Treating skin and soft tissue and bone and joint infections in acute and OPAT settings
Andrew Seaton
Infectious Diseases Consultant and Lead Doctor Antimicrobial Management Team,
Brownlee CentreGartnavel General Hospital
NES Training Day to support Antimicrobial Pharmacists
Friday 30 August 2013
Cellulitis• Cellulitis vs Erysipelas
• Risk factors: Previous cellulitis, lymphoedema,
DM, Obesity, varicose excema, insect bites
(summer), tinea pedis….
• Usually caused by:– Beta haemolytic Streptococci Gp A>> Gps B, C, G
– Staphylcoccous aureus
– Rarely Gram negatives (immunocompromised)
Cellulitis: First line antibiotic management
• Flucloxacillin (vs MSSA, BHS (most))– Oral 7 days if mild
– IV-IVOST if moderately severe 7-10 days total
– IVOST when significant reduction in heat, erythema and
swelling
• Should Ben Pen be added?
• Penicillin allergic– Clarithromycin or Clindamycin (PO)
– Vancomycin (IV)
How is severity assessed?
• Extent, speed of progression and presence of systemic inflammatory response
• Abrupt onset fever, rigors and confusion ++
• Rapidly progressive Cellulitis of leg• BP 80 systolic, HR 140,Temp 39.80C
• Abrupt onset fever, rigors and confusion ++
• Rapidly progressive Cellulitis of leg
• BP 80 systolic, HR 140,Temp 39.80C
Severe GAS Sepsis• “Eagle effect”
– Static growth phase– Failure to produce PBPs– Exotoxin: STSP
28 day Mortality & Sepsis SeverityPatients suspected of bacteraemia
0
10
20
30
40
50
60
SIRS 0 SIRS 2 SIRS 3 SIRS 4 SEVERE SHOCKINFECTION SEVERITY
Jones & Lowes, QJM 1996
Mortality Risk and time to initiation of effective therapy
Necrotising Fasciitis
• Usually caused by:– Beta haemolytic Streptococci Gp A>> Gps B, C, G
– Staphylcoccous aureus
– Rarely Gram negative organisms
• Pain out with appearance
• Masked by NSAIDs
• Rapidly progressive with multiorgan failure
Management of severe/ rapidly progressive SSTIs
• SEPSIS 6, Fluid resuscitation and inotropes
• HDU setting
• Antibiotic considerations:– Cover: BHS, Anaerobes, Staph aureus and Gram –ves
– Cidality: Beta lactam based regimen
– Toxin production/ EAGLE effect: Clindamycin
• Immunoglobulin (GAS)
• SURGERY
MRSA carrier.not getting better on VANCOMYCINWhy not?
Surgical Site Infections
Diabetic with forefoot cellulitis Not getting better on FLUCLOXACILLINWhy not?
Drug users:MSSA and GAS most usuallyCellulitis, deep SSTIs, Abscesses, Vascular infections, DVTs and bacteraemia
OPAT and SSTIs
OPAT Evidence in SSTI
• 2 RCTs of OPAT: 1999 (n=100, variety) and 2004 (n=200, SSTI). – Mainly Cefazolin BD
• RCTs of new antimicrobials includes OPAT Rx pts
Corwin et al BMJ doi 10.1136/bmj.38309.447975.EB; Board et al Aust N Z J Public Health 2000; 24:305
When to consider OPAT• Non-life-threatening SSTI amenable for home
care and requiring i.v. therapy• Admission avoidance or early discharge• Exclusions:
– The system• Lack of facility/ system for FU/ emergency cover
– The infection• Sepsis syndrome• Rapidly progressive/ progression not clear
– The patient• Unstable co-morbidity• Psycho-social
Good Practice Recommendations
4.1 Patients with superficial skin and soft tissue infection should be reviewed daily by the OPAT team to optimize speed of intravenous to oral switch.
Patient group direction for SSTIs
• ‘Patient group’: non-life-threatening cellulitis amenable for home care and requiring i.v. therapy
• Uniform therapeutic management• Suitable protocol in place
– Exclusions– Prior physician review– Indications for specialist review– Indications for IVOST
• Trained, experienced staff• Approved by ADTC
Seaton RA et al. J Antimicrob Chemother 2005;55:764–767
IVOST, i.v. antibiotic – oral switch therapy
OPAT treatment pathway for SSTIs: empiric antibiotic choice
Yes No
History of MRSA or Beta-lactam allergy?
Teicoplanin▼
Clindamycin*
Ceftriaxone ▼
Clindamycinor
Flucloxacillin *If Beta-lactam allergy or sensitive MRSA
Nurse-led Mx for OPAT SSTIs
Comparison of patients pre- and post-introduction of a nurse-led management protocol
Protocol management was associated with reduced duration of outpatient i.v. therapy (from 4 to 3 days, P=0.02)
Seaton RA et al. J Antimicrob Chemother 2005;55:764–767
Dur
atio
n of
OP
AT
(day
s)
0
12
34
56
78
910
1112
1314
Year
2001 2002 2003 2004 2005 2006 2007 2008
Data shown are median, lower quartile and upper quartile
SSTI: Median duration of OPAT (days)Nurse-led IVOST
Seaton RA et al, IJAA, 2011
Linear time trend in log (OPAT days)
Estmate 0.904 (0.886-0.922) p<0.0001
No. Duration (days)
Progression (%)
Readmission (%)
Significant AE
OPAT failure*
Ceftriaxone 811 3 (2-4) 2.6 5.3 5.5 10.5
Teicoplanin 144 8 (3-12) 4.2 10.4 14.6 25.7
Common OPAT Antibiotics in SSTI
Seaton RA et al, IJAA 2011
*Switch of antibiotic, progression of infection or readmission
Factors Associated with OPAT Failure* in SSTI (n=963)
Multiple logistic Regression
Variable OR (95% CI) P value
Female 1.65 (1.10-2.47) 0.016
Diabetes 2.02 (1.12-3.67) 0.020
Teico vs Ceftriaxone 1.87 (1.05-3.33) 0.033
Seaton RA et al, IJAA 2011*Switch of antibiotic, progression of infection or readmission
OPAT SSTI: Factors Associated with increase in duration of OPAT
Multiple linear regression
Variable Estimate* (95% CI) P value
Age (per additional 10 years) 1.03 (1.01-1.05) 0.0097
MRSA 1.47 (1.17-1.84) 0.0010
Vascular disease 1.29 (1.01-1.64) 0.041
Teicoplanin vs Ceftriaxone 1.32 (1.16-1.50) <0.0001
Referred from community 0.91 (0.84-0.99) 0.021
Managed via PGD 0.71 (0.65-0.77) <0.0001
Infection type
Bursitis vs cellulitis 1.81 (1.45-2.25) <0.0001
Wound infection vs cellulitis 1.74 (1.31-2.3) 0.0001
Other infection vs cellulitis 1.25 (1.00, 1.56) 0.0049
* Estimates: percentage change in number of days in OPAT: for example, an estimate of 1.10 means that, on average, a variable is associated with a 10% increase in the number of days of treatment.
Seaton RA et al, IJAA 2011
OPAT SSTI: Antibiotic therapy• Nurse led IVOST effective and associated
with reduced duration of IV Rx• OPAT failure and Teicoplanin
– confounded by another variable?– Teicoplanin less effective / more adverse
events?– Less subject to daily IVOST review therefore
longer therapy?• Alternative therapies when ceftriaxone
contraindicated
65 yr old female diabetic• Bilateral amputee with recent admission with ?UTI
• Readmitted 2/52 post discharge with fever, fatigue,
headache and confusion– Temp 39
– HR 120
– BP 134/90
– WCC 16
– Urinalysis; glycosuria
GAS, Pneumococcus, Meningococcus, other Strep sp
MSSA
Gram negs
Gram positive cocci on blood culture @ 24 hours
• Continue empirical Rx until confirmed and
assuming clinical repsonse
• S. aureus confirmed (MSSA)
• Where is it coming from and what are the dangers?
Bone and joint Infection
• Diversity of presentations• Managed by many specialties• About 1m Implants/annum world wide
– 0.5% of THR– 0.5-2% of other PJs
• BJI in Glasgow; >500 per year
Bone and joint Infection
Classification of Osteomyelitis• OM due to contiguous spread
– Eg Trauma, Surgery or joint replacement• OM due to vascular insufficieny
– Eg Following Soft tissue infection in a diabetic (associated neuropathy)
• Haematogenous OM– Eg Discitis
• Onset– Acute; Days – weeks– Chronic; Months - years
Lew and Waldvogel, Lancet 2004; 364369
Likely Organisms
• Device related– Coagulase negative Staphylococci > Staph
aureus > Enterococci (sub-acute)– Staph aureus, BHS, Gram negatives (acute)
• Non device related– Staph aureus, BHS– Gram negatives
How do bugs get in?• Through the skin or wound
– Health care workers– Environment
• From the Blood stream– Community– Cannulae / Catheters
• Via surgery– Asepsis– Foreign material
Mechanism of disease:The bone
• Acute suppurative inflammation• Micro-organism embedded• Tissue necrosis and destruction of bone
trabeculae and matrix• Vascular channels compressed and
obliterated
Pathogenesis: Host and micro-organisms
• Staphylococcus aureus– Most common and important– Virulence through extracellular and cell-associated
factors:• Attachment: Adhesins allow attachment to extracellular matrix
proteins• Evading the host defence; Protein A, some toxins, capsular
polysaccharide• Promote invasion or tissue penetration: Exotoxins and
hydrolases
Pathogenesis: Host and micro-organisms
• Staphylococcal species– Capacity to colonise and persist– Promote own uptake by endothelial and
endocytic cells and can survive within osteoblasts
– Can exist in metabolically altered status as small colony variants
Pathogenesis: Host and micro-organisms
• Staphylococcal species– May persist in biofilm (“Slime”)
• Cells attach to each other and substratum or interface• Matrix of extracellular polymeric substance• Altered growth, gene expression and protein production• Quorum sensing between organisms• Inherent resistance to antimicrobials
– Metabolic alteration– Reduced cell division– “Layered variation” in phenotype
BJI Management
• Microbiological Dx is essential• Imaging: Xray, CT, MRI, Bone scan• Acute Presentation
– Blood cultures / joint aspiration– Management of sepsis: empirical therapy– Identify and remove foci of infection
• Sub-acute presentation– Sample off antibiotics– Empirical Rx after sampling
Principles of antibiotic management
• Combined with surgical management• Deliver to site of infection (bone/joint
penetration)• Activity in biofilm• Route of administration: IV (by convention not
evidence) initial and consider IVOST• Length of Rx: ≥6 weeks BUT dependent on
surgical management• Cure vs Suppression• Maintenance of function
Choice of Antibiotic
• Best guess: Glycopeptide vs flucloxacillin• Favour Flucloxacillin with Gentamicin if
acute presentation• Consider 2nd oral agent
Rifampicin>Sodium fusidate/ Doxycycline/ TMP/ Pristinamycin
• Gram negative cover: Ciprofloxacin
OPAT
When to consider OPAT
• When (prolonged) IV Rx anticipated• Ambulant / well supported patient• Stable comorbidity• Agreed plan between surgical team and
OPAT• Clear lines of communication• No logistic obstacles• Usually self/ carer administration
a. OPAT patient episodes b. OPAT days
Seaton and Barr, EJIM, 2013
Distribution of patients within the Glasgow OPAT service (2001-2011)
Good Practice Recommendations3.2 The treatment plan is the responsibility
of the OPAT infection specialist, following discussion with the referring clinician. It should include choice and dose, frequency and duration. Should take into account flexibility based on clinical response
3.3 Antimicrobial choice within OPAT should be subject to review by the local antimicrobial stewardship programme
SSTI BJI CVS Bacteraemia CNS UTI Abdo. Abscess
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Relative frequency of first line antimicrobial agent use in Glasgow OPAT service.
Seaton and Barr, EJIM, 2013
Lamont E et al. J Antimicrob Chemother 2009;doi:10.1093/jac/dkp147
Lamont E et al. J Antimicrob Chemother 2009;doi:10.1093/jac/dkp147
Duncan et al, Int J Clin PharmDOI 10.1007/s11096-012-9637-z
Multivariate odds ratio of failing initial OPAT therapy
Odds Ratio 95% C. I. P
Diabetic foot infection 5.94 2.14-16.48 0.001MRSA infection 3.30 1.15-9.46 0.026CoNS/Diptheroids 4.53 1.18-17.47 0.02880-89 yrs 5.32 1.41-20.11 0.014
Goodness of fit: log likelihood -66.5, r2 0.144 P=0.0004
Mackintosh CL, White H.A, and Seaton R.A, JAC 2011
0.00
0.25
0.50
0.75
1.00
0 20 40 60 80 100
analysis time (weeks)
0.00
0.25
0.50
0.75
1.00
0 20 40 60 80 100
analysis time (weeks)
Figure 2 Kaplan-Meier survival estimate of time to treatment failure for all patients per diagnosis
MWI
VOM
SA
DFI
PK/PH/OM
weeks 0 20 40 60 80 100
number at risk/number failing
DFI 39/0 23/16 15/20 11/21 9/22 8/22
MWI 23/0 21/0 15/1 10/1 9/1 4/1
OM 30/0 24/5 18/6 10/7 6/8 5/8
PH 25/0 20/5 18/6 10/6 9/6 7/7
PK 40/0 32/6 26/10 17/11 13/12 11/12
SA 20/0 19/1 10/5 9/5 9/5 6/5
VOM 21/0 19/2 15/3 13/4 12/4 9/4
weeks 0 20 40 60 80 100
number at risk/number failing
DFI 39/0 23/16 15/20 11/21 9/22 8/22
MWI 23/0 21/0 15/1 10/1 9/1 4/1
OM 30/0 24/5 18/6 10/7 6/8 5/8
PH 25/0 20/5 18/6 10/6 9/6 7/7
PK 40/0 32/6 26/10 17/11 13/12 11/12
SA 20/0 19/1 10/5 9/5 9/5 6/5
VOM 21/0 19/2 15/3 13/4 12/4 9/4
Mackintosh CL, White H.A, and Seaton R.A, JAC 2011
Kaplan-Meier survival estimate of time to treatmentfailure for all patients per diagnosis
Association of the initial IV Antibiotic with failure over the follow up period in
OPAT BJI (Cox regression)
Initial IV Rx No. No. Failing
Hazard ratio
CI p
Teicoplanin 140 48 1Ceftriaxone 51 10 0.54 0.27-1.06 0.074Other 5 1
Outcome @ 28 days
Anaphylactoid
Other
Nature of ADR unrecorded
Hepatotoxicity
Nephrotoxicity
Leucopenia, thrombocytopenia or anaemia
Chills or fever
Severe gastro-intestinal
Rash
0 10 20 30 40 50 60 70 80 90 100
Frequency of ADR type
Relative frequency of adverse drug reaction (ADR) types, in all first OPAT episodes over 10 year study period.
Note: An ADR in an individual patient in some instances involved multiple drug reaction types (e.g. rash and fever); each ADR type is counted separately in frequency bars even where they stem from one ADR event.
CVS
BJI
SSTI
Bacteraemia
0
2
4
6
8
10
12
14
16
18
DaptomycinCeftriaxone
Teicoplanin
% w
ith A
DR
ADRs, Infection Type and AB Used (GGC OPAT)
OVIVA study
• Randomised to IV vs oral before completion of 1 week of IV Rx
• Use of bio-available antibiotics with good bone penetration (Rifampicin, Ciprofloxacin, Tetracyclines)
• Staph aureus bacteraemia excluded (and those in whom only IV Rx available)
Conclusions• SSTIs and BJIs: Gram positive infections
(MSSA, BHS and CNS)• Initial IV therapy is usual standard of care• OPAT is useful for both patient groups• In SSTI Teicoplanin associated with poorer
OPAT outcome cf ceftriaxone• Antimicrobial Stewardship principles
important in OPAT esp IVOST in SSTI• Role of oral therapy in BJI currently being
explored
AcknowledgementsOPAT Nurses: Lindsay Semple, Claire
Vallance, Deepa Matthew, Emma SharpAntimicrobial Pharmacist: Fiona Robb
OPAT Medics past and present: David Barr, Chris Duncan, Claire Mackintosh
Current Practice: Gram Positive Infections
INFECTION AGENT DOSE COMMENT
Cellulitis/ SSTI
Ceftriaxone 1-2 g OD
Review daily: Oral switch Clinda/ fluclox/ Linezolid
Teicoplanin Variable dose
Daptomycin 4-6mg/kg
Ertapenem 1g OD
Bone/Joint infection
Daptomycin 6-8mg/kg + Oral RIF or Sodium fusidate or Doxy
Teicoplanin 15-20mg/Kg 3 xs / week
Ceftriaxone 2g OD
Clostridium difficile and OPAT
• 4 per 3,356 UK OPAT episodes (0.1%)• 2 per 2,233 Glasgow OPAT episodes (0.05
events per 1000 OPAT patient days)
Chapman et al JAC 2009; 64:1316Mathews et al JAC 2007; 60: 356Seaton et al IJAA 2011; 38: 243Barr et al IJAA 2012; 39: 407
