

d(o

ral);

4g

pipe

racil

lin tw

ice a

day

(i.v.)

I2: (

n=

21)

SVI

– n

etilm

ycin

Patie

nts g

iven

(at 9

a.m

.,3

p.m

., 9

p.m

.) 10

0m

gne

tilm

ycin

; 50

mg

bufe

dil;

2500

I.U. h

epar

in a

ll in

rheo

mac

rode

x. A

t 9 a

.m. –

4m

g D

exam

etha

sone

. 4 g

pipe

racil

lin tw

ice a

day

(i.v.

).

Con

curr

ent t

reat

men

t i.v.

:C

lean

sed

with

hyd

roge

npe

roxi

de, p

ovid

one

iodi

ne p

ad,

ster

ile b

anda

ge. D

ieta

ry a

ndm

edica

l tre

atm

ents

for

diab

etes

I1I2

Ulce

r hea

led:

8 (3

3%)

3 (1

4%)

At le

ast 3

0%

10 (4

2%)

4 (1

9%)

redu

ctio

n in

are

aRe

duct

ion

in

93 ±

642

±8

puru

lent

are

aAm

puta

tion

3 (1

3%)

4 (1

9%)

Appendix 4

188

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Tan

(199

3),10

8U

SA

Stud

y de

sign:

RC

T (d

oubl

e-bl

ind)

Met

hod

of ra

ndom

isatio

n:

Com

pute

r-ge

nera

ted

sche

dule

. 3:2

ratio

I1:I2

to a

llow

larg

er sa

fety

data

base

for r

egist

ratio

nof

I1 d

rug

Uni

t of a

lloca

tion:

Pa

tient

Calc

ulat

ion

of st

atist

ical

pow

er: E

stim

ated

appr

oxim

atel

y 50

% o

fra

ndom

ised

patie

nts

(sam

ple

size

I1 n

= 1

50an

d I2

n=

100

) wou

ldbe

eva

luab

le fo

r prim

ary

analy

ses.

Proj

ecte

dev

aluab

le p

atie

nts

prov

ided

a p

ower

of

70%

for o

bser

ved

trea

tmen

t diff

eren

ce(s

ignifi

canc

e: �

= 0

.05,

two-

taile

d) if

the

true

trea

tmen

t diff

eren

ce in

unde

rlyin

g po

pulat

ion

not

mor

e th

an 2

0%. A

llpa

tient

s qua

lifie

d fo

rin

tent

ion

to tr

eat

analy

sis. P

roje

cted

num

bers

pro

vided

pow

erof

82%

for o

bser

ved

trea

tmen

t diff

eren

ce(s

ignifi

canc

e, �

= 0

.05,

two

taile

d) if

true

trea

tmen

t diff

eren

ce w

asno

mor

e th

an 1

5%

Popu

latio

n:

251

hosp

italis

edpa

tient

s with

com

plica

ted

skin

/skin

stru

ctur

ein

fect

ions

(a

ge 1

6+ y

ears

)

Inclu

sion

crite

ria:

Puru

lent

dra

inag

e or

colle

ctio

n pl

us a

tle

ast 3

of t

hefo

llow

ing:

tem

pera

ture

>38

°C, p

erip

hera

lle

ukoc

yte

coun

t>

10,0

00/m

m3

(with

>5%

imm

atur

ene

utro

phils

), lo

cal

eryt

hem

a, lo

cal

swel

ling,

tend

erne

ss, p

ain, o

rflu

ctua

nce.

Sev

erity

asse

ssed

by

inve

stiga

tor a

s mild

,m

oder

ate

or se

vere

at b

asel

ine

Exclu

sion

crite

ria:

Know

n or

susp

ecte

dhy

pers

ensit

ivity

tobe

ta-la

ctam

antib

iotic

s or

�-la

ctam

ase

inhi

bito

rs; m

oder

ate

to se

vere

rena

ldy

sfunc

tion;

evid

ence

of a

ctive

liver

dise

ase;

perip

hera

lgr

anul

ocyt

e co

unts

Tota

l no.

of p

artic

ipan

ts:

I1: (

all) 1

53, (

evalu

able

) 67

I2: (

all) 9

8, (e

valu

able

) 44

Male

/fem

ale (n

umbe

rs):

I1: (

all) 1

15/3

8, (e

valu

able

) 53/

14I2

: (all

) 69/

29, (

evalu

able

) 32/

12

Ethn

icity

(num

bers

): All

Evalu

able

I1:

Cau

casia

n11

143

Blac

k29

12O

ther

race

1312

I2:

Cau

casia

n69

29Bl

ack

208

Oth

er ra

ce9

7

Age:

mea

n ±

SD(y

ears

):I1

: (all

) 53,

(eva

luab

le) 5

3I2

: (all

) 52,

(eva

luab

le) 5

5

Num

ber/%

with

diab

etic

foot

ulce

rs (c

lasse

d as

‘wou

ndin

fect

ion’

by

auth

or):

I1: (

all) 3

1 (2

0), (

evalu

able

) 16

(24)

I2: (

all) 1

8 (1

8), (

evalu

able

) 7 (1

6)

Prio

r/cur

rent

use

of a

ntim

icrob

ialag

ents

: see

Exc

lusio

n cr

iteria

I1: (

n =

153

) Pat

ient

s dos

edev

ery

6 ho

urs w

ithpi

pera

cillin

–taz

obac

tam

, 3 g

and

375

mg,

resp

ectiv

ely

for a

min

imum

of 5

days

and

for a

tle

ast 4

8ho

urs a

fter t

here

solu

tion

of si

gns a

ndsy

mpt

oms.

I2: (

n =

98)

Pat

ient

s dos

edev

ery

6ho

urs w

ithtic

arcil

lin–c

lavul

anat

e, 3

g an

d10

0m

g, re

spec

tivel

y, fo

r am

inim

um o

f 5 fu

ll da

ys a

nd fo

rat

leas

t 48

hour

s afte

r the

reso

lutio

n of

sign

s and

sym

ptom

s

Surg

ical d

ebrid

emen

t or

drain

age

allow

ed a

nd a

ccep

ted

as p

art o

f pat

ient

man

agem

ent.

Nee

d fo

r sur

gery

or o

ther

adju

nctiv

e th

erap

y w

asde

term

ined

by

the

inve

stiga

tor

and

the

colla

bora

ting

surg

eon

Stat

istica

l met

hods

: num

bers

(%);

Wilc

oxon

, �2

test

s.[s

ignifi

canc

e te

stin

g –

�(tw

o-ta

iled)

= 0

.05]

Mea

n du

ratio

n of

trea

tmen

t(d

ays)

I1: (

all) 8

.2, (

evalu

able

) 10.

2I2

: (all

) 9.1

, (ev

aluab

le) 1

0.5

Evalu

able

pat

ient

s divi

ded

bydi

agno

sis:

1st:

Cel

lulit

is2n

d: C

utan

eous

abs

cess

3rd:

Diab

etic

or is

chae

mic

foot

infe

ctio

n4t

h: in

fect

ed w

ound

s and

ulce

rs–

inclu

des p

ress

ure

ulce

rs o

n th

efo

ot.

Clin

ical r

espo

nse

(no.

gro

up a

nd%

gro

up) f

or w

ound

or u

lcer

infe

ctio

n [th

ese

wer

e ev

aluab

lepa

tient

s with

diab

etic

foot

ulce

rs,

as c

onfir

med

by

auth

or]:

I1:

Cur

ed9/

16 (5

6)Im

prov

ed1/

16 (6

)Fa

vour

able

10/1

6 (6

3)

I2:

Cur

ed6/

7 (8

6)Im

prov

ed1/

7 (1

4)Fa

vour

able

7/7

(100

)

(p =

0.1

7)

Clin

ical f

ailur

es (w

ound

/ulce

rpa

tient

s):

I1: 2

(sw

itche

d to

ano

ther

antib

iotic

)

Clin

ical f

ailur

es:

I1: 5

I2: 4

3 pa

tient

s in

each

trea

tmen

tar

m d

ue to

ampu

tatio

n of

infe

cted

lim

b. 2

patie

nts i

n I1

and

1 in

I2 sw

itche

dto

ano

ther

antib

iotic

Que

ry w

heth

er th

ose

with

wou

nd in

fect

ion

(aut

hors

say

thes

e w

ere

foot

ulce

r pat

ient

s) w

ere

also

diab

etic?

Shar

p re

duct

ion

innu

mbe

rs a

vaila

ble

for

final

evalu

atio

n

Evalu

abilit

y cr

iteria

:

Failu

re to

mee

t crit

eria

for d

iagno

sis; n

o ba

selin

epa

thog

en, i

nade

quat

ecli

nica

l fol

low

-up;

pre

-st

udy

antib

iotic

;co

ncom

itant

infe

ctio

n;re

sista

nt p

atho

gen

atba

selin

e; o

ther

(inco

rrec

t diag

nosis

,in

adeq

uate

dru

gsu

scep

tibilit

y da

ta,

inad

equa

teba

cter

iolo

gical

follo

w-u

p,in

adeq

uate

trea

tmen

tre

gimen

)

Stud

y sp

onso

rshi

p:In

fect

ions

Lim

ited?

Mul

ti-ce

ntre

(20

sites

)

cont

inue

d


189


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Out

com

e as

sess

men

t:C

linica

l:(1

) Cur

ed: r

ecov

ery

from

infe

ctio

n;

(2) i

mpr

oved

– sh

owed

impr

ovem

ent i

n at

leas

t3

of th

e fo

llow

ing

para

met

ers c

ompa

red

with

valu

es o

btain

ed a

tpr

e-en

rolm

ent

evalu

atio

n: q

uant

ity o

fdr

ainag

e, e

ryth

ema,

seve

rity

of sw

ellin

g,te

nder

ness

, pain

,flu

ctua

nce,

lym

phan

gitis,

rigor

s, te

mpe

ratu

re,

perip

hera

l leu

cocy

teco

unt;

(and

no

new

antim

icrob

ial th

erap

yne

cess

ary)

(1) a

nd (2

) C

lasse

d as

favo

urab

lecli

nica

l res

pons

e.

(3)

Unf

avou

rabl

e: re

lapse

from

initi

al im

prov

emen

tan

d w

orse

ning

of

para

met

ers a

bove

, or

failu

re, r

equi

ring

chan

gein

ant

imicr

obial

ther

apy.

They

use

d 2

sets

of

outc

ome

crite

ria –

regis

trat

ion

crite

ria (u

sed

for d

rug

regis

trat

ion

purp

oses

) and

revis

edou

tcom

e de

term

inat

ions

Clin

ical f

ailur

es: c

riter

ia(1

) am

puta

tion

atin

fect

ion

site,

eve

n if

of <

1000

/mm

3or

plat

elet

cou

nts o

f<

50,0

00/m

m3 ;

rece

ipt o

f mor

eth

an 2

dos

es o

fan

othe

r ant

ibac

teria

lag

ent w

ithin

72ho

urs p

rior t

oen

rolm

ent;

rece

ipt

of a

noth

erin

vest

igatio

nal d

rug

with

in 1

mon

thpr

ior t

o en

rolm

ent;

activ

e or

trea

ted

leuk

aem

ia; A

IDS;

need

for

haem

odial

ysis,

perit

onea

l dial

ysis,

plas

map

here

sis o

rhe

mop

erfu

sion,

oste

omye

litis

cont

iguou

s with

ask

in/sk

in st

ruct

ure

infe

ctio

n; p

oten

tial

requ

irem

ent f

oram

puta

tion

ofin

fect

ed a

rea;

pres

sure

ulce

rin

fect

ions

of

>2

wee

ks d

urat

ion;

conc

omita

ntin

fect

ion

othe

r tha

nsk

in/sk

in st

ruct

ure

infe

ctio

n

Endp

oint

era

dica

tion

of b

acte

rial

path

ogen

s (iso

lated

from

the

infe

cted

site

in e

valu

able

pat

ient

s):

Tota

l no.

of i

solat

eser

adica

ted/

no. o

f iso

lates

reco

vere

d (%

)I1

I2To

tal1

03/1

35 (7

6)82

/99

(82.

8)

Adve

rse

even

ts (a

ll pa

tient

sex

perie

ncin

g at

leas

t one

adv

erse

even

t):

I1: 6

5 (4

2%)

I2: 4

1 (4

2%)

Of w

hich

:I1

: 11%

gas

troi

ntes

tinal

trac

t6.

5% d

iarrh

oea

I2: 1

1% g

astr

oint

estin

al tr

act

4.1%

diar

rhoe

a

(ns)

bet

wee

n gr

oups

cont

inue

d

Appendix 4

190

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

non-

infe

ctio

n-re

lated

of

impr

ovem

ents

obs

erve

d,or

(2) p

atie

nt sw

itche

dto

ora

l ant

ibio

tics e

ven

ifth

ey h

ad li

ttle

or n

oin

fect

ion

at th

at ti

me,

esta

blish

ed to

ass

ess

effic

acie

s of d

rugs

for

regis

trat

ion

purp

oses

Bact

erio

logic

alou

tcom

es: O

rgan

isms

isolat

ed fr

om e

valu

able

patie

nts a

nd fr

eque

ncy

with

whi

ch th

ey w

ere

erad

icate

d. E

radi

catio

n:ba

selin

e pa

thog

ens

erad

icate

d. E

radi

catio

npr

esum

ed: i

mpr

ovem

ent

but n

o m

ater

ial a

vaila

ble

for a

nalys

is. P

ersis

tenc

e:at

leas

t one

pat

hoge

nfro

m in

itial

sam

ple

still

pres

ent a

t fol

low

up.

Pers

isten

ce p

resu

med

:un

favo

urab

le re

spon

sebu

t no

mat

erial

ava

ilabl

efo

r ana

lysis

Setti

ng a

nd le

ngth

of

trea

tmen

t: M

ulti-

cent

re (2

0)ho

spita

l set

ting.

Min

imum

5da

ytr

eatm

ent p

lus a

t lea

st48

hour

s afte

r res

olut

ion

of si

gns a

nd sy

mpt

oms.

Early

follo

w-u

p:

24–7

2 ho

urs a

fter

ther

apy

com

plet

ion.

Lat

efo

llow

-up:

10–

14 d

ays

afte

r the

rapy

com

plet

ion


191


Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Vand

eput

te (1

996)

125

Belgi

um

Stud

y de

sign:

RC

T

Met

hod

ofra

ndom

isatio

n:

Pre-

prep

ared

rand

omise

d lis

ting

Uni

t of a

lloca

tion:

Patie

nt

Calc

ulat

ion

of st

atist

ical

pow

er:

Not

stat

ed

Out

com

e as

sess

men

t: W

ound

hea

ling

time

(by

phot

ogra

phic

mea

sure

ever

y 4

wee

ks);

pres

sure

relie

f, m

obilit

y, dr

essin

gdu

rabi

lity,

infe

ctio

ndu

ring

trial

, call

usfo

rmat

ion,

nee

d fo

rsy

stem

ic lo

cal a

ntib

iotic

sor

ant

isept

ic cr

eam

s,am

puta

tion.

Pat

ient

inte

rvie

wed

dur

ing

trial

abou

t com

fort

and

pain

Setti

ng:

Not

stat

ed

Leng

th o

f tre

atm

ent:

3m

onth

s

Writ

ten

cons

ent

Inclu

sion

crite

ria:

29 d

iabet

ic pa

tient

sw

ith fo

ot u

lcers

(neu

ropa

thic

or n

ot)

Exclu

sion

crite

ria:

Patie

nts t

akin

gsy

stem

ic an

tibio

tics

Num

bers

in st

udy:

I1: 1

5I2

: 14

Male

/fem

ale:

I1: 7

/8I2

: 6/8

Mea

n ±

SDag

e (y

ears

):I1

: 62.

6 (1

4.7)

I2: 6

5.3

(14.

3)

Com

plet

ely

mob

ile:

I1:

12/1

5 (8

0%)

I2: 1

1/14

(79%

)

Trea

ted

with

ora

l ant

idiab

etic

med

icatio

n/in

sulin

dep

ende

nt:

All p

atie

nts r

ecei

ved

optim

alin

sulin

trea

tmen

t and

die

tre

gulat

ion

(acc

ordi

ng to

inte

rnat

iona

l rec

ogni

sed

diab

etic

regu

latio

n pr

otoc

ols)

Evid

ence

of n

euro

path

y:

I1: 9

/15

(60%

)I2

: 9/1

4 (6

4%)

Infe

ctio

n pr

esen

t bef

ore

trial

:I1

: 1/1

5 (7

%)

I2: 1

/14

(7%

)

I1: P

atie

nts (

n=

15)

trea

ted

with

hyd

roge

ldr

essin

g an

d de

rmal

wou

nd c

lean

ser (

Flam

i-C

lens

= sa

line

wat

er +

0.8%

vin

egar

acid

as

buffe

r). (

From

pre

vious

data

ext

ract

ion:

wou

ndca

vitie

s wer

e fil

led

with

an a

lgina

te d

ress

ing)

I2: P

atie

nts (

n=

14)

trea

ted

with

a d

ry g

auze

(twice

a d

ay) a

ndirr

igate

d w

ithch

lorh

exid

ine

(0.0

5%so

lutio

n).

[Fro

m p

revio

us d

ata

extr

actio

n: a

ll pa

tient

sre

ceive

d sy

stem

ic or

topi

cal a

ntib

iotic

s or

topi

cal a

ntise

ptic

crea

ms.

6 pa

tient

sre

ceive

d sy

stem

ican

tibio

tics.

The

mos

tfre

quen

tly u

sed

topi

cal

prep

arat

ion

was

povid

one-

iodi

ne c

ream

]

Mor

talit

y:

I2: 2

pat

ient

s die

d du

ring

trial

Ampu

tatio

n (o

ne o

r mor

e to

es):

I1: 1

/15

(7%

)I2

: 5/1

4 (3

6%)

(p<

0.0

53)

Patie

nt c

ould

walk

with

dre

ssin

g on

:I1

: 12/

15 (8

0%)

I2: 9

/14

(64%

)(p

< 0

.01)

Aver

age

time

dres

sing

stay

ed o

n w

ound

:I1

5 d

ays

I2: 1

day

(p<

0.0

01)

Infe

ctio

n du

ring

trial

:I1

: 1/

15 (7

%)

I2: 7

/14

(50%

)(p

< 0

.01)

Form

atio

n of

call

us:

I1 7

/15

(47%

)I2

: 14/

14 (1

00%

)(p

< 0

.05)

Nee

d fo

r sys

tem

ic/lo

cal a

ntib

iotic

s or

loca

l ant

isept

ic cr

eam

s:I1

: 1/

15 (7

%)

I2:

14/1

4 (1

00%

)(p

< 0

.000

1)

Com

plet

e he

aling

at 3

mon

ths:

I1: 1

4/15

(93%

)I2

: 5/1

4 (3

6%)

(p<

0.0

5)

Impr

oved

sligh

tly:

I1: 0

/15

(0%

)I2

: 1/1

4 (7

%)

(p<

0.0

5)

Not

impr

oved

:I1

: 1/1

5 (7

%)

I2: 4

/14

(29%

)(p

< 0

.05)

2 pa

tient

s die

d(I2

gro

up) d

urin

gtr

ial

Rele

vanc

e to

DAS

IDU

are

findi

ngs f

or c

ontr

olgr

oup

(chl

orhe

xidi

ne).

Com

pare

d w

ith u

se o

fhy

drog

el, c

ontr

ol g

roup

requ

ired

addi

tiona

l loc

alan

tibio

tics/a

ntise

ptics

,ha

d hi

gher

incid

ence

of

ampu

tatio

ns, a

nd g

reat

erhe

aling

tim

e re

quire

d.Po

ssib

ly/pr

obab

ly no

tin

tent

ion-

to-tr

eat

analy

sis a

s the

y ex

clude

dth

e pa

tient

who

die

dfro

m th

e an

alysis

Appendix 4

192

Stud

y an

d de

sign

Part

icip

ants

Bas

elin

e ch

arac

teri

stic

sIn

terv

entio

n de

tails

Resu

ltsW

ithdr

awal

sC

omm

ents

Yone

m (2

001)

,120

Turk

ey

Stud

y de

sign:

RC

T

Met

hod

ofra

ndom

isatio

n:

Not

spec

ified

Uni

t of a

lloca

tion:

pat

ient

Calc

ulat

ion

of st

atist

ical

pow

er: N

ot sp

ecifi

ed

Out

com

e as

sess

men

t:Pr

imar

y: ti

me

tore

solu

tion

of in

fect

ion,

time

to h

ospi

tal

disc

harg

eSe

cond

ary:

nee

d fo

rsu

rgica

l int

erve

ntio

n,ef

fect

s of G

-CSF

on n

eutr

ophi

l fun

ctio

n

Setti

ng a

nd le

ngth

of

trea

tmen

t: N

ot sp

ecifi

ed/n

ot c

lear

Inclu

sion

crite

ria:

30 d

iabet

ic pa

tient

sw

ith p

edal

cellu

litis

or W

agne

r’scla

ssifi

catio

n gr

ade

2or

less

foot

lesio

n

Exclu

sion

crite

ria:

Pres

ence

of

haem

atol

ogica

ldi

seas

e, h

istor

y or

prev

ious

or c

urre

ntm

align

ancy

, ren

al or

hepa

tic fa

ilure

,pr

egna

nt o

rlac

tatin

g, se

vere

leg

ischa

emia,

dee

p or

seve

re in

fect

ions

,re

ceivi

ngim

mun

osup

pres

sive

ther

apy.

Abso

lute

neut

roph

il co

unt

<1.

5 ×

10 (9

)/l o

r>

20 ×

10 (9

)/l

Male

/fem

ale:

I1: 9

/6I2

: 8/7

Mea

n ±

SDag

e (y

ears

):I1

: 61

±1.

4I2

: 60.

3 ±

1.3

Mea

n ±

SDdu

ratio

n of

diab

etes

(yea

rs):

I1: 1

2.7

±0.

9I2

: 13.

5 ±

1.2

Neu

trop

hil c

ount

/mm

3 :I1

: 570

0 ±

600

I2: 5

200

±50

0

Phag

ocyt

osis

test

(%):

I1: 6

8.1

±2.

2I2

: 70.

4 ±

2.0

Resp

irato

ry b

urst

(mV)

:I1

: 2.0

±0.

4I2

: 1.6

±0.

3

No

signi

fican

t diff

eren

ces

repo

rted

bet

wee

n gr

oups

on

abov

e cr

iteria

Cul

ture

s for

aer

obes

and

anae

robe

s tak

en fr

om th

eul

cers

with

an

appr

opria

tete

chni

que.

The

n:

I1: 1

5 pa

tient

s in

the

‘stan

dard

gro

up’ r

ecei

ved

class

ical t

reat

men

tco

mpr

ising

a c

ombi

natio

n of

loca

l wou

nd c

are

and

antib

ioth

erap

y (in

trav

enou

scip

roflo

xacin

and

met

roni

dazo

le)

I2: 1

5 pa

tient

s in

the

‘G-C

SFgr

oup’

rece

ived

the

abov

ecla

ssica

l tre

atm

ent,

plus

reco

mbi

nant

hum

an G

-CSF

[Filg

rast

im (N

eupo

gen)

]. G

-CSF

(5�

g/kg

) adm

inist

ered

subc

utan

eous

ly on

ce d

aily.

Ifth

e ab

solu

te n

eutr

ophi

lco

unt w

as >

30 ×

10 (9

)/laf

ter 3

con

secu

tive

dose

s,th

e do

se w

as c

hang

ed to

2.5

µg/k

g da

ily o

n alt

erna

teda

ys. I

f tot

al w

hite

blo

odce

ll co

unt w

as

>70

×10

(9)/l

or t

heab

solu

te n

eutr

ophi

l cou

ntw

as >

45 ×

10 (9

)/l, G

-CSF

trea

tmen

t was

stop

ped

All p

atie

nts p

laced

on

daily

mul

tiple

-dos

e in

ject

ion

ofsh

ort-a

ctin

g in

sulin

Stat

istica

l met

hods

:M

ann–

Whi

tney

U-te

st, W

ilcox

onm

atch

ed p

airs,

signe

d ra

nks a

nd �

2

test

s. Sp

earm

an c

orre

latio

n an

alyse

s.M

eans

±SD

. Sign

ifica

nce

betw

een

stud

y gr

oups

Tim

e to

reso

lutio

n of

infe

ctio

n (d

ays)

:I1

: 22.

3 ±

1.7

I2: 2

3.6

±1.

8ns D

urat

ion

of h

ospi

talis

atio

n (d

ays)

I1: 2

8.3

±2.

2I2

: 26.

9 ±

2.0

ns Nee

d fo

r sur

gical

inte

rven

tion

(am

puta

tion)

:I1

: 3 (2

0%)

I2: 2

(13.

3%)

ns Effe

ct o

n ne

utro

phils

(pos

t-tr

eatm

ent):

Neu

trop

hil c

ount

(mea

n ±

SD):

I1: 4

800

±30

0/m

m3

I2: 4

8700

±10

00/m

m3

p<

0.0

01

Phag

ocyt

osis

test

(%):

I1: 6

9.4

±1.

9I2

: 74.

5 ±

1.9

ns Resp

irato

ry b

urst

(mV)

:I1

: 2.3

±0.

4I2

: 2.3

±0.

5ns D

urat

ion

of p

aren

tera

l A/B

:

I1: 2

3.3

±1.

9I2

: 22.

9 ±

2.0

Adve

rse

even

ts: n

one

Not

stat

edAu

thor

s dra

w a

ttent

ion

to v

ery

limite

def

fect

ivene

ss o

f G-C

SF in

the

trea

tmen

t of d

iabet

icfo

ot in

fect

ion.

How

ever

,st

udy

lacks

pow

er

Writ

ten

info

rmed

cons

ent.

Loca

l eth

icsap

prov

al ob

tain

ed

High

whi

te b

lood

cel

lco

unts

may

pre

disp

ose

to c

oron

ary/

cere

brov

ascu

lar e

vent

s


193


Cos

t-ef

fect

iven

ess

data

ext

ract

ion

tabl

es

Stud

y id

entif

ier

and

Key

ele

men

ts o

f C

linic

al e

ffect

iven

ess

data

Econ

omic

ana

lysis

Resu

ltsC

omm

ents

obje

ctiv

eth

e st

udy

Apel

qvist

(199

6),12

2,12

6

Swed

en

Stud

y ob

ject

ive:

To c

ompa

re th

e cli

nica

lef

fect

and

eco

nom

ic co

stof

cad

exom

er io

dine

with

that

of s

tand

ard

trea

tmen

t in

diab

etic

patie

nts w

ith c

avity

foot

ulce

rs

Type

of e

cono

mic

evalu

atio

n:C

EASi

nce

no d

iffer

ence

sin

clin

ical r

esul

tsw

ere

obse

rved

, aco

st-m

inim

isatio

nan

alysis

was

perfo

rmed

Pers

pect

ive:

Hea

lth se

rvice

Setti

ng:

Lund

, Sw

eden

Dat

es to

whi

ch d

ata

relat

e:Th

e da

tes t

o w

hich

the

effe

ctive

ness

analy

sis a

ndre

sour

ce u

se d

ata

refe

rred

wer

e no

tre

port

ed. P

rice

year

was

199

3

Cur

renc

y: S

wed

ishKr

oner

(SEK

). A

conv

ersio

n to

UK

poun

ds w

aspe

rform

ed u

sing

a19

93 e

xcha

nge

rate

of £

1= S

EK12

.10.

A co

nver

sion

to U

Sdo

llars

was

perfo

rmed

usin

g a

1993

exc

hang

e ra

teof

US$

1= S

EK8.

10

Sour

ce:

Sing

le R

CT

Det

ails o

f par

ticip

ants

,in

terv

entio

ns, o

utco

mes

and

resu

lts o

f the

clin

ical t

rial a

resu

mm

arise

d ab

ove

(clin

ical

effe

ctive

ness

tabl

e)

Link

bet

wee

n cli

nica

l effe

ctive

ness

and

cost

dat

a:Th

e da

ta fo

r the

eco

nom

icev

aluat

ion

wer

e co

llect

ed d

urin

gth

e cli

nica

l tria

l

35 p

atie

nts w

ere

inclu

ded

in th

eec

onom

ic an

alysis

Mea

sure

of h

ealth

ben

efits

use

d:N

o su

mm

ary

bene

fit m

easu

re w

asus

ed, a

nd o

nly

sepa

rate

clin

ical

outc

omes

wer

e re

port

ed

Reso

urce

use

:Fr

eque

ncy

of d

ress

ing

chan

ges,

drug

pres

crip

tion,

mat

erial

con

sum

ptio

nan

d tim

e in

volve

d w

ere

reco

rded

.Ty

pe o

f dre

ssin

gs/d

rugs

, per

son

who

chan

ged

dres

sings

, tim

e in

volve

d, a

ndlo

catio

n of

dre

ssin

g ch

ange

wer

edo

cum

ente

d

Des

crip

tion

of c

osts

:D

irect

cos

ts w

ere

estim

ated

for

dres

sing

mat

erial

s, dr

ugs,

staf

f and

tran

spor

t. Th

e au

thor

s sta

ted

that

,sin

ce m

ost p

atie

nts i

n th

e st

udy

wer

eab

ove

wor

king

age

, no

indi

rect

cos

tsfo

r los

t pro

duct

ion

wer

e es

timat

ed.

Cos

ts a

nd q

uant

ities

wer

e re

port

edse

para

tely.

The

ope

ratin

g co

sts

(mat

erial

s and

dru

gs, s

taff

and

tran

spor

t) an

d co

st o

f com

plica

tions

wer

e m

easu

red.

The

est

imat

ion

ofqu

antit

ies a

nd u

nit c

osts

was

bas

ed o

nac

tual

data

apa

rt fr

om th

ose

for

tran

spor

t. Th

e av

erag

e va

lues

for

tran

spor

t for

the

patie

nt to

visi

t an

outp

atie

nt c

are

unit

or fo

r the

staf

f to

visit

the

patie

nt a

t hom

e w

ere

estim

ated

in te

rms o

f dist

ance

/pric

e at

10 k

m/S

EK24

.50.

If th

e pa

tient

or a

relat

ive li

ving

in th

e sa

me

hous

ehol

dpe

rform

ed th

e dr

essin

g ch

ange

, no

Estim

ated

hea

lth b

enef

its u

sed

in th

eec

onom

ic an

alysis

:N

ot a

pplic

able

Reso

urce

use

:M

ean

(ran

ge) d

ress

ing

chan

ges p

er w

eek,

and

adhe

renc

e:C

: 9.9

(3.1

–13.

9)Lo

wer

mea

n th

an e

xpec

ted

– pr

escr

ibed

once

or t

wice

dail

y:I:

4.7

(3.2

–6.9

)H

igher

mea

n th

an e

xpec

ted

– pr

escr

ibed

daily

dur

ing

wee

k 1

and

daily

or e

very

2or

3 d

ays t

here

afte

r

Num

ber (

%) d

ress

ing

chan

ges p

erfo

rmed

by:

Nur

seC

: 591

(30.

0%)

I: 21

0 (2

6.8%

)Au

xilia

ry n

urse

C: 1

,095

(55.

6%)

I: 35

0 (4

4.6%

)Pa

tient

or s

pous

eC

: 7 (0

.4%

)I:

113

(14.

4%)

Oth

erC

: 276

(14.

0%)

I: 11

2 (1

4.3%

)

Mea

n (r

ange

) min

utes

per

dre

ssin

gch

ange

:C

: 11

(5–2

3)I:

13 (8

–24)

Type

of d

ress

ing

(num

ber o

f pat

ient

str

eate

d C

/I):

Cad

exom

er io

dine

0/1

7G

enta

mici

n so

lutio

n 14

/0

Not

es a

bout

dup

licat

epu

blica

tion:

See

clini

cal e

ffect

ivene

ssta

ble

(pp.

134

–5)

Lim

itatio

ns o

f the

stud

y, as

note

d by

the

stud

y au

thor

s:1.

Pat

ient

s sho

uld

befo

llow

ed u

p un

til fi

nal

outc

ome

(com

plet

ehe

aling

or d

eath

).H

owev

er, i

t may

be

diffi

cult

to c

olle

ct a

ccur

ate

data

on

reso

urce

use

ifda

ta a

re c

olle

cted

ove

r alo

nger

per

iod

of ti

me

2. N

o tim

e co

sts w

ere

calcu

lated

for p

atie

nts o

rre

lative

s who

cha

nged

dres

sings

with

out h

elp

from

the

healt

hcar

esy

stem

3. P

atie

nts i

n a

clini

cal t

rial

may

be

mor

e clo

sely

mon

itore

d an

d tr

eatm

ent

patte

rns m

ay d

iffer

from

norm

al cli

nica

l pra

ctice

.M

ore

reso

urce

s may

ther

efor

e be

con

sum

edAd

here

nce

with

ther

apy

may

be lo

wer

in re

gular

pra

ctice

than

in a

trial

. In

the

futu

re,

it m

ay b

e ad

visab

le to

mak

ead

just

men

ts to

the

econ

omic

evalu

atio

n in

ord

er to

refle

ctcli

nica

l pra

ctice

cont

inue

d

Appendix 4

194

Stud

y id

entif

ier

and

Key

ele

men

ts o

f C

linic

al e

ffect

iven

ess

data

Econ

omic

ana

lysis

Resu

ltsC

omm

ents

obje

ctiv

eth

e st

udy

trav

ellin

g co

sts a

nd n

o lab

our c

osts

wer

e es

timat

ed. T

he so

urce

of

quan

titie

s was

the

stud

y re

cord

s. Th

eda

tes d

urin

g w

hich

the

quan

titie

sw

ere

mea

sure

d w

ere

not r

epor

ted

Info

rmat

ion

on p

rices

for d

rugs

and

mat

erial

s was

obt

ained

from

FAS

S(1

995)

: Läk

emed

el i

Sver

ige.

Stoc

khol

m, S

wed

en(L

äkem

edel

sinfo

rmat

ion

AB, 1

995)

and

curr

ent m

arke

t pric

es. T

heav

erag

e w

ages

for n

ursin

g st

aff i

n19

91, w

ith n

on-w

age

labou

r cos

tsad

ded

(taxe

s, na

tiona

l ins

uran

ce),

wer

e ad

just

ed to

199

3 pr

ices.

Labo

urco

sts i

nclu

ded

the

time

requ

ired

topr

epar

e fo

r the

dre

ssin

g ch

ange

, to

redr

ess t

he w

ound

and

to ti

dy u

paf

ter t

he p

roce

dure

. If t

rave

lling

was

invo

lved,

an

extr

a 30

min

utes

was

adde

d to

the

trea

tmen

t tim

e.

The

cost

s of o

utpa

tient

visi

ts, w

hich

wer

e th

ough

t not

to d

iffer

infre

quen

cy b

etw

een

trea

tmen

top

tions

, wer

e ex

clude

d

Met

hods

use

d fo

r sta

tistic

al an

alysis

of

quan

titie

s and

cos

ts:

The

Man

n–W

hitn

ey U

-test

(tw

o-ta

iled)

was

use

d th

e co

mpa

re c

osts

betw

een

the

two

grou

ps

Assu

mpt

ions

use

d:1.

Wee

kly

reso

urce

cos

ts w

ill re

main

cons

tant

unt

il co

mpl

ete

heali

ng.

2. T

he h

ealin

g ra

te in

pat

ient

s in

grou

p I w

ill be

at l

east

as g

ood

as in

patie

nts i

n gr

oup

C u

ntil

com

plet

ehe

aling

occ

urs

Stre

ptod

orna

se/st

rept

okin

ase

2/0

Dry

salin

e ga

uze

9/1

Vase

line

gauz

e 6/

8

Mea

n (r

ange

) wee

ks o

f tre

atm

ent:

C: 1

1 (5

–12)

I: 10

(1–1

2)

Cos

t res

ults

:M

ean

(ran

ge) w

eekl

y st

aff (

SEK)

:C

: 884

(315

–149

2)I:

380

(96–

570)

p<

0.0

01

Mea

n (r

ange

) wee

kly

tran

spor

t cos

ts(S

EK):

C: 2

43 (7

6–34

1)I:

100

(29–

156)

p<

0.0

01

Mea

n (r

ange

) wee

kly

cost

for m

ater

ials

and

drug

s SEK

:C

: 294

(37–

981)

I: 42

3 (1

66–1

113)

ns Mea

n (r

ange

) tot

al w

eekl

y (S

EK):

C: 1

421

(428

–267

9)I:

903

(524

–169

7)p

< 0

.01

Synt

hesis

of c

osts

and

ben

efits

Wee

kly

cost

per

pat

ient

hea

led:

C: S

EK12

,790

I: S

EK30

70ns Se

nsiti

vity

analy

ses:

1. T

he re

sults

wer

e se

nsiti

ve to

the

assu

mpt

ions

abo

ut tr

avel

ling

dist

ance

and

time.

If a

trav

ellin

g di

stan

ce o

f 5in

stea

d of

10

km w

as a

ssum

ed, t

he

Stud

y sp

onso

rshi

p:Pe

rsto

rp P

harm

a, L

und,

Swed

en, a

nd th

e Sw

edish

Diab

etes

Ass

ociat

ion co

ntin

ued


195


Stud

y id

entif

ier

and

Key

ele

men

ts o

f C

linic

al e

ffect

iven

ess

data

Econ

omic

ana

lysis

Resu

ltsC

omm

ents

obje

ctiv

eth

e st

udy

Met

hods

use

d fo

r sen

sitivi

ty a

nalys

es:

The

para

met

ers u

sed

wer

e tr

ansp

ort

cost

s, ty

pe o

f sta

ff pe

rform

ing

the

dres

sing,

the

abilit

y of

pat

ient

s to

chan

ge th

eir u

lcer d

ress

ings

with

out

help

from

the

healt

h ca

re st

aff a

ndst

rict a

dher

ence

with

phy

sician

s'pr

escr

iptio

ns. A

lso, o

ne (o

rigin

ally

exclu

ded)

hos

pita

lisat

ion

was

inclu

ded

in th

e an

alysis

and

the

corr

espo

ndin

gre

sults

wer

e co

mpa

red

Synt

hesis

of c

osts

and

ben

efits

:Al

thou

gh a

synt

hesis

of c

osts

and

bene

fits w

as n

ot re

quire

d du

e to

the

inte

rven

tion

bein

g a

dom

inan

tst

rate

gy, t

he w

eekl

y co

st p

er p

atie

nthe

aled

was

calc

ulat

ed

estim

ated

tim

e fo

r tra

vellin

g w

asas

sum

ed to

be

redu

ced

by 1

5m

inut

es,

resu

lting

in a

redu

ctio

n of

the

tota

lw

eekl

y co

st o

f 20%

for p

atie

nts

trea

ted

with

cad

exom

er io

dine

and

31%

for p

atie

nts t

reat

ed w

ith th

eco

ntro

l reg

imen

. Tra

vellin

g co

sts w

ould

be 5

0% lo

wer

in b

oth

grou

ps, w

here

asst

aff c

osts

wou

ld b

e 35

and

36%

low

er,

resp

ectiv

ely.

2. If

pat

ient

s or r

elat

ives l

iving

in th

e sa

me

hous

ehol

d co

uld

perfo

rm 5

0% o

f the

dres

sing

chan

ges,

tota

l wee

kly

cost

sw

ould

dec

reas

e by

27%

in I

and

by40

% in

C.

3. S

taff

cate

gory

: the

redu

ctio

n in

tota

lw

eekl

y co

sts i

f all

dres

sing

chan

ges

wer

e pe

rform

ed b

y au

xilia

ry n

urse

sco

mpa

red

with

if n

urse

s per

form

all

the

chan

ges i

s 7%

for I

pat

ient

s and

9%

for

C p

atie

nts.

4. A

dher

ence

: if p

atie

nts w

ere

trea

ted

exac

tly a

ccor

ding

to p

resc

riptio

n, th

eto

tal w

eekl

y co

st w

ould

be

SEK8

36 fo

rpa

tient

s tre

ated

with

cad

exom

er io

dine

and

SEK1

914

for p

atie

nts t

reat

ed w

ithth

e co

ntro

l reg

imen

(ass

umin

g th

at st

aff

prop

ortio

n an

d av

erag

e tr

eatm

ent t

ime

wer

e th

e sa

me

as in

this

stud

y).

5. R

esul

ts w

ere

also

sens

itive

to a

pos

sible

adve

rse

reac

tion

resu

lting

inho

spita

lisat

ion.

Bas

ed o

n da

ta fr

om o

nepa

tient

who

was

hos

pita

lised

due

tofe

ver,

the

tota

l cos

ts w

ere

estim

ated

as

SEK9

916

for g

roup

I an

d SE

K891

0 fo

rgr

oup

C, a

nd w

eekl

y co

sts w

ere

estim

ated

as S

EK 1

040

for g

roup

I an

dSE

K903

for g

roup

C

CEA

, cos

t-effe

ctive

ness

ana

lysis.

Appendix 4

196

Stud

y id

entif

ier

and

Key

ele

men

ts o

f C

linic

al e

ffect

iven

ess

data

Econ

omic

ana

lysis

Resu

ltsC

omm

ents

obje

ctiv

eth

e st

udy

McK

inno

n (1

997)

,113

USA

To c

ompa

re th

e co

st-

effe

ctive

ness

of A

/S

(I1 g

roup

) ver

sus

I/C

(I2 g

roup

) in

the

trea

tmen

t of d

iabet

icfo

ot in

fect

ions

. See

Gra

yson

et a

l.(1

994)

44

for e

ffect

ivene

ss d

ata

extr

actio

n

Pers

on in

vest

igatin

g w

asun

awar

e w

hich

regim

enw

as u

sed

for e

ach

patie

nt

Type

of e

cono

mic

evalu

atio

n: C

EA

Pers

pect

ive:

Inst

itutio

n (h

ospi

tal)

Setti

ngs o

f clin

ical

effe

ctive

ness

stud

yan

d ec

onom

icev

aluat

ion:

Dea

cone

ss H

ospi

tal

Podi

atry

Ser

vices

,Bo

ston

, MA,

USA

Clin

ical t

rial w

asov

er 1

year

; 199

4pr

ices (

US

$) u

sed.

No

spec

ific

date

s,bu

t eco

nom

icev

aluat

ion

star

ted

on d

ay st

udy-

drug

trea

tmen

t ini

tiate

dan

d ce

ased

whe

nan

tibio

ticad

min

istra

tion

stop

ped

(unl

ess

trea

tmen

t not

succ

essfu

l, in

whi

chca

se su

bseq

uent

cost

s wer

eca

lculat

ed)

Sour

ce:

Sing

le st

udy

(dou

ble-

blin

d, R

CT)

.

Det

ails o

f par

ticip

ants

,in

terv

entio

ns a

nd re

sults

of

clini

cal e

ffect

ivene

ss g

iven

inG

rays

on e

t al.

(199

4).44

Econ

omic

data

ava

ilabl

e fo

r 90/

93 o

f the

origi

nal s

ampl

e. (I

1, n

= 4

5, I2

, n

= 4

5)

Econ

omica

lly si

gnifi

cant

adv

erse

even

ts(i.

e. re

quiri

ng tr

eatm

ent a

ndre

latin

g to

stud

y dr

ug o

r of

unkn

own

origi

n)

I1: 7

(16%

)I2

: 9 (2

0%)

Due

to:

Diar

rhoe

a: I1

: 1 I2

: 4Se

izure

: I1:

0 I2

: 1O

ther

a : I1:

6 I2

: 4a

Rash

, nau

sea/

vom

iting

or f

unga

lsu

perin

fect

ion

Mea

sure

of h

ealth

ben

efits

use

d:

No

clini

cally

sign

ifica

nt d

iffer

ence

sw

ere

foun

d be

twee

n th

e tw

otr

eatm

ent r

egim

ens,

ther

efor

eec

onom

ic an

alysis

com

pare

d co

sts

only

Cos

ting

unde

rtak

en re

tros

pect

ively

Des

crip

tion

of c

osts

:

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199

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197


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199


Appendix 5

Quality assessment

Quality assessment of diagnostic studies

Study

Item Gardner Bill Ratliff and et al. (2001)90 et al. (2001)91 Rodeheaver (2002)92

1. Was the spectrum of patients representative of the No Yes Yespatients who will receive the test in practice?

2. Were selection criteria clearly described? Yes Yes Yes

3. Is the reference standard likely to classify the target Unclear Unclear Unclearcondition correctly?

4. Is the time period between reference standard and Yes for 3 out of Yes Unclearindex test short enough to be reasonably sure that 4 study centres the target condition did not change between the that participated two tests? in the evaluation

5. Did the whole sample or a random selection of Yes Yes Yesthe sample receive verification using a reference standard of diagnosis?

6. Did patients receive the same reference standard Yes Yes Yesregardless of the index test result?

7. Was the reference standard independent of the Yes Yes Yesindex test (i.e. the index test did not form part of the reference standard)?

8a. Was the execution of the index test described in Yes Yes Yessufficient detail to permit replication of the test?

8b. Was the execution of the reference standard Yes Yes Yesdescribed in sufficient detail to permit its replication?

9a. Were the index test results interpreted without Unclear Unclear Unclearknowledge of the results of the reference standard?

9b. Were the reference standard results interpreted Unclear Unclear Unclearwithout knowledge of the results of the index test?

10. Were the same clinical data available when test Unclear Unclear Unclearresults were interpreted as would be available when the test is used in practice?

11. Were uninterpretable/intermediate test results Noa Noa Noa

reported?

12. Were withdrawals from the study explained? Noa Noa Noa

a No, not applicable as there did not appear to be any uninterpretable results or withdrawals.

Appendix 5

200

Quality assessment for RCTs and CCTs

Study Score for Score for double Score for Score for randomisationa blindingb reporting of allocation

withdrawalsc concealmentd

Apelqvist (1996)122 2 0 0 C

Bouter (1996)106 2 0 1 C

Bradsher (1984)43 2 0 1 B

Chantelau (1996)74 2 1 0 B

de Lalla (2001)119 1 0 1 B

Dwivedi (2000)127 1 0 0 B

Erstad (1997)107 1 1 1 B

Gough (1997)100 2 2 1 A

Grayson (1994)44 2 1 1 B

Kastenbauer (2003)118 1 0 1 B

Lipsky A114 1 2 1 B

Lipsky B114 1 2 1 B

Lipsky (2004)109 1 0 0 B

Lipsky (1990)75 1 0 1 B

Marchina (1997)123 1 0 NA B

Markevich (2000)105 1 0 0 B

Peterson (1989)101 2 1 1 A

Rhaiem (1998) 124 1 0 0 B

Seidel (1991)110 (CCT)e

NA Patients chose therapy. 0 CBaseline comparability: unclear.Adjustments: none

Seidel (1993,1994)111, 112 NA Patients chose therapy. 0 C(CCT)e Baseline comparability:

unclear.

Adjustments: none

Tan (1993)108 2 1 1 B

Vandeputte (1996)125 2 0 1 B

Yonem (2001)120 1 0 0 B

NA, not applicablea Randomisation. score: 0 or 1 or 2. One point was given if the study described using words such as random or

randomisation. One extra point was given if the method of randomisation was described and was appropriate. One pointwas deducted if the method of randomisation was described and was considered to be inappropriate.

b Double-blinding. score: 0 or 1 or 2. One point was given if the study was described as double-blind. One extra point wasgiven if the method of double-blinding was described and was appropriate. One point was taken away if the method ofdouble-blinding was described and was inappropriate.

c Withdrawals. score: 0 or 1. One point was given if the number and reasons for withdrawals in each group were stated.d Allocation concealment. score: A or B or C. A, Adequate: if adequate measures were taken to conceal allocation. B, Unclear:

if report of allocation concealment was not reported or did not fit in category A or C. C, Inadequate: trials in whichallocation concealment was inadequate.

e The critical appraisal of CCTs included the points above, with the exception of the first (randomisation). In CCTs thefollowing additional items were assessed: method of allocation to treatment groups; degree of baseline comparabilitybetween treatment groups; and appropriateness of adjustment during data analysis for observed imbalances betweentreatment groups.


201


Quality assessment of economic evaluations

Study

Criterion Apelqvist et al. McKinnon et al. (1996)122 (1997)113

1. Was a well-defined question posed in answerable form?� Study examined both costs and effects? Y Y� Study involved a comparison of alternatives? Y Y� Viewpoint for analysis stated? Y Y

2. Was a comprehensive description of the competing alternatives given?� Any important alternative omitted? N Unclear� Was a ‘do nothing’ alternative considered? N NA

3. Was the effectiveness of the programmes or services established?� Was it via an RCT? If so did the protocol reflect real practice? Y Y� Was it via an overview of clinical studies? N N� Were observational data or assumptions used to establish effectiveness. N N

If so what are the potential biases?

4. Were all the important and relevant costs and consequences for each alternative identified?� Was the range wide enough for the research question? Y Y� Did it cover all relevant viewpoints? Y Y� Were capital and operating costs included? N N

5. Were costs and consequences measured accurately in appropriate physical units?� Were any items omitted from the measurement? If so, does this mean N N

they carried no weight in the subsequent analysis?� Were there any circumstances that made measurement difficult? If so, N N

were these handled appropriately?

6. Were costs and consequences valued credibly?� Were the sources of values clearly identified? Y Y� Were market values employed for changes involving resources Y Y

gained or depleted?� Where market values were absent, or market values did not reflect Y NA

actual values, were adjustments made?� Was the valuation of consequences appropriate for the question? Y Y

7. Were costs and consequences adjusted for differential timing?� Were costs and consequences that occur in the future discounted? N NA� Was any justification of the discount rate used given? N

8. Was an incremental analysis of costs and consequences of alternatives performed?� Were the incremental costs generated by one alternative over another Y NA

compared with the additional benefits?

9. Was allowance made for uncertainty in the estimates of costs and consequences?� If data on costs or consequences were stochastic, were appropriate Y Y

statistical analyses performed?� If a sensitivity analysis was employed, was justification provided for N N

the range of values?� Were study results sensitive to changes in values? Y Y

10. Did the presentation and discussion of study results include all issues of concern to users?� Were the conclusions of the analysis based on an overall index or ratio N NA

of costs to consequences? If so, was the index interpreted intelligently?� Were the results compared with those of others who have studied the N N

same question?� Did the study discuss the generalisability of the results? N Y� Did the study take account of other important factors in the choice Y N

or decision, e.g. ethics?� Did the study discuss issues of implementation, such as feasibility of N N

the preferred programme?


203


Appendix 6

Summary of excluded studies

Summary of excluded diagnostic studiesa

Study Description Reason for exclusion

Basak (1992)177 Evaluation of microbiology of burns, traumatic wounds No DFUs or venous leg ulcers in the sampleand pressures sores using wound swab and tissue biopsy

Bessman (1992)178 Comparison of prevalence of diphtheroids in reliable Unclear how many patients had ulceration; (derived from deep tissue intra-operatively) and 2 × 2 diagnostic data not reportednon-reliable cultures (specimen taken at bedside) in patients with diabetic foot infection

Buntinx (1996)179 Assessment of several different types of wound Assessment of inter-observer variation, not classification systems, including one for assessing diagnostic performanceclinical signs of infection, in wounds of various aetiologies including venous leg ulcers

Cooper (1995)180 Assessment of the association between clinical Swabs were processed exclusively for the signs of infection and the presence of Lancefield detection of streptococci, and the presence group G streptococci detected by wound swab in of other pathogens could not be excluded. venous leg ulcers There was therefore no diagnostic

verification for the presence of woundinfection

Crerand (1996)181 Description of various investigations done in a series Focus of study was diagnosis of of patients with clinically infected DFUs osteomyelitis rather than wound infection;

no diagnostic verification

Cutting (1994)93 Description of criteria for identifying wound infection Description of clinical signs and symptoms,not an evaluation

Davies (2001)38 Description of molecular techniques in analysing the Description of molecular techniques, not an microflora of chronic wounds evaluation

Edwards (2000)182 Comparison of different methods of swabbing in acute Unable to ascertain whether the sample or chronic wounds included people with DFUs or venous leg

ulcers; no outcome data available

Greenwood Pilot study of electronic aroma detection to determine No diagnostic verification(1997)183 changes in aroma of venous leg ulcers

Huovinen (1992)184 Letter to the editor reporting an evaluation of fine 2 × 2 diagnostic data not availableneedle aspiration biopsy, curettage and swab used to detect infection in leg ulcers

Johnson (1995)37 Use of needle aspiration and swab to detect anaerobic 2 × 2 diagnostic data not availablebacteria in DFUs

Kessler (2002)185 Evaluation of adverse effects and microbiological 2 × 2 diagnostic data not availableidentification of thin needle puncture compared with superficial swab for DFUs

Lee (1985)186 Evaluation of fine-needle aspiration biopsy and 2 × 2 diagnostic data not availablewound swab in patients with wounds of various aetiologies, including DFUs and venous leg ulcers

Levine (1976)187 Evaluation of swab and smear versus flamed tissue Sample did not include people with DFU or biopsy in patients with burns venous leg ulcers; 2 × 2 diagnostic data not

reported

continued

Appendix 6

204


Lorentzen (1999)188 Evaluation of the Red–Yellow–Black wound classification Assessment of inter-observer variation, not system used with various types of chronic wounds diagnostic performance

Neil (1997)189 Comparison of swab culture and tissue culture used to Wound aetiologies unclear; no diagnostic detect bacterial counts and identification in chronic verification of wound infectionwounds

Pellizzer (2001)33 Comparison of wound swab and deep tissue biopsy No diagnostic verificationin DFUs

Sapico Evaluation of deep-tissue microbiology in people with Some patients did not have foot ulceration; (1980, 1984)190,191 diabetic foot infection using different sampling no diagnostic verification for detection of

techniques (ulcer swab pre- and post-amputation, wound infectioncurettage and needle aspiration)

Schneider (1983)192 Comparison of two methods of tissue sampling (single 2 × 2 diagnostic data not availabletissue sample divided into 4 specimens versus tissue samples taken from 4 separate areas of the wound) in pressure sores and infected surgical wounds

Sharp (1979)193 Comparison of cultures taken at the bedside with 2 × 2 diagnostic data not availablethose obtained via surgical dissection at the infection site in patients undergoing a surgical procedure for infected DFUs

a A number of other studies focusing on the prevalence and sensitivities of microorganisms, and the diagnosis ofosteomyelitis, were identified through the diagnostic search strategy, but have not been listed here.


205


Summary of excluded effectiveness studies


Acevedo (1990)194 Antibiotics infused into limb with tourniquet vs Failed to meet study design inclusion criteriaconventional systemic antibiotics

Akova (1996)195 Prospective follow-up of patients treated with No comparison of interventionsparenteral S/A

Anon (1992)196 Guidelines for diabetic foot care No comparison of interventions

Anon (1996)197 Guidelines for diabetic foot care No comparison of interventions

Apelqvist (1989)198 Wound classification No comparison of interventions

Armstrong (1997)199 Risk factors associated with puncture wounds in No comparison of interventionsdiabetics vs non-diabetics

Armstrong (1997)200 Retrospective case survey of seasonal variation in No comparison of interventionslower extremity amputation

Beam (1989)201 CCT of oral vs intravenous ciprofloxacin Not DFU patients

Bendy (1965)202 RCT of standard therapy vs standard therapy plus Not DFU patientstopical gentamicin cream

Bonham ( 2001)203 Systematic review of antibiotic treatment for Focus on osteomyelitisosteomyelitis

Bose (1979)204 Case series study of surgical approach to treatment Failed to meet study design inclusioncriteria. No data by ulcer group

Bowering (2001)205 Non systematic overview of DFU aetiology, Failed to meet study design inclusion criteriaassessment and treatments

Boxer (1969)206 RCT of collagenase vs placebo in patients with venous, Not DFU patientsarterial or pressure ulcers

Brill (2000)207 CCT of HBO2 vs standard care No antimicrobial intervention

Brunner (1999)208 Overview of microbiology and antimicrobial Failed to meet study design inclusion criteriatreatments for diabetic foot infection

Calhoun (1988)209 Retrospective evaluation of Wagner classification No comparison of interventionsprotocol

Cappelli (1969)210 Uncontrolled study (Italian) Failed to meet study design inclusioncriteria. Not DFU patients

Chapuis (1964)211 Uncontrolled study (French) Failed to meet study design inclusion criteria

Close-Tweedie Povidone-iodine in podiatric wounds Failed to meet study design/intervention (2001)212 inclusion criteria

Collier (1997)213 Correspondence regarding compression and venous Failed to meet study design/intervention leg ulcers inclusion criteria

Combe (1999)214 Non-systematic overview of assessment and Failed to meet study design criteriatreatment of diabetic feet

Cunha (2000)215 Non-systematic overview of diabetic foot infection Failed to meet study design criteria

Danziger (1988)216 RCT of imipenem vs gentamicin/clindamycin Insufficient number of DFU patients anddata on foot ulcer patients not presentedseparately

Davies (1982)217 RCT of augmentin vs co-trimoxazole No data presented for infected DFUs

Degreef (1998)218 Non-systematic overview Failed to meet study design inclusioncriteria. Not specific to DFUs

Dereume (1985)219 Survey of yeast culture from leg ulcers and risk factors Failed to meet study design/intervention for yeast infection inclusion criteria

continued

Appendix 6

206


Dillon (1990)220 Case series study of local antibiotic injections and Failed to meet study design inclusion criteriaend-diastolic compression boot

Dominguez (1989)221RCT of intravenous/oral ciprofloxacin vs intravenous No data for DFUsceftazidime

Donaghue (1998)222 RCT of collagen–alginate dressing vs saline gauze Failed to meet intervention inclusion criteria

Draszkiewicz Report on diabetic foot care Failed to meet study design inclusion criteria(1992)223

Edmonds (2001)224 Pathophysiology of the diabetic foot Failed to meet study design inclusioncriteria. No comparison of interventions

Edmonds (2000)225 Non-systematic overview of novel treatments for DFUs Failed to meet study design inclusion criteria

Faglia (1996)226 RCT of hyperbaric oxygen therapy vs standard Failed to meet intervention inclusion criteria treatment as not an antimicrobial intervention

Fass (1989)227 RCT of intravenous/oral ciprofloxacin vs ceftadime Insufficient number of DFU patients anddata on foot ulcer patients not presentedseparately

Fejfarova (2002)228 Microbiological resistance as risk factor for amputation Failed to meet study design/interventioninclusion criteria

Fernandez CCT of antimicrobial interventions in diabetic amputees Not DFU patientsMontequin (1991)229

File (1983)230 RCT of amdinocillin plus cefoxitin vs cefoxitin Insufficient numbers of diabetic patients.Unclear as to how many patients had footulcers

File (1991)231 Non-systematic overview of T/C therapy Failed to meet study design inclusion criteria

File (1991)232 Overview of treatments for bacterial skin/soft tissue Failed to meet study design/intervention infections inclusion criteria

File (1994)233 Overview of trials of piperacillin/tazobactam Failed to meet study design inclusion criteria

Foster (2001)234 Overview of diabetic foot management Failed to meet study design inclusioncriteria. No comparison of interventions

Foster (2001)235 Overview of diabetic foot management Failed to meet study design inclusioncriteria. No comparison of interventions

Frykberg (2000)79 Clinical guidelines No comparison of interventions

Fuentes Sermeño Evaluation of oral levofloxacin vs ciprofloxacin Not DFU patients(2001)236

Gentry (1989)237 RCT of oral ciprofloxacin vs parenteral cefotaxime Not clear whether DFU patients

Gentry (1991)238 RCT of ofloxacin vs parenteral therapy for osteomyelitis Not DFU patients

Gentry (1992)239 Overview of lactam and quinolone agents for skin/skin Failed to meet study design inclusion criteriastructure infections

Gentry (1993)240 Diagnosis and management of DFU No comparison of interventions

Gentry (1989)241 RCT of oral ofloxacin vs intravenous cefotaxime Not clear whether DFU patients

Goldenheim Correspondence Failed to meet study design inclusion criteria(1995)242

Gomez (1992)243 Risk factors for diabetic foot infection Failed to meet study design/interventioninclusion criteria

Gomis (1990)244 Uncontrolled case series study of antimicrobial therapy Failed to meet study design inclusion criteria

Grayson (1995)245 Non-systematic overview of diabetic foot infection and Failed to meet study design inclusion criteriaantimicrobial treatment

Hanft (2002)246 RCT of Dermagraft vs standard care Failed to meet intervention inclusion criteria

continued


207



Hart (1996)247 Non-systematic overview of �-lactamase inhibitors Failed to meet study design inclusion criteria

Hartemann-Heurtier Non-systematic review of antibiotics used with diabetic Failed to meet study design inclusion criteria(2000)248 foot patients

Helaly (1988)249 RCT/CCT of enzyme applications Failed to meet intervention inclusioncriteria. Unclear whether DFU patients

Henyk (1999)250 CCT of sea buckthorn ointment Failed to meet intervention inclusion criteria

Hodges (1986)251 Non-systematic overview of diabetic foot management Failed to meet study design inclusion criteria

Hughes (1987)45 RCT of cefoxitin vs ceftizoxime Not all patients diabetic and not clear howmany had a foot ulcer

Huizinga (1986)252 RCT/CCT of antibiotic prophylaxis Insufficient number of diabetic patients anddata on DFU patients not presentedseparately

Ignacio (1984)253 Uncontrolled case series study of hyberbaric Failed to meet study design/intervention oxygen therapy inclusion criteria

Jamil (2001)254,255 Uncontrolled case series on management of diabetic Failed to meet study design/intervention foot infections inclusion criteria

Jensen (1998)256 RCT of moist wound dressing protocols Failed to meet intervention inclusion criteriaas not an antimicrobial intervention. Infectedulcer patients excluded

Johnson (1985)257 Evaluation of ticarcillin plus clavulanic acid No comparison of interventions. Noseparate data for DFU patients

Joseph (1990)258 Non-systematic overview of diabetic foot infection Failed to meet study design criteria

Joseph (1987)259 Non systematic overview of physiopathology in the Failed to meet study design criteriadiabetic foot

Joseph (1987)260 Puncture wound infections Failed to meet patient inclusion criteria

Kacy (1982)261 Uncontrolled case series of amputation in Failed to meet study design/intervention diabetic/non-diabetic patients inclusion criteria

Kaltenthaler (1998)98 Systematic review of antimicrobial agents for DFU Used for reference purposes only

Karchmer (1999)262 Overview of fluroquinolones Failed to meet study design/interventioninclusion criteria

Karsegard (1995)263 Non-systematic overview of antibiotic therapy for Failed to meet study design inclusion criteriadiabetic foot infection

Kaufman (1994)264 Non-systematic review on prevention of DFUs Failed to meet study design inclusion criteria

Kerstein (1997)265 Retrospective case review of toe amputation in Failed to meet study design inclusion criteriadiabetic patients

Klepser (1997)266 RCT of piperacillin/tazobactam vs ticarcillin/clavulanate Not DFU patientsvs ampicillin/sulbactam

Koveker (2000)267 Review of growth factors in wound repair Failed to meet study design/interventioninclusion criteria

Krikava (1999)268 Survey of isolates and sensitivity to antibiotics in Not clear whether DFU patientsdiabetic feet

Laing (1994)269 Non systematic overview of DFU management Failed to meet study design inclusion criteria

Larsson (1995)270 Review of amputation rates, costs and prevention Failed to meet study inclusion/interventioninclusion criteria

Lee (1997)271 Case series study of diabetic foot patients receiving Failed to meet study inclusion/intervention hyperbaric oxygen therapy inclusion criteria

LeFrock (1983)272 Evaluation of cefoxitin in diabetic patients with Failed to meet study design criteria: as no lower extremity infections control/comparison group

continued

Appendix 6

208


Lentino (1991)273 Evaluation of oral and intravenous ofloxacin Not clear whether DFU patients

Lipsky (1997)46 RCT of intravenous ofloxacin followed by oral ofloxacin Insufficient number of DFU patients and vs intravenous ampicillin/sulbactam followed by oral data on foot ulcer patients not presented amoxicillin/clavulanate separately

Loffler (1986)274 RCT of sulbactam plus ampicillin vs cefotaxime Insufficient number of DFU patients anddata on foot ulcer patients not presentedseparately

Madsen RCT comparing oral and intravenous penicillin vs Insufficient number of diabetic patients and (1996,1998)275,276 no treatment data on foot ulcer patients not presented

separately

Mason (1999)99,277 Systematic review addressing different methods of For reference purposes onlytreating DFU

Mayer (1993)278 Non-systematic review of povidone-iodine wound Failed to meet study design inclusion criteriahealing products

Mizel (1989) 279 Non-systematic overview of diabetic foot infection Failed to meet study design inclusion criteria

Motarjeme (1993)280 Retrospective study of thrombolysoangioplasty as an Not clear whether DPU patientsalternative to amputation

Murphy (1981)281 Non-systematic overview of diabetic foot infections Failed to meet study design inclusion criteria

Nichols (1997)282 RCT of levofloxacin vs ciprofloxacin Unable to identify data for DFU patients

Ohsawa (2001)283 Case series study of amputation outcomes in Failed to meet study design inclusion diabetic foot patients criteria. No comparison of interventions.

Parish (1993) 284 RCT of fleroxacin vs. ceftazidime Not clear whether DFU patients

Parish (1984) 285 CCT of augmentin vs cefaclor No data on DFU infections

Parish (1984) 285 RCT of ceftizoxime vs cefamandole Not DFU patients

Parish (1987)286 RCT of cefuroxime axetil vs cefaclor Insufficient number of DFU patients anddata on foot ulcer patients not presentedseparately

Partsch (1993)287 RCT of intravenous pressure infusions containing No comparison of antimicrobial radioactive tracers interventions

Pepe (1999)288 RCT of ASA, Ginko Biloba extract, arginine plus No comparison of antimicrobial magnesium vs ASA plus conventional interventionshaemorrheology

Perez-Ruvalcaba RCT of ciprofloxacin vs cefotaxime No data for DFU patients(1987)289

Peters (2001)290 RCT of electrical stimulation vs placebo No comparison of antimicrobialinterventions

Pien (1983)291 CCT of two dosage regimens of Cefaclor and No data for DFU patientsamoxicillin/clavulanic acid

Pinzur (1993)292 Non-systematic overview of amputation level selection Failed to meet study design inclusion in the diabetic foot patient criteria. No comparison of antimicrobial

interventions

Pinzur (1999)293 Summary of guidelines for diabetic foot care Failed to meet study design/interventioninclusion criteria

Pitkin (1995)294 Comparison of meropenem with other agents in Failed to meet study design inclusion skin/soft tissue infections criteria. No data by wound type

Powers (1993)295 RCT of oral fleroxacin vs A/C No data on DFU patients

Real (2001)296 Prospective cohort study of risk factors for Failed to meet study design inclusion hospitalisation criteria. No comparison of interventions

continued


209



Rice (2001)297 RCT of biofeedback-assisted relaxation vs relaxation No comparison of antimicrobialinterventions

Rittenhouse CCT of zinc–saline wet dressings vs normal saline wet No comparison of antimicrobial (1996)298 dressings interventions

Saltzman (1999)299 Non-systematic review of diabetic foot infection Failed to meet study design inclusion criteria

Sauerwein (1994)300 Commentary on antibiotic treatments relating to DFUs Failed to meet study design inclusion criteria

Schwegler (2002)301 Overview of diabetic foot management Failed to meet study design inclusion criteria

Seewald (1999)302 Non-systematic overview of microbiological aspects Failed to meet study design inclusion criteriaof the diabetic foot

Segev (1990)303 RCT of pefloxacin vs ceftazidime Insufficient number of patients with diabetesand not clear how many had an ulcer

Self (1987)304 RCT of ciprofloxacin vs cefotaxime No data on DFU patients

Senneville (2002)305 Case series study of rifampicin and fluoroquinolone Failed to meet study design inclusion criteria

Sesin (1990)306 Case series study of oral clindamycin and ciprofloxacin Failed to meet study design inclusion criteria

Siami RCT of clinafloxacin vs piperacillin/tazobactam Not DFU patients(2001, 2002)307,308

Sibbald (2001)309 Case series study of ionised nanocrystalline silver Failed to meet study design inclusion criteriadressing in chronic wound care

Siebert (1985)310 RCT of ticarcillin plus clavulanic acid vs moxalactam Not clear whether DFU patients

Smith (1996)311 Overview of soft tissue and diabetic foot infections Failed to meet study design inclusion criteria

Smith (2001)312 Protocol description on debridement of DFUs Failed to meet study design/interventioninclusion criteria

Steed (1992)313 RCT of topical CT-102 activated platelet supernatant Failed to meet intervention inclusion criteria vs placebo as not an antimicrobial intervention

Storm (1994)314 Correspondence regarding analysis of tissue Failed to meet study design inclusion concentration of cefuroxime criteria. Not clear whether all patients had

ulcers

Stromberg (1986)315 RCT of sulbactam and ampicillin vs clindamycin and Not clear whether diabetic foot ulcer tobramycin patients

Sussman (1992)316 Non-systematic review of diabetic foot problems Failed to meet study design inclusion criteria

Tammelin (1998)317 Case series study of flora, antimicrobial resistance Failed to meet study design inclusion criteriaand treatment

Tan (1985)318 Comparison of timentin vs moxalactam Insufficient number of DFU patients anddata on foot ulcer patients not presentedseparatelyNo outcome data

Tan (1996)319 Retrospective case review of intravenous antibiotics Failed to meet study design inclusion criteriavs surgery plus intravenous antibiotics

Tannenbaum Case series study of venous bypass grafting Failed to meet study design/intervention (1992)320 inclusion criteria

Tassler (1993)321 RCT of oral fleroxacin vs A/C Not clear whether DFU patients

Tassler (1993)322 Non-comparative study of piperacillin/tazobactam Failed to meet study design inclusion criteria

Temple (2000)323 Semi-systematic review of antibiotic treatments for Failed to meet study design inclusion criteriaDFUs

van de Meer Overview of antibiotic treatments for diabetic foot Failed to meet study design inclusion criteria(1996)324 infection

continued

Appendix 6

210


Vanscheidt (2002)325 RCT of Butcher’s broom extract vs placebo Failed to meet intervention inclusion criteriaas not an antimicrobial intervention

Wheatley (2001)326 Audit protocol relating to diabetic foot ulcers Failed to meet study design/interventioninclusion criteria

Young (1995)327 Measurement of metatarsal pressure using plantar Failed to meet study design/intervention ultrasound inclusion criteria

Zlatkin (1987)328 Non-systematic overview of diabetic foot management Failed to meet study design inclusion criteria

Summary of excluded cost-effectiveness studies


Bentkover (1993)329 Cost-effectiveness analysis of thrombin induced platelet Focus is not management of infection in releasate versus saline solution to treat DFUs DFUs

Apelqvist Cost analysis of primary healing and healing with No synthesis of costs and benefits (1994,1995)131,137,138 amputation in DFUs (costs only)

Eckman (1995)15 Markov model used to estimate the cost-effectiveness Focus is management of osteomyelitis rather of different aspects of the diagnosis and treatment of than wound infectiondiabetic patients with foot infections and suspected osteomyelitis

Morrison (1995)330 Evaluation of the sensitivity, specificity, clinical utility Focus is diagnosis of osteomyelitis rather and cost-effectiveness of magnetic resonance imaging than wound infection; 56% of feet studied in the diagnosis of osteomyelitis of the foot in diabetics were not diabetic; magnetic resonance

imaging was not compared directly with areference standard


211


Appendix 7

Experts’ views on definition and management ofclinically infected diabetic foot ulcers

Appendix 7

212

A: s

econ

dary

B

: ter

tiar

y re

ferr

al

C: s

econ

dary

ref

erra

l D

: ter

tiar

y re

ferr

al

E: t

erti

ary

refe

rral

F:

ter

tiar

y re

ferr

al

refe

rral

cen

tre

cent

re in

Eng

land

cent

re in

Eng

land

cent

re, W

ales

cent

re, C

anad

ace

ntre

, Eng

land

(DG

H w

ith

(wor

ks c

lose

ly w

ith

a di

abet

es c

entr

e),

bone

infe

ctio

n te

am)

Engl

and

Que

stio

n↓

Podi

atri

stPo

diat

rist

Vas

cula

r su

rgeo

nN

urse

spe

cial

ist

Med

ical

doc

tor

Dia

beto

logi

st

cont

inue

d

A. D

iagn

osis

of i

nfec

tion

1. In

gen

eral

, wha

t se

t of

crite

ria w

ould

you

say

is us

ed t

o di

agno

secl

inic

ally

an

infe

cted

foot

ulc

er?

Swel

ling,

red

col

our,

smel

l and

pai

n

If th

ere

are

2 of

thes

e sig

ns t

hen

she

acts

on

them

; if

ther

e is

only

1 s

ign

she

take

s a

swab

Redn

ess,

pai

n,in

dura

tion,

disc

harg

e,he

at, s

wel

ling,

sm

ell.

Ifce

llulit

is le

ss t

han

2cm

from

the

ent

ry p

oint

of

infe

ctio

n, li

kely

to

be a

min

or in

fect

ion.

Ifex

tens

ive

cellu

litis,

like

lyto

be

mod

erat

e or

seve

re in

fect

ion

The

y of

ten

do a

n X

-ray

, or

bloo

dte

st/t

empe

ratu

re t

o se

eif

pyre

xial

Surr

ound

ing

cellu

litis,

pres

ence

of

unde

rmin

ing,

oed

ema,

failu

re t

o he

al w

hen

you

thou

ght

it sh

ould

(cha

nges

in p

lain

X-r

ayov

ertim

e, M

RI –

incr

easin

g tis

sue

oede

ma)

“We

don’

t us

e sw

abs

todi

agno

se in

fect

ion,

the

clin

ical

impr

essio

n is

the

diag

nosis

, sw

abs

simpl

yco

nfirm

the

org

anism

”

Pres

ence

of u

nder

min

ing,

exce

ssiv

e or

mal

odor

ous

exud

ate,

pai

n, p

us,

spre

adin

g ce

llulit

is,bl

eedi

ng w

ound

bed

,ce

llulit

is ar

ound

the

wou

nd, p

robe

to

bone

With

the

exc

eptio

n of

prob

e to

bon

e, fo

r al

l the

othe

rs 1

fact

or =

hig

hsu

spic

ion,

pre

senc

e of

2fa

ctor

s =

def

initi

ve

Pain

in a

pai

nles

s fo

ot (a

neur

opat

hic

foot

) Sw

ellin

g ab

ove

the

foot

Incr

ease

d ex

udat

e sin

cela

st w

eek,

Pr

obe

to b

one,

X-r

ayES

R>65

C

RP >

30

Diff

eren

ce in

4–5

degr

ees

as m

easu

red

byth

erm

omet

ry

Puru

lent

disc

harg

e,er

ythe

ma,

war

mth

,sw

ellin

g. A

lso m

ore

subt

le s

igns

– c

hang

e in

both

ulc

er b

ase

and

colo

ur; i

ncre

ase

inex

udat

e vo

lum

e

B. I

ncid

ence

of c

linic

ally

dia

gnos

ed in

fect

ion

2. O

ut o

f 10

cons

ecut

ive

outp

atie

nts

with

diab

etic

foot

ulc

ers,

how

man

y of

the

m w

illfu

lfil t

he s

et o

f crit

eria

you

outli

ned

in t

hepr

evio

us q

uest

ion?

3/10

> 5

/10

Rem

arks

the

y ar

e a

spec

ialis

t ce

ntre

1/10

out

-pat

ient

s

10/1

0 in

-pat

ient

s(in

fect

ion

is a

key

reas

onfo

r ad

miss

ion)

4 or

5/1

04

wou

ld g

et o

ral A

B1

wou

ld g

et IV

AB

(ifpe

rson

is ‘u

nwel

l, if

ulce

rca

n pr

obe

to b

one,

or

ther

e is

out

of c

ontr

oldi

abet

es, s

prea

ding

infe

ctio

n’)

5 or

6/1

0T

he lo

nger

the

ulc

er h

asbe

en t

here

the

mor

elik

ely

the

ulce

r is

infe

cted

; the

dee

per

the

ulce

r, th

e hi

gher

cha

nce

of in

fect

ion.

With

poo

rdi

abet

ic c

ontr

ol, t

here

islik

ely

to b

e in

fect

ion.

Also

, poo

r co

ntro

l is

asy

mpt

om o

f inf

ectio

n

4 or

5/1

0


213


A: s

econ

dary

B

: ter

tiar

y re

ferr

al

C: s

econ

dary

D

: ter

tiar

y re

ferr

al

E: t

erti

ary

refe

rral

F:

ter

tiar

y re

ferr

al

refe

rral

cen

tre

cent

re in

Eng

land

re

ferr

al c

entr

e ce

ntre

, Wal

esce

ntre

, Can

ada

cent

re, E

ngla

nd(D

GH

wit

h (w

orks

clo

sely

wit

h a

in E

ngla

nddi

abet

es c

entr

e),

bone

infe

ctio

n te

am)

Engl

and

Que

stio

n↓

Podi

atri

stPo

diat

rist

Vas

cula

r su

rgeo

nN

urse

spe

cial

ist

Med

ical

doc

tor

Dia

beto

logi

st

cont

inue

d

C. A

lter

nati

ve c

ours

es o

f act

ion

3. O

ut o

f 10

cons

ecut

ive

outp

atie

nts

initi

ally

diag

nose

d w

ith a

clin

ical

ly in

fect

ed D

FU(a

ccor

ding

to

the

set

ofcr

iteria

you

des

crib

edin

que

stio

n on

e), h

owm

any

of t

hese

will

com

men

ce a

cou

rse

ofor

al s

yste

mic

ant

ibio

tics

with

out

a fo

rmal

diag

nost

ic t

est

havi

ngta

ken

plac

e?

All

of t

hem

Maj

ority

go

onto

em

piric

alth

erap

yVi

rtua

lly a

ll of

the

m,

beca

use

infe

ctio

n so

easil

y be

com

es a

plan

tar

spac

ein

fect

ion.

Onc

e yo

uha

ve d

iagn

osed

infe

ctio

n, y

ou t

reat

until

oth

erw

isepr

oven

All

of t

hem

wou

ld g

etan

tibio

tics

imm

edia

tely.

The

con

sequ

ence

s of

faili

ng t

o ac

t ar

e se

rious

–so

not

left

to c

hanc

e

5 to

7/1

0H

ighe

r ris

k of

har

m if

you

wai

t

All

of t

hem

4. W

hat

patie

nt, f

oot

orul

cer

char

acte

ristic

spr

ompt

you

to

pres

crib

e or

al s

yste

mic

antib

iotic

s to

com

men

ceim

med

iate

ly?

All

patie

nts

get

antib

iotic

s so

not

rele

vant

Prac

tical

ly a

ll w

ould

get

antib

iotic

s im

med

iate

ly: o

nly

patie

nts

with

hig

h su

spic

ion

of o

steo

mye

litis

and

not a

tris

k of

sys

tem

ic in

fect

ion

wou

ld g

et a

bon

e bi

opsy

befo

re h

avin

g an

y an

tibio

tics

NB:

day

of w

eek

also

impo

rtan

t – o

n a

Frid

ay th

eygi

ve a

ntib

iotic

s fo

r a

supe

rfic

ial l

ooki

ngre

dnes

s/in

fect

ion,

whe

reas

Mon

day–

Thu

rsda

y th

eyw

ould

brin

g pa

tient

bac

kan

d se

e pr

ogre

ss b

efor

est

artin

g w

ith a

ntib

iotic

s (a

nddo

so

only

if r

edne

ssin

crea

sing)

See

abov

e –

they

all

get

antib

iotic

sSe

e ab

ove

– th

ey a

ll ge

tan

tibio

tics

Lim

b-th

reat

enin

gin

fect

ion

See

the

infe

ctio

n cr

iteria

abov

e

Appendix 7

214

A: s

econ

dary

B

: ter

tiar

y re

ferr

al

C: s

econ

dary

ref

erra

l D

: ter

tiar

y re

ferr

al

E: t

erti

ary

refe

rral

F:

ter

tiar

y re

ferr

al

refe

rral

cen

tre

cent

re in

Eng

land

ce

ntre

in E

ngla

ndce

ntre

, Wal

esce

ntre

, Can

ada

cent

re, E

ngla

nd(D

GH

wit

h (w

orks

clo

sely

wit

h a

diab

etes

cen

tre)

, bo

ne in

fect

ion

team

)En

glan

d

Que

stio

n↓

Podi

atri

stPo

diat

rist

Vas

cula

r su

rgeo

nN

urse

spe

cial

ist

Med

ical

doc

tor

Dia

beto

logi

st

cont

inue

d

5. H

ow m

any

of t

he s

ame

10 p

atie

nts

will

be

form

ally

tes

ted

usin

gon

e or

mor

e fo

rmal

diag

nost

ic t

ests

for

infe

ctio

n, i.

e. w

ound

biop

sy, w

ound

sw

ab,

X-r

ay, a

mon

g ot

hers

,an

d re

ceiv

e no

syst

emic

ant

ibio

tics

until

the

res

ults

of t

hefo

rmal

tes

t ar

eob

tain

ed?

1 or

2/1

0Pe

ople

with

sus

pect

edos

teom

yelit

isN

one

Non

e3

to 5

/10.

The

y w

ould

be d

ebrid

ed, t

reat

edw

ith lo

cal c

adex

omer

iodi

ne o

r sil

ver,

and

then

reas

sess

ed in

2w

eeks

No

repl

y

6. W

hich

dia

gnos

tic t

est

wou

ld y

ou m

ost

com

mon

ly u

se?

Swab

Dee

p tis

sue

biop

sy a

fter

debr

idem

ent

Prob

e to

bon

e

Swab

Swab

(the

ir la

bora

tory

cann

ot d

eal w

ith b

iops

ysp

ecim

ens

very

wel

l)

Swab

Neu

ropa

thic

ulc

ers

wou

ld b

e sc

rape

d fo

r a

sam

ple

Neu

ro-is

chae

mic

ulc

erw

ould

be

swab

bed.

(7/1

0 ul

cers

are

neur

opat

hic)


215


A: s

econ

dary

B

: ter

tiar

y re

ferr

al

C: s

econ

dary

ref

erra

l D

: ter

tiar

y re

ferr

al

E: t

erti

ary

refe

rral

F:

ter

tiar

y re

ferr

al

refe

rral

cen

tre

cent

re in

Eng

land

ce

ntre

in E

ngla

ndce

ntre

, Wal

esce

ntre

, Can

ada

cent

re, E

ngla

nd(D

GH

wit

h (w

orks

clo

sely

wit

h a

diab

etes

cen

tre)

, bo

ne in

fect

ion

team

)En

glan

d

Que

stio

n↓

Podi

atri

stPo

diat

rist

Vas

cula

r su

rgeo

nN

urse

spe

cial

ist

Med

ical

doc

tor

Dia

beto

logi

st

cont

inue

d

7. If

an

initi

al d

iagn

ostic

test

pro

ved

unin

form

ativ

e an

d th

eul

cer

still

app

eare

din

fect

ed, w

ould

you

repe

at t

he s

ame

test

,O

R w

ould

you

use

adi

ffere

nt t

est

(e.g

.w

ould

you

rep

eat

aw

ound

sw

ab, o

r w

ould

you

use

a w

ound

biop

sy t

o ge

t a

bett

ersa

mpl

e?).

Plea

se li

st t

heop

tions

you

wou

ld u

sein

the

ord

er y

ou w

ould

use

them

Act

on

the

sym

ptom

s no

t th

esw

abM

ight

res

wab

Deb

ride

ulce

r ag

ain

and

take

bio

psy

agai

nD

epen

ds o

n w

ho t

ook

1st

swab

; if i

t w

as h

im,

resw

ab a

nd r

eque

st M

RIsc

an. I

f it

was

ano

ther

clin

icia

n, h

e w

ould

sw

aban

d w

ait

(bio

psy

is no

tpa

rtic

ular

ly u

sefu

l)

Mig

ht c

uret

tage

the

wou

nd. I

f the

pro

be t

obo

ne r

evea

led

a ch

unk

ofbo

ne, t

hey

wou

ld p

ick

that

out

and

sen

d it

off f

orm

icro

biol

ogy

MRI

sca

ns t

ake

too

long

to g

et in

the

ir se

ttin

g

Mig

ht t

ake

an X

-ray

if t

hepa

tient

has

not

had

one

ina

whi

le

Resw

ab, t

hen

biop

syD

eepe

r sa

mpl

ere

quire

d if

neur

opat

hic

ulce

r

8. W

hat

patie

nt, f

oot

orul

cer

char

acte

ristic

spr

ompt

ed y

ou t

o us

e a

form

al d

iagn

ostic

tes

t?

If on

ly o

ne o

f the

char

acte

ristic

s of

infe

ctio

n pr

esen

t

If I w

ere

plan

ning

to

use

a sk

in s

ubst

itute

, the

n I

wou

ld w

ant

to c

heck

the

wou

nd b

ed w

as ‘s

teril

e’be

fore

usin

g th

e re

ally

expe

nsiv

e sk

in

Appendix 7

216

A: s

econ

dary

B

: ter

tiar

y re

ferr

al

C: s

econ

dary

ref

erra

l D

: ter

tiar

y re

ferr

al

E: t

erti

ary

refe

rral

F:

ter

tiar

y re

ferr

al

refe

rral

cen

tre

cent

re in

Eng

land

ce

ntre

in E

ngla

ndce

ntre

, Wal

esce

ntre

, Can

ada

cent

re, E

ngla

nd(D

GH

wit

h (w

orks

clo

sely

wit

h a

diab

etes

cen

tre)

, bo

ne in

fect

ion

team

)En

glan

d

Que

stio

n↓

Podi

atri

stPo

diat

rist

Vas

cula

r su

rgeo

nN

urse

spe

cial

ist

Med

ical

doc

tor

Dia

beto

logi

st

cont

inue

d

9. H

ow m

any

of t

hese

sam

e 10

pat

ient

s w

illne

ither

be

trea

ted

with

sys

tem

ican

tibio

tics

orpe

rfor

med

adi

agno

stic

tes

t?

Up

to 1

/10

wou

ld b

etr

eate

d w

ith t

opic

alag

ents

Smal

l pro

port

ion

Less

tha

n 1/

10. T

here

are

patie

nts

with

infe

ctio

n bu

t th

etr

eatm

ent

they

nee

d is

surg

ery

(e.g

. isc

haem

ic).

One

app

roac

h is

tom

umm

ify t

he in

fect

ion

with

top

ical

antim

icro

bial

s an

d pu

lsedo

ses

of a

ntib

iotic

s

Non

e –

the

cons

eque

nces

too

dire

(leg

- an

d lif

eth

reat

enin

g)

Non

eN

one

10. W

hat

patie

nt, f

oot

orul

cer

char

acte

ristic

spr

ompt

you

to

cont

inue

with

cur

rent

man

agem

ent

of t

hese

DFU

s?

Prol

onge

d pr

esen

ceof

just

one

sig

n M

onda

y m

orni

ng –

patie

nt lo

oks

wel

l,no

rmal

CRP

and

ESR

Old

. Fra

il an

d ve

ry il

lan

yway

11. H

ow lo

ng w

ould

you

cont

inue

with

you

rcu

rren

t m

anag

emen

tof

the

se D

FUs

befo

rem

akin

g a

chan

ge?

D. T

he ‘u

ninf

ecte

d’, s

tati

c ul

cer

14da

ysD

epen

ds o

n th

e pa

tient

12. H

ow lo

ng w

ould

you

cont

inue

with

the

stan

dard

tre

atm

ent

befo

re m

akin

g a

chan

ge?

4w

eeks

6–8

wee

ks

Nee

d to

che

ck if

pres

sure

is r

eally

bei

ngof

fload

ed a

nd if

art

eria

lsu

pply

is r

eally

OK

If it

is slo

wly

impr

ovin

g,ne

ver

swab

. T

hey

have

a ‘p

athw

ay’ –

an

impr

essio

n of

how

an

ulce

r pr

ocee

ds, a

nd o

nly

swab

if it

dev

iate

s fr

omth

is

The

re is

no

time

guid

eU

ses

the

Mar

golis

crite

ria (t

here

sho

uld

bea

30%

red

uctio

n in

are

aby

wee

k 4)

3–4

wee

ks


217


A: s

econ

dary

B

: ter

tiar

y re

ferr

al

C: s

econ

dary

ref

erra

l D

: ter

tiar

y re

ferr

al

E: t

erti

ary

refe

rral

F:

ter

tiar

y re

ferr

al

refe

rral

cen

tre

cent

re in

Eng

land

ce

ntre

in E

ngla

ndce

ntre

, Wal

esce

ntre

, Can

ada

cent

re, E

ngla

nd(D

GH

wit

h (w

orks

clo

sely

wit

h a

diab

etes

cen

tre)

, bo

ne in

fect

ion

team

)En

glan

d

Que

stio

n↓

Podi

atri

stPo

diat

rist

Vas

cula

r su

rgeo

nN

urse

spe

cial

ist

Med

ical

doc

tor

Dia

beto

logi

st

cont

inue

d

13. H

ow m

any

of t

hese

patie

nts

(out

of 1

0co

nsec

utiv

e) w

illco

mm

ence

a c

ours

eof

ora

l sys

tem

ican

tibio

tics

with

out

afo

rmal

dia

gnos

tic t

est

havi

ng t

aken

pla

ce?

Non

e. S

wab

firs

t an

dth

en d

epen

ding

on

the

resu

lts g

ive

antib

iotic

s

Neg

ligib

le

Oth

er t

reat

men

tsin

clud

e sil

ver/

iodi

nedr

essin

gs, r

emov

al o

fslo

ugh

Neg

ligib

le –

virt

ually

all

wou

ld b

e sa

mpl

ed. A

sth

e ch

oice

of a

ntib

iotic

sin

the

se p

eopl

e de

pend

sto

tally

on

the

bact

eria

pres

ent

0/10

(He

wou

ld s

wab

all

10 (b

efor

eus

ing

anan

tibio

tic) a

nd g

ive

topi

cal a

ntim

icro

bial

sw

hile

dec

idin

g w

hat

todo

Non

e –

he w

ould

sw

aban

d if

a ba

cter

ial r

epor

tco

mes

bac

k as

++

+,

then

he

wou

ld t

reat

14. W

hat

patie

nt, f

oot

orul

cer

char

acte

ristic

spr

ompt

ed y

ou t

opr

escr

ibe

oral

syst

emic

ant

ibio

tics

toco

mm

ence

imm

edia

tely

?

Non

eA

ver

y lo

ngst

andi

ngw

ound

See

abov

eIf

the

pers

on’s

dia

betic

cont

rol a

ppea

rs t

o be

dete

riora

ting

– th

enco

nsid

er in

fect

ion

as t

heca

use

Non

e –

he w

ould

not

15. H

ow m

any

of t

hesa

me

10 p

atie

nts

will

be fo

rmal

ly t

este

dus

ing

one

or m

ore

form

al d

iagn

ostic

tes

tsfo

r in

fect

ion,

i.e.

wou

nd b

iops

y, w

ound

swab

, X-r

ay, a

mon

got

hers

, and

rec

eive

no

syst

emic

ant

ibio

tics

until

the

res

ults

of t

hefo

rmal

tes

t ar

eob

tain

ed?

10/1

010

/10

10/1

0Re

asse

ss w

ith a

hig

her

inde

x of

sus

pici

on,

1. X

-ray

2. M

RI (a

sk lo

cal

radi

ogra

pher

for

advi

ce o

nim

agin

g)

10/1

010

/10

Neu

ropa

thic

=cu

rett

age

Neu

ro/is

chae

mic

=sw

ab

Appendix 7

218

A: s

econ

dary

B

: ter

tiar

y re

ferr

al

C: s

econ

dary

ref

erra

l D

: ter

tiar

y re

ferr

al

E: t

erti

ary

refe

rral

F:

ter

tiar

y re

ferr

al

refe

rral

cen

tre

cent

re in

Eng

land

ce

ntre

in E

ngla

ndce

ntre

, Wal

esce

ntre

, Can

ada

cent

re, E

ngla

nd(D

GH

wit

h (w

orks

clo

sely

wit

h a

diab

etes

cen

tre)

, bo

ne in

fect

ion

team

)En

glan

d

Que

stio

n↓

Podi

atri

stPo

diat

rist

Vas

cula

r su

rgeo

nN

urse

spe

cial

ist

Med

ical

doc

tor

Dia

beto

logi

st

cont

inue

d

16. W

hich

dia

gnos

tic t

est

wou

ld y

ou m

ost

com

mon

ly u

se?

Swab

Biop

sySw

ab

17. I

f an

initi

al d

iagn

ostic

test

pro

ved

unin

form

ativ

e an

d th

eul

cer

still

app

eare

din

fect

ed, w

ould

you

repe

at t

he s

ame

test

,O

R w

ould

you

use

adi

ffere

nt t

est

(e.g

.w

ould

you

rep

eat

aw

ound

sw

ab, o

rw

ould

you

use

aw

ound

bio

psy

to g

et a

bett

er s

ampl

e?).

Plea

se li

st t

he o

ptio

nsyo

u w

ould

use

in t

heor

der

you

wou

ld u

seth

em

Biop

sy (p

artic

ular

ly

if yo

u su

spec

t vi

ral

infe

ctio

n)

Bone

bio

psy

MRI

Resw

ab a

fter

a fe

ww

eeks

Mig

ht a

lso d

o an

X-r

ayan

d M

RI s

can

– pa

rtly

to

info

rm a

sses

smen

t of

prog

ress

, also

to

plan

surg

ery,

AN

D t

ope

rsua

de p

atie

nt t

hat

som

ethi

ng is

hap

peni

ngin

the

ir fo

ot (a

wal

king

time

bom

b)



A: s

econ

dary

B

: ter

tiar

y re

ferr

al

C: s

econ

dary

ref

erra

l D

: ter

tiar

y re

ferr

al

E: t

erti

ary

refe

rral

F:

ter

tiar

y re

ferr

al

refe

rral

cen

tre

cent

re in

Eng

land

ce

ntre

in E

ngla

ndce

ntre

, Wal

esce

ntre

, Can

ada

cent

re, E

ngla

nd(D

GH

wit

h (w

orks

clo

sely

wit

h a

diab

etes

cen

tre)

, bo

ne in

fect

ion

team

)En

glan

d

Que

stio

n↓

Podi

atri

stPo

diat

rist

Vas

cula

r su

rgeo

nN

urse

spe

cial

ist

Med

ical

doc

tor

Dia

beto

logi

st

cont

inue

d

E. D

efin

itio

n of

clin

ical

infe

ctio

n

18. O

ne a

utho

r ha

s us

edth

e fo

llow

ing

defin

ition

of c

linic

alin

fect

ion

in d

iabe

ticfo

ot u

lcer

atio

n,‘e

ryth

ema,

indu

ratio

nan

d di

scha

rge’

(Cap

uto,

200

0).25

Are

ther

e an

y el

emen

ts o

fth

is de

finiti

on t

hat

you

disr

egar

d w

hen

asse

ssin

g D

FUs?

All

are

OK

Incl

ude

them

all

NB:

red

ness

and

pai

nm

ay c

ome

from

aC

harc

ot fo

ot, n

otin

fect

ion

(nee

d to

X-r

ayto

exc

lude

bon

ech

ange

s)

Indu

ratio

n: b

ecau

se o

fth

e m

odifi

ed r

espo

nse

to n

euro

path

y, t

hesy

mpa

thet

ic r

espo

nse

mea

ns t

hat

swel

ling

does

not

alw

ays

equa

lin

fect

ion.

Eryt

hem

a: im

port

ant,

but

in s

ever

ene

urop

athy

lack

of

eryt

hem

a do

es n

otm

ean

lack

of i

nfec

tion.

Disc

harg

e: n

ot u

sefu

l – if

you

alre

ady

see

pus

disc

harg

e yo

u ar

e to

ola

te! N

eed

to a

sses

sco

ntin

ually

the

vol

ume

and

char

acte

ristic

s of

disc

harg

e an

d ac

t if

ther

e is

a ch

ange

inth

ese

All

appe

ar r

elev

ant

All

appe

ar r

elev

ant.

Also

uses

ery

them

a gr

eate

rth

an 2

cm a

roun

d m

argi

nof

ulc

er.

Prob

e to

bon

e is

enou

ghon

its

own

to e

qual

infe

ctio

n, O

R th

epr

esen

ce o

f at

leas

t 2

signs

Wou

ld n

ot d

rop

any

219

Appendix 7

220

A: s

econ

dary

B

: ter

tiar

y re

ferr

al

C: s

econ

dary

ref

erra

l D

: ter

tiar

y re

ferr

al

E: t

erti

ary

refe

rral

F:

ter

tiar

y re

ferr

al

refe

rral

cen

tre

cent

re in

Eng

land

ce

ntre

in E

ngla

ndce

ntre

, Wal

esce

ntre

, Can

ada

cent

re, E

ngla

nd(D

GH

wit

h (w

orks

clo

sely

wit

h a

diab

etes

cen

tre)

, bo

ne in

fect

ion

team

)En

glan

d

Que

stio

n↓

Podi

atri

stPo

diat

rist

Vas

cula

r su

rgeo

nN

urse

spe

cial

ist

Med

ical

doc

tor

Dia

beto

logi

st

cont

inue

d

Oth

er in

form

atio

n

19.W

hat

is th

e lo

cal

choi

ce o

f firs

t lin

ean

tibio

tics

for

empi

rical

the

rapy

?

Cip

roflo

xaci

n,cl

inda

myc

in a

ndm

etro

nida

zole

(the

y al

lha

ve e

qual

tiss

uepe

netr

atio

n w

heth

ergi

ven

oral

or

i.v.)

–in

patie

nts

get

i.v.,

outp

atie

nts

get

oral

Clin

dam

ycin

and

cipr

oflo

xaci

nIn

patie

nts

get

amox

icill

in (f

or t

hest

rep.

), flu

clox

acill

in (f

orth

e st

aph.

), an

dm

etro

nida

zole

for

the

anae

robe

s an

dce

ftazi

dim

e fo

r th

eG

ram

neg

ativ

es

Out

patie

nts

get

diffe

rent

reg

imen

depe

ndin

g on

sev

erity

of in

fect

ion.

Supe

rfic

ial:

amox

icill

inan

d flu

clox

acill

inD

eep:

Am

oxic

illin

+flu

clox

acill

in +

met

roni

dazo

le +

cipr

oxin



A: s

econ

dary

B

: ter

tiar

y re

ferr

al

C: s

econ

dary

ref

erra

l D

: ter

tiar

y E:

ter

tiar

y re

ferr

al

F: t

erti

ary

refe

rral

re

ferr

al c

entr

e ce

ntre

in E

ngla

nd

cent

re in

Eng

land

refe

rral

cen

tre,

ce

ntre

, Can

ada

cent

re, E

ngla

nd(D

GH

wit

h (w

orks

clo

sely

wit

h a

Wal

esdi

abet

es c

entr

e),

bone

infe

ctio

n te

am)

Engl

and

Que

stio

n↓

Podi

atri

stPo

diat

rist

Vas

cula

r su

rgeo

nN

urse

spe

cial

ist

Med

ical

doc

tor

Dia

beto

logi

st

20. O

ther

info

rmat

ion

The

y de

brid

e th

e ul

cers

dow

n to

a g

ood

base

Patie

nts

with

app

aren

tlysu

perf

icia

l inf

ectio

n ge

tflu

clox

acill

in. P

atie

nts

with

mor

eex

tens

ive/

seve

re m

ayge

t bi

opsie

s an

d ch

ange

antib

iotic

s on

tha

t ba

sis

NB:

ost

eom

yelit

is an

dso

ft tis

sue

infe

ctio

nstr

eate

d in

diff

eren

t w

ays

– yo

u m

ust

have

ade

finiti

ve c

ultu

re t

o ge

tth

e os

teom

yelit

istr

eate

d pr

oper

ly. T

oes

som

etim

es r

espo

nd t

oem

piric

al t

hera

py –

bac

kfo

ot b

ones

do

not

Onc

e as

sess

ed a

sin

fect

ed –

sw

ab a

ndst

art

loca

l ‘em

piric

alth

erap

y’ im

med

iate

ly.Re

asse

ss t

heap

prop

riate

ness

of t

hean

tibio

tic g

iven

in t

helig

ht o

f bot

h a

24 a

nd a

72-h

our

swab

res

ult

from

labo

rato

ry

Whe

n bo

ne is

infe

cted

the

cour

se o

f ant

ibio

tics

last

s fo

r 3

mon

ths

Stan

dard

car

e m

ust h

ave

vasc

ular

cor

rect

ion

whe

repo

ssib

le, c

ontr

ol o

f inf

ectio

nan

d pr

essu

re o

ff lo

adin

g

You

need

a g

ood

swab

bing

tech

niqu

e

Thi

nks

labo

rato

ry r

esul

tssh

ould

be

at le

ast s

emi-

quan

titat

ive

You

mus

t sam

ple

ever

ythi

ng a

tba

selin

e as

sess

men

t of

infe

ctio

n be

caus

e if

the

loca

l'e

mpi

rical

ther

apy'

does

not

wor

k th

en y

ou c

an ta

ilor

next

dose

A s

wab

doe

s no

t dia

gnos

ein

fect

ion

– th

e cl

inic

ian

does

that

. In

fect

ion

= d

ose/

host

resp

onse

You

do n

ot tr

eat t

he s

wab

, you

trea

t the

pat

ient

The

y su

rvey

ed 1

00 p

eopl

ew

ith n

euro

path

ic fo

ot u

lcer

s –

60%

had

had

ant

ibio

tics

in th

ela

st 6

mon

ths

Stat

ed ‘a

loca

l sw

ab m

irror

sth

e ba

cter

ia s

ampl

ed fr

om a

deep

er b

iops

y’

Men

tione

d cr

itica

l col

onisa

tion

– th

e w

ound

doe

s no

t loo

kin

fect

ed b

ut is

faili

ng to

impr

ove,

so

it m

ust b

e in

fect

ed

221


235

Health Technology AssessmentProgramme

Prioritisation Strategy GroupMembers

Chair,Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool

Professor Bruce Campbell,Consultant Vascular & GeneralSurgeon, Royal Devon & ExeterHospital

Dr Edmund Jessop, MedicalAdvisor, National Specialist,Commissioning Advisory Group(NSCAG), Department ofHealth, London

Professor Jon Nicholl, Director,Medical Care Research Unit,University of Sheffield, Schoolof Health and Related Research

Dr John Reynolds, ClinicalDirector, Acute GeneralMedicine SDU, RadcliffeHospital, Oxford

Dr Ron Zimmern, Director,Public Health Genetics Unit,Strangeways ResearchLaboratories, Cambridge

Director, Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool

Deputy Director, Professor Jon Nicholl,Director, Medical Care ResearchUnit, University of Sheffield,School of Health and RelatedResearch

HTA Commissioning BoardMembers

Programme Director, Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool

Chair,Professor Jon Nicholl,Director, Medical Care ResearchUnit, University of Sheffield,School of Health and RelatedResearch

Deputy Chair, Professor Jenny Hewison,Professor of Health CarePsychology, Academic Unit ofPsychiatry and BehaviouralSciences, University of LeedsSchool of Medicine

Dr Jeffrey AronsonReader in ClinicalPharmacology, Department ofClinical Pharmacology,Radcliffe Infirmary, Oxford

Professor Deborah Ashby,Professor of Medical Statistics,Department of Environmentaland Preventative Medicine,Queen Mary University ofLondon

Professor Ann Bowling,Professor of Health ServicesResearch, Primary Care andPopulation Studies,University College London

Dr Andrew Briggs, PublicHealth Career Scientist, HealthEconomics Research Centre,University of Oxford

Professor John Cairns, Professorof Health Economics, PublicHealth Policy, London School ofHygiene and Tropical Medicine,London

Professor Nicky Cullum,Director of Centre for EvidenceBased Nursing, Department ofHealth Sciences, University ofYork

Mr Jonathan Deeks, Senior Medical Statistician,Centre for Statistics inMedicine, University of Oxford

Dr Andrew Farmer, SeniorLecturer in General Practice,Department of Primary Health Care, University of Oxford

Professor Fiona J Gilbert,Professor of Radiology,Department of Radiology,University of Aberdeen

Professor Adrian Grant,Director, Health ServicesResearch Unit, University ofAberdeen

Professor F D Richard Hobbs,Professor of Primary Care &General Practice, Department ofPrimary Care & GeneralPractice, University ofBirmingham

Professor Peter Jones, Head ofDepartment, UniversityDepartment of Psychiatry,University of Cambridge

Professor Sallie Lamb, Professor of Rehabilitation,Centre for Primary Health Care, University of Warwick

Professor Stuart Logan,Director of Health & SocialCare Research, The Peninsula Medical School, Universities of Exeter &Plymouth

Dr Linda Patterson, Consultant Physician,Department of Medicine,Burnley General Hospital

Professor Ian Roberts, Professorof Epidemiology & PublicHealth, Intervention ResearchUnit, London School ofHygiene and Tropical Medicine

Professor Mark Sculpher,Professor of Health Economics,Centre for Health Economics,Institute for Research in theSocial Services, University of York

Dr Jonathan Shapiro, SeniorFellow, Health ServicesManagement Centre,Birmingham

Ms Kate Thomas,Deputy Director,Medical Care Research Unit,University of Sheffield

Ms Sue Ziebland,Research Director, DIPEx,Department of Primary HealthCare, University of Oxford,Institute of Health Sciences

Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)


Health Technology Assessment Programme

236

Diagnostic Technologies & Screening PanelMembers

Chair,Dr Ron Zimmern, Director ofthe Public Health Genetics Unit,Strangeways ResearchLaboratories, Cambridge

Ms Norma Armston,Lay Member, Bolton

Professor Max BachmannProfessor of Health Care Interfaces, Department of Health Policy and Practice,University of East Anglia

Professor Rudy BilousProfessor of Clinical Medicine &Consultant Physician,The Academic Centre,South Tees Hospitals NHS Trust

Dr Paul Cockcroft, Consultant MedicalMicrobiologist and ClinicalDirector of Pathology,Department of ClinicalMicrobiology, St Mary'sHospital, Portsmouth

Professor Adrian K Dixon,Professor of Radiology,University Department ofRadiology, University ofCambridge Clinical School

Dr David Elliman, Consultant Paediatrician/Hon. Senior Lecturer,Population Health Unit, Great Ormond St. Hospital,London

Professor Glyn Elwyn,Primary Medical Care Research Group,Swansea Clinical School,University of Wales Swansea

Mr Tam Fry, HonoraryChairman, Child GrowthFoundation, London

Dr Jennifer J Kurinczuk,Consultant ClinicalEpidemiologist,National PerinatalEpidemiology Unit, Oxford

Dr Susanne M Ludgate, MedicalDirector, Medicines &Healthcare Products RegulatoryAgency, London

Professor William Rosenberg,Professor of Hepatology, LiverResearch Group, University ofSouthampton

Dr Susan Schonfield, Consultantin Public Health, SpecialisedServices Commissioning NorthWest London, HillingdonPrimary Care Trust

Dr Phil Shackley, SeniorLecturer in Health Economics,School of Population andHealth Sciences, University ofNewcastle upon Tyne

Dr Margaret Somerville, PMSPublic Health Lead, PeninsulaMedical School, University ofPlymouth

Dr Graham Taylor, ScientificDirector & Senior Lecturer,Regional DNA Laboratory, TheLeeds Teaching Hospitals

Professor Lindsay WilsonTurnbull, Scientific Director,Centre for MR Investigations &YCR Professor of Radiology,University of Hull

Professor Martin J Whittle,Associate Dean for Education,Head of Department ofObstetrics and Gynaecology,University of Birmingham

Dr Dennis Wright, Consultant Biochemist &Clinical Director, Pathology & The KennedyGalton Centre, Northwick Park & St Mark’sHospitals, Harrow

Pharmaceuticals PanelMembers

Chair,Dr John Reynolds, ChairDivision A, The John RadcliffeHospital, Oxford RadcliffeHospitals NHS Trust

Professor Tony Avery, Head of Division of PrimaryCare, School of CommunityHealth Services, Division ofGeneral Practice, University ofNottingham

Ms Anne Baileff, ConsultantNurse in First Contact Care,Southampton City Primary CareTrust, University ofSouthampton

Professor Stirling Bryan,Professor of Health Economics,Health Services Management Centre,University of Birmingham

Mr Peter Cardy, ChiefExecutive, Macmillan CancerRelief, London

Professor Imti Choonara,Professor in Child Health,Academic Division of ChildHealth, University ofNottingham

Dr Robin Ferner, ConsultantPhysician and Director, WestMidlands Centre for AdverseDrug Reactions, City HospitalNHS Trust, Birmingham

Dr Karen A Fitzgerald,Consultant in PharmaceuticalPublic Health, National PublicHealth Service for Wales,Cardiff

Mrs Sharon Hart, Head of DTB Publications, Drug &Therapeutics Bulletin, London

Dr Christine Hine, Consultant inPublic Health Medicine, SouthGloucestershire Primary CareTrust

Professor Stan Kaye,Cancer Research UK Professor of Medical Oncology,Section of Medicine, The Royal Marsden Hospital,Sutton

Ms Barbara Meredith,Lay Member, Epsom

Dr Andrew Prentice, SeniorLecturer and ConsultantObstetrician & Gynaecologist,Department of Obstetrics &Gynaecology, University ofCambridge

Dr Frances Rotblat, CPMPDelegate, Medicines &Healthcare Products RegulatoryAgency, London

Professor Jan Scott, Professor of Psychological Treatments,Institute of Psychiatry,University of London

Mrs Katrina Simister, AssistantDirector New Medicines,National Prescribing Centre,Liverpool

Dr Richard Tiner, MedicalDirector, Medical Department,Association of the BritishPharmaceutical Industry,London

Dr Helen Williams,Consultant Microbiologist,Norfolk & Norwich UniversityHospital NHS Trust



237

Therapeutic Procedures PanelMembers

Chair, Professor Bruce Campbell,Consultant Vascular andGeneral Surgeon, Departmentof Surgery, Royal Devon &Exeter Hospital

Dr Aileen Clarke,Reader in Health ServicesResearch, Public Health &Policy Research Unit, Barts &the London School of Medicine& Dentistry, London

Dr Matthew Cooke, Reader inA&E/Department of HealthAdvisor in A&E, WarwickEmergency Care andRehabilitation, University ofWarwick

Dr Carl E Counsell, ClinicalSenior Lecturer in Neurology,Department of Medicine andTherapeutics, University ofAberdeen

Ms Amelia Curwen, ExecutiveDirector of Policy, Services andResearch, Asthma UK, London

Professor Gene Feder, Professorof Primary Care R&D,Department of General Practiceand Primary Care, Barts & theLondon, Queen Mary’s Schoolof Medicine and Dentistry,London

Professor Paul Gregg,Professor of OrthopaedicSurgical Science, Department ofGeneral Practice and PrimaryCare, South Tees Hospital NHSTrust, Middlesbrough

Ms Bec Hanley, Co-Director,TwoCan Associates,Hurstpierpoint

Ms Maryann L Hardy, Lecturer, Division ofRadiography, University ofBradford

Professor Alan Horwich,Director of Clinical R&D,Academic Department ofRadiology, The Institute ofCancer Research, London

Dr Simon de Lusignan,Senior Lecturer, Primary Care Informatics,Department of CommunityHealth Sciences,St George’s Hospital MedicalSchool, London

Professor Neil McIntosh,Edward Clark Professor of Child Life & Health,Department of Child Life &Health, University of Edinburgh

Professor James Neilson,Professor of Obstetrics andGynaecology, Department ofObstetrics and Gynaecology,University of Liverpool

Dr John C Pounsford,Consultant Physician,Directorate of Medical Services,North Bristol NHS Trust

Karen Roberts, NurseConsultant, Queen ElizabethHospital, Gateshead

Dr Vimal Sharma, ConsultantPsychiatrist/Hon. Senior Lecturer,Mental Health Resource Centre,Cheshire and Wirral PartnershipNHS Trust, Wallasey

Dr L David Smith, ConsultantCardiologist, Royal Devon &Exeter Hospital

Professor Norman Waugh,Professor of Public Health,Department of Public Health,University of Aberdeen


Health Technology Assessment Programme

238Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)

Expert Advisory NetworkMembers

Professor Douglas Altman,Director of CSM & CancerResearch UK Med Stat Gp,Centre for Statistics inMedicine, University of Oxford,Institute of Health Sciences,Headington, Oxford

Professor John Bond,Director, Centre for HealthServices Research, University ofNewcastle upon Tyne, School ofPopulation & Health Sciences,Newcastle upon Tyne

Mr Shaun Brogan, Chief Executive, RidgewayPrimary Care Group, Aylesbury

Mrs Stella Burnside OBE,Chief Executive, Office of theChief Executive. TrustHeadquarters, AltnagelvinHospitals Health & SocialServices Trust, Altnagelvin AreaHospital, Londonderry

Ms Tracy Bury, Project Manager, WorldConfederation for PhysicalTherapy, London

Professor Iain T Cameron,Professor of Obstetrics andGynaecology and Head of theSchool of Medicine,University of Southampton

Dr Christine Clark,Medical Writer & ConsultantPharmacist, Rossendale

Professor Collette Clifford,Professor of Nursing & Head ofResearch, School of HealthSciences, University ofBirmingham, Edgbaston,Birmingham

Professor Barry Cookson,Director, Laboratory ofHealthcare Associated Infection,Health Protection Agency,London

Professor Howard Cuckle,Professor of ReproductiveEpidemiology, Department ofPaediatrics, Obstetrics &Gynaecology, University ofLeeds

Dr Katherine Darton, Information Unit, MIND – The Mental Health Charity,London

Professor Carol Dezateux, Professor of PaediatricEpidemiology, London

Mr John Dunning,Consultant CardiothoracicSurgeon, CardiothoracicSurgical Unit, PapworthHospital NHS Trust, Cambridge

Mr Jonothan Earnshaw,Consultant Vascular Surgeon,Gloucestershire Royal Hospital,Gloucester

Professor Martin Eccles, Professor of ClinicalEffectiveness, Centre for HealthServices Research, University ofNewcastle upon Tyne

Professor Pam Enderby,Professor of CommunityRehabilitation, Institute ofGeneral Practice and PrimaryCare, University of Sheffield

Mr Leonard R Fenwick, Chief Executive, Newcastleupon Tyne Hospitals NHS Trust

Professor David Field, Professor of Neonatal Medicine,Child Health, The LeicesterRoyal Infirmary NHS Trust

Mrs Gillian Fletcher, Antenatal Teacher & Tutor andPresident, National ChildbirthTrust, Henfield

Professor Jayne Franklyn,Professor of Medicine,Department of Medicine,University of Birmingham,Queen Elizabeth Hospital,Edgbaston, Birmingham

Ms Grace Gibbs, Deputy Chief Executive,Director for Nursing, Midwifery& Clinical Support Services, West Middlesex UniversityHospital, Isleworth

Dr Neville Goodman, Consultant Anaesthetist,Southmead Hospital, Bristol

Professor Alastair Gray,Professor of Health Economics,Department of Public Health,University of Oxford

Professor Robert E Hawkins, CRC Professor and Director ofMedical Oncology, Christie CRCResearch Centre, ChristieHospital NHS Trust, Manchester

Professor Allen Hutchinson, Director of Public Health &Deputy Dean of ScHARR,Department of Public Health,University of Sheffield

Dr Duncan Keeley,General Practitioner (Dr Burch& Ptnrs), The Health Centre,Thame

Dr Donna Lamping,Research Degrees ProgrammeDirector & Reader in Psychology,Health Services Research Unit,London School of Hygiene andTropical Medicine, London

Mr George Levvy,Chief Executive, MotorNeurone Disease Association,Northampton

Professor James Lindesay,Professor of Psychiatry for theElderly, University of Leicester,Leicester General Hospital

Professor Julian Little,Professor of Human GenomeEpidemiology, Department ofEpidemiology & CommunityMedicine, University of Ottawa

Professor Rajan Madhok, Medical Director & Director ofPublic Health, Directorate ofClinical Strategy & PublicHealth, North & East Yorkshire& Northern Lincolnshire HealthAuthority, York

Professor David Mant, Professor of General Practice,Department of Primary Care,University of Oxford

Professor Alexander Markham, Director, Molecular MedicineUnit, St James’s UniversityHospital, Leeds

Dr Chris McCall, General Practitioner, TheHadleigh Practice, Castle Mullen

Professor Alistair McGuire,Professor of Health Economics,London School of Economics

Dr Peter Moore, Freelance Science Writer, Ashtead

Dr Sue Moss, Associate Director,Cancer Screening EvaluationUnit, Institute of CancerResearch, Sutton

Mrs Julietta Patnick, Director, NHS Cancer ScreeningProgrammes, Sheffield

Professor Tim Peters,Professor of Primary CareHealth Services Research,Academic Unit of PrimaryHealth Care, University ofBristol

Professor Chris Price, Visiting Chair – Oxford, ClinicalResearch, Bayer DiagnosticsEurope, Cirencester

Professor Peter Sandercock,Professor of Medical Neurology,Department of ClinicalNeurosciences, University ofEdinburgh

Dr Eamonn Sheridan,Consultant in Clinical Genetics,Genetics Department,St James’s University Hospital,Leeds

Dr Ken Stein,Senior Clinical Lecturer inPublic Health, Director,Peninsula TechnologyAssessment Group, University of Exeter

Professor Sarah Stewart-Brown, Professor of Public Health,University of Warwick, Division of Health in theCommunity Warwick MedicalSchool, LWMS, Coventry

Professor Ala Szczepura, Professor of Health ServiceResearch, Centre for HealthServices Studies, University ofWarwick

Dr Ross Taylor, Senior Lecturer, Department ofGeneral Practice and PrimaryCare, University of Aberdeen

Mrs Joan Webster, Consumer member, HTA –Expert Advisory Network

How to obtain copies of this and other HTA Programme reports.An electronic version of this publication, in Adobe Acrobat format, is available for downloading free ofcharge for personal use from the HTA website (http://www.hta.ac.uk). A fully searchable CD-ROM is alsoavailable (see below).

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Please use the form on the HTA website (www.hta.ac.uk/htacd.htm). Or contact York PublishingServices (see contact details above) by email, post, fax or phone. HTA on CD is currently free of chargeworldwide.

The website also provides information about the HTA Programme and lists the membership of the variouscommittees.

HTA

Health Technology A

ssessment 2006;Vol. 10: N

o. 12A

decision analysis for sampling and treating infected diabetic foot ulcers


EA Nelson, S O’Meara, D Craig, C Iglesias, S Golder, J Dalton, K Claxton, SEM Bell-Syer, E Jude, C Dowson, R Gadsby, P O’Hareand J Powell


HTAHealth Technology AssessmentNHS R&D HTA Programme

The National Coordinating Centre for Health Technology Assessment,Mailpoint 728, Boldrewood,University of Southampton,Southampton, SO16 7PX, UK.Fax: +44 (0) 23 8059 5639 Email: [email protected]://www.hta.ac.uk ISSN 1366-5278

FeedbackThe HTA Programme and the authors would like to know

your views about this report.

The Correspondence Page on the HTA website(http://www.hta.ac.uk) is a convenient way to publish

your comments. If you prefer, you can send your comments to the address below, telling us whether you would like

us to transfer them to the website.

We look forward to hearing from you.

April 2006

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