Therapy duration and Therapy duration and Short-Course Short-Course

Antimicrobial Therapy Antimicrobial Therapy Approaches in PneumoniasApproaches in Pneumonias

Prof. Dr. Tevfik Özlü

KTÜ, School of Medicine, Trabzon.

Ayasofya-Trabzon

How long should antimicrobial therapy in pneumonia last?

WHO

• Recomended duration for oral amoxicilline, co-trimoxazole and chloramphenicol is 5 days for outpatient treatment of children with pneumonia.

WHO, 1990.

TTS Guideline for CAP

• After becoming afebrile 1 wk

– Pneumococcal pneumonia 7 - 10 days– Legionella pneumonia 14 - 21 days– Mycoplasma and C. pneumoniae 10 - 14 days

• In severe pneumonia 2 – 3 wkArseven O, et al. Toraks Dergisi 2002.

BTS

Case DaysMild, treatment at home, unknown etiology 7

Mild, treatment in hospital, unknown etiology 7

Severe, treatment in hospital, unknown etiology 10

Legionella infection 14-21

Atypical micro-organisms 14

Pneumococcal infection with no complications 7

Staphylococcal infection 14-21

GNEB 14-21

BTS. Thorax 2001.

ALAT2004

• Therapy duration in CAP: 7-14 days

• Using azithromycin, 5 days, and using new fluoroquinolones and telithromycine, 7-10 days

ALAT Work Group. Arch Bronconeumol 2004

SEPAR2005

• Therapy duration in CAP, usually 10-14 days

• Antibiotics with longer half life: 5-7 days

• Not less than 14 days in L.pneumophila, S.aureus and P.aeruginosa infections

• 4 wks in the case of anaerobic infection or presence of a cavity.

SEPAR Working Group. Arch Bronconeumol 2005.

ERS2005

Outpatient treatment • Therapy duration 7-10 days• At least 14 days, for intacellular pathogens

such as Legionella spp, Inpatient treatment • Therapy duration 7-10 days• At least 14 days, for intacellular pathogens

such as Legionella spp, Woodhead M, et al. Eur Respir J 2005

IDSA and ATS2007

• Therapy duration in CAP 7-10 days or longer• In most pts, clinical stability is obtained in 3-7 days• Shorter therapy duration is possible with azithromycine,

telithromycine and levofloxacine is possible• Prolong treatment in cases of instability, bacteriemic

S.aureus, rare etiological agents (Burkholderia pseudomallei, fungi etc), complications such as menengitis / endocarditis, presence of cavity / necrosis, or in case of microbial resistance to initial treatment

• Minimum therapy duration in CAP, 5 days– There should be a 48-72 hours afebrile period– There should be clinical stability

Prescription of antibiotics in CAP for longer than 10 days

is not based on powerfull

scientific data.

Short-course therapy

• Short-course therapy means the use of antibiotics for 5 days or less (for azithromycine ≤ 3 days).

Guay DRP. Drugs 2003.

Respiratory infections

• Respiratory infections are the most common cause of primary health care admissions.

• Antibiotics are used in most of these cases.

McCraig LF, Hughes JM. J Am Med Assoc 1995

Jacobs R. Pediatr Infect Dis 2000.

Özlü T ve ark. Toraks Dergisi 2002.

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Factors affecting the length of therapy

• Etiological agent• Comorbidity • Severity of the disease• Bacteriemia• Complications• Drugs used• Response to therapy

• 76 VAP pts were investigated using bronchoscopic PSB.

• With 3 days of antibiotic use, complete sterilization was achieved in 51 pts and the intensity of infection decreased in 16 pts

Montravers P, et al. Am Rev Respir Dis 1993.

Bacteriological response to treatment

Clinical response to treatment

• Time to afebrility was 14 hours (2-127) in 153 paediatric pts with uncomplicated CAP; hospitalization time was 48 hours (17-240).

Juven T, et al. Eur J Pediatr 2004.

• Mean time afebrility was 3 days in 134 pts with pneumonia improvement of cough and weakness was determined in 14 days.

Metlay JP, et al. Respir Med 1998.

• In Nigeria, 73 uncomplicated pneumonia pts aged between 12 and 60 were treated for 2.54 days (mean) (most with benzilpenicilline) and then discharged from hospital in 4 days. Afebrility for 24 hours was regarded as a criterion for stopping treatment. Etiological agent was S.pneumoniae in more than half of the pts (19 were bacteriemic). Mean time to complete radiological resolution was determined as 25,6 (14-56) days.

Awunor-Renner C. Ann Trop Med Parasitol 1979.

Clinical response to treatment

• Mean time to afebrility was 30 hours (17-68 hours) in 13 uncomplicated adult CAP pts (in whom cure achieved) with the use of ß-lactam antibiotics (pneumococcal pneumonia).

Stralin K, et al. Clin Infect Dis 2004.

Clinical response to treatment

Clinical response to treatment

• In a prospective, multisentric, cohort study, 686 hospitalized adult CAP pts, time to afebrility after the start of treatment was determined as;– 2 days (<38,3 °C)– 3 days (<37,8 °C)

Halm EA, et al. JAMA 1998.

• In an open, randomized study, 84 pts with atypical bacterial pneumonia (Mycoplasma

pneumoniae, Chlamydia psittaci, Coxiella burnetti) were treated with azithromycine;– Most pts became afebrile in 48 h.– Complete cure was achieved in all cases in 5

days.

Schönwald S, et al. Eur J Clin Microbiol Infect Dis 1991.

Clinical response to treatment

Clinical recovery in CAP

• Eskişehir, clinical improvement according to TTS’s Guide.

– Group I pneumonia 4.1 days; – Group II pneumonia 5.2 days; – Grup III pneumonia 8.6 days and – Group IV pneumonia 15 days (42).

• Clinical improvement time in pts with complications is 14.7 days, and 8.2 days in pts without complications

Kolsuz M et al. Tuberk Toraks  2002.

• In a study from İzmir, 31 CAP pts were treated with clarithromycine. Cure was achieved in 3 pts and improvements were determined in 25 pts on the thirth day, at which therapy was switched to oral form.

Yalnız E, et al. Tüberküloz Toraks 2000.

Clinical response to treatment

• A total of 615 hospitalized CAP pts

GROUP I: Azithromycin– IV therapy duration 3,6 days – Complete therapy duration 8,6 days

GROUP II: Cefuroxime+erithromycin– IV therapy duration 4 days– Complete therapy duration 10,3 days

Plouffe J, Schwarts DB et al. Antimicrob Agents Chemother 2000.

Therapy duration in pneumonia

Therapy duration in CAP

• In a study performed in 5 teaching hospitals in Northern Spain, mean time period for antibiotic use among 844 hospitalized CAP pts was determined as be 12.9 and 16,4 days.

Capelastegui A, et al. Respir Med 2005.

• In Ankara, mean time period for the treatment of 64 CAP pts (group-1) treated consecutively (with penicilline, cephalocporine,

macrolids), was determined 12,5 days (10-21

days).

Ekim N 1999, Tüberküloz Toraks.

Therapy duration in pneumonia

• In Edirne, mean antibiotherapy duration in 35 CAP pts (group 3-4), treated consecutively, was reported as 12,5 days

Karlıkaya C, et al. Solunum Hastalıkları 1999.

Therapy duration in pneumonia

Therapy duration preferences of 208 physicians in pneumonia in Afyon, Turkey

Duration Specialist G. Practit. Total

5 days 0 % 2.5 % 1.9 %

7 days 13.0 % 12.3 % 12.5 %

10 days 56.5 % 58.0 % 57.7 %

15 days 30.4 % 22.2 % 24.0 %

30 days 0 % 5.0 % 3.8 %

Ünlü M et al. Akciğer Arşivi, 2002.

Overtreatment

• Physicians generally tend to overtreat pts. Treatment duration is frequently 2 weeks, especially in hospitalized pts.

Mandell LA, File TM Jr. Clin Infect Dis 2003

Benefits expected from antibiotics

• To eradicate etiological micro-organisms

• To improve the clinical situation

• To prevent developement of resistant bacteria

• Low cost,

• Fewer side effects

Short-Course Therapy

• Low cost • Fewer adverse effects• Less drug resistance• High compliance • Increased patients’

satisfaction

• Treatment failure ?• Relapse ?• Complications ?• Scarring ?• Mortality ?

Patients Satisfaction

• In a study including 3254 pts from different European countries, a short-course treatment regimen has been shown to be more effective, to meet pts expectations better than longer treatment regimens and to enhance pts compliance.

Perez-Gorricho B, et al. Intern J Antimicrob Agents 2003.

Cost

• In an investigation of prescribed on prescripted antibiotics in England between 1992 and 1993;– 7 day treatment versus – 5 day treatment

increased direct treatment costs at least 1,9 and 7,2 million sterling were determined in relation to the use of original or generic drugs.

Harris CM, Lloyd DC. BMJ 1994.

Drug resistance

• In 795 children aged 6 to 59 months (73 with pneumonia), short-course, high dose amoxicilline (5 days, 90 mg/kg) was shown to reduce penicilline resistant S.pneumoniae carriage and TMP/SMZ resistance in nasopharingeal flora. It has also been shown that the protective effect was stronger in househoulds with higher compliance when compared to the standard regimen (10 days, 40 mg/kg)

Schrag SJ, et al. JAMA, 2001.

Drug resistance

• In a study of 941 children, it was shown that the use of beta lactams for longer than 5 days increased penicilline-resistant S.pneumoniae carriage in the pharynx compared to a shorter duration.

Guillemot D, et al. JAMA 1998.

Drug resistance

• Short-course antibiotic treatment reduces nasopharyngeal colonisation by resistant pneumococci.

Canet JJ, Garau J. J Antimicrob Chemother 2002.

• In a study performed on 941 French children aged 3-6 years, it was shown that treatment with ß–lactams for longer than 5 days was associated with an increased risk of penicilline-resistant S.pneumoniae carriage in pharingeal flora.

Guillemot D, et al. JAMA 1998.

Drug resistance

Determination of antibiotic dose

• Formulation

• Bioavailability

• Tissue distribution

• Free drug concentration relative to mean bactericidal concentration

• Elimination rate constant (half life)

• Clerance Gordon EM, Blumer JL. Pediatr Infect Dis J 2004.

Pharmacokinetics of antibiotics

• Concentration-dependent killing with prolonged post antibiotic effects– Cmax/MIC

• Concentration and time-dependent killing with moderate to prolonged postantibiotic effects – AUC0-24/MIC

• Time-dependent killing with no postantibiotic effect – Time to when antibiotic concentration exceeds the MIC

File TM. Clin Infect Disesas 2004.

Postantibiotic effect

• Specific to antibiotic-microorganism pair• For Gram positives:

– Beta-lactams, glycopeptides, aminoglycosides, flouroquinolone, macrolide antibiotics, rifampine, clindamycine, tetracycline

• For Gram negatives:– Carbapenem, flouroquinolone, aminoglycosides,

chloramphenicol, tetracycline, rifampinArman D. Güncel Bilgiler Işığında Antibiyotikler 2003.

Azithromycin

• Longer half-life (>50 hrs).• Very high I/E concentration ratio.• Concentrates in phagocytic cells (PNL,

macrophage) and is carried into infection site in those cells.

• Secretion from cells increases in the case of a bacterial presence.

• Inflammatory cells increase azithromycin concentrations in the infection site.

• Despite low serum levels, its concentration is still high in infected foci.

Flouroquinolones

• Pharmacodynamics and pharmacokinetics of flouroquinolones are suited to high and low-dose therapy regimens.

• Cmax and AUC/MIC values obtained in higher doses increase bactericidal activity and the eradication of invasive pathogens

File TM. Clin Cornerstone 2003.Gotfried MH, et al. Chest 2001

Lister PD. Diagn Microbiol Infect Dis 2002.Lister PD, Sanders CC. J Antimicrob Chemother 1999.

Beta-lactams

• Penicilline and cefuroxime were given for 4 and 7 days to 154 children with childhood infections including pneumonia,

• 4 days of treatment was determined to be safe. Cost, the risk of nosocomial infection and adverse events were determined to be decreased.

Peltola H, et al. Int J Infect Dis 2001.

• In a prospective randomized study including 795 Dominician children (aged 6-59 months) with respiratory tract infection – 90 mg/kg/day (5 days) and– 40 mg/kg/day (10 days) amoxicilline

were found to have similar activity. Adherence to treatment was higher in a short-course regimen, and the carriage of penicilline and TMP/SMZ resistant S.pneumoniae on the 28th day was found to have decreased.

Schrag SJ et al. JAMA 2001.

Amoxicillin

Amoxicillin

• In Pakistan, 2000 children aged 2-59 months with non-severe pneumonia were divided into two groups

• Three days of amoxicilline was administered to one group and 5 days of amoxicilline to other group (outpatient treatment)

• Both regimens to have a similar level of effectivity• The most important risk factor for treatment failure was

found to be non-compliance with treatment. MASCOT, Lancet 2002.

Amoxicillin

• In India, the effects of 31-54 mg/kg/day of amoxicilline for 3 and 5 days were compared in 2188 children (aged 2-59 months) with non-severe pneumonia. Success rates were 89.5% and 89.9% respectively.

ISCAP BMJ 2004.

Cefuroxime

• In a randomized, prospective and double blind study, 52 moderately severe CAP pts were treated with 3x750 mg IV cefuroxime for 2 days. Then;

GROUP I: – Received 8 days of 2x500 mg oral cefuroxime

GROUP II:– Received 5 days of 2x500 mg cefuroxime and then a

placebo for 3 days

Cure rates were determined to be similar.Siegel RE, et al. Am J Ther 1999.

Levofloxacin

• In a multicentric, randomized, double blind parallel group study, CAP pts were treated with IV/PO levofloxacine for;

– 5 days at 2x750 mg (198 pts) – 10 days at 2x500 mg (192 pts)

Clinical and bacteriological cure rates were equal.

Dunbar LM, et al. CID 2003.

Levofloxacin

• In a randomized, active-controlled, double blind and multisentric study, 123 atypical CAP pts were evaluated.– 750 mg levofloxacin for 5 days+ placebo 5

days– 500 mg levofloxacin for 10 days

In terms of succes and relaps rates both regimen were similar. Symptom resolution was faster with short term therapy arm.

Dunbar LM, et al. Current Med Research Opinion 2004.

Telithromycin

• In a multicentric, randomized, double blind, parallel group study;

– 5 days of 1x800 mg telithromycin – 7 days of 1x800 mg telithromycin– 10 days of 2x500 mg clarithromycin

were administered to 581 CAP pts. Cure rates were similar in each of the three groups. Cure rates were also similar in terms of pathogens. The cost of the treatment was lowest in the telithromycine-group.

Tellier G, et al. ICAAC, 2002.Tellier G, et al. J Antimicrob Chemother 2004.

Sullivan SD, et al. ATS, 2003.

Azithromycin

• In 203 adult CAP pts with mild / moderate (S pneumoniae, H influenzae, M pneumoniae, C pneumoniae ve L

pneumophila) pneumonia

– 3 days of 1x500mg/days azithromycin– 10 days of 2x250mg/days clarithromycin

were administered to have similar activity and similar advers events.

O’Doherty B, et al. Eur J Clin Microbiol Infect Dis 1998.

Azithromycin

• In 144 pts with COPD exacerbation, pneumonia and purulent bronchitis– 10 days of 3x625 mg co-amoxilav or– 3 days of 1x500 mg azithromycin

were administered. Similar clinical and microbiological results were obtained.

Hoepelman IM, et al. Antimicrob Agents 1998.

Azithromycin

• In a multicentric, double blind, parallel group study,

– 5 days of azithromycin and – 10 days of co-amoxiclav (age≤5) or erithromycin (age>5)

were compared in 456 CAP pts aged 6 months to 16 years. The effectiveness of both treatments was similar but there were fewer side effects in the azithromycin group.

Harris JS, et al. Pediatr Infect Dis 1998.

Azithromycin

• 85 children with community acquired Lower Respiratory Tract Infection (80%

pneumonia 20% bronchitis) were treated with

– 3 days of 1x10 mg/kg azithromycin and – 10 days of 40 mg/kg/day erithromycin (in 3 doses)

Efficacy and safety were similar. Roord JJ, et al. Antimicrob Agents Chemother 1996.

Azithromycin

• In an open, randomised, multisentric study on atypical pneumoniae (Mycoplasma pneumoniae, Chlamydia spp., Coxiella burnetti)

– 89 pts were treated with 1x500 mg azithromycin (3 days)

– 53 pts were treated with 2x150 mg roxitromycin (10 days)

Efficacy was similar in both treatments.

Schönwald S, et al. Scand J Infect Dis 1994.

Azithromycin

• In a double blind, randomized, multisentric study,

– Azithromycin at 1x500mg (1st day), than 1x250 mg (2nd-5th. days) – Cefaclor at 3x500 mg (10 days)

were given to 119 pts with typical bacterial pneumonia. Clinical and bacteriological cure rates were found similar.

Kinasewitz G, Wood RG. Eur J Clin Microbiol Infect Dis 1991.

• In an open, randomized study, 84 pts with atypical bacterial pneumonia (Mycoplasma pneumoniae, Chlamydia psittaci, Coxiella burnetti)

were treated with

– Azithromycin (1x500 mg, 3 days) – Azithromycin (1st day 2x250 mg, then 1x250 mg 2nd-

5th days)

Efficacy levels were similar. Schönwald S, et al. Eur J Clin Microbiol Infect Dis 1991.

Azithromycin

• In an open, randomized, multisentric study; atypical bacterial pneumoniae pts were divided into 2 groups (Mycoplasma pneumoniae, Chlamydia psittaci, Coxiella burnetti)

GROUP I: 57 pts– Azithromycin (1st. day 2x250 mg, 2nd-5th. days 1x250 mg)

GROUP II: 44 pts– Erythromycin (10 days of 4x500 mg)

Efficacy levels were similarSchönwald S, et al. J Antimicrob Chemother 1990.

Azithromycin

Azithromycin

• In an open, prospetive study, 20 mild CAP pts with no risk factor, were treated with 3 days of oral 1x500 mg azithromycin and clinical cure was obtained in all pts.

Mocan MZ et al. ANKEM 1997.

• In an open comparative and randomized study, 100 adult pts with atypical CAP were given (M pneumoniae, C pneumoniae, C psittaci, C burnetii, L pneumophila)

– A single dose of 1.5 gr of azithromycin, or– 500 mg azithromycin once daily (3 days)

Response and efficacy levels were equal in both groups.

Schönwald S, et al. Infection 1999.

Azithromycin

• Short-course teratment regimens are preferred in the treatment of most infectious diseases.

• In addition to URTIs such as sinusitis, tonsillitis, pharyngitis and otitis media, short-course regimens are also used in LRTIs such as pneumonia and COPD exacerbations.

• Short-course treatment regimens decrease costs, adverse events and resistance rates and increase patients’ treatment compliance to and satisfaction.

Conclusion

Conclusion

• Short-course treatment is especially advised in CAP. However, there are also some data regarding its applicability in nosocomial pneumonia and VAP pts.

• Some antibiotics seem to be more suitable for short-course therapy because of their longer half-life, postantibiotic effect and different pharmacokinetics

Conclusion

• There are studies on the suitability of azithromycin, telithromycin, beta-lactams and fluoroquinolones in the short-course pneumonia therapy.

• Wide and comparative studies are needed to determine the length of definitive therapy in pneumonia

ATS• Shorter therapy duration with azithromycin • 7 to 10 days of IV azithromycin therapy• 7 days of therapy with new fluoroquinolones• 7-10 days for the treatment of pneumococcal and

other bacterial pneumonias • If there is a clinical improvement in bacteriemic pts,

no data suggest prolongation of the treatment.• 10-14 days of therapy for M.pneumoniae,

C.pneumoniae and Legionella pneumonia• Treatment longer than 14 days if pts are receiving

corticosteroids.

ATS, Am J Tespir Crit care Med 2001.

IDSA

• Afebrile for 72 hours for S.pneumoniae • 7-14 days for C.pneumoniae• 10-21 days for Legionella• Longer than 14 days for necrotizing

pathogens (S.aureus, P.aeruginosa, Klepsiella sp and anaerobes)

Mandell LA, et al. Clin Infect Dis 2003.

Therapy duration in CAP ?

• Time to clinical stability in CAP varies among pts.

Halm EA, et al. JAMA 1998.

• First response after the onset of treatment may be helpful in determining therapy duration

Stralin K, et al. CID 2004.

Legionella pneumonia

• A minumum 14-21 days of therapy is recommended in severe infections.

Edelstein PH. Ann Intern Med 1998.

Short-Course Therapy

• Quick symptom relief• Low cost

(direct and indirect)• Fewer adverse effects• Less drug resistance• High compliance • Increased patients’

satisfaction

• Treatment failure ?• Relapse ?• Complications ?• Disability-Scarring ?• Mortality ?

FDR approved short-course therapies in adult respiratory infections

Guay DRP. Drugs 2003

Drugs Indication Duration

Cefdinir KBAA, F, T 5-10 days

Cefpodoxime Pharyngitis, Tonsillitis 5-10 days

Moxifloxacin KBAA 5 days

Gemifloxacin KBAA 5 days

Gatifloxacin KBAA 5 days

Dritromycin KBAA 5-7 days

Azithromycin

Telithromycin

KBAA

KBAA, sinusitis

3 days

5 days

Ventilator Associated Pneumonia

• In two different studies, performed on VAP pts, optimal therapy duration was found to be 5-6 days shorter and, longer treatments were reported to cause tracheal colonization with resistant microorganisms.

Dennesen P et al. Respir Crit Care Med 2001

Luna CM et al. Crit Care Med 2003.

• In a prospective, randomized, double blind study, 401 VAP pts were treated for– 8 days (197 pts) – 15 days (204 pts)

• Mortality and relapse rates were similar. At the end of 2 months, the number of MV-free days and the number of organ failure-free days, the length of ICU stay and, also mortality rates were all similar.

Chastre J et al. JAMA 2003.

Ventilator Associated Pneumonias

Short-course antibiotherapy in ICU

• Of 81 pts in ICU who developed pulmonary infiltrations with no clinical criteria of pneumonia – 42 were treated with standard antibiotics for 10-21 days.– 39 were treated with 3x400 mg ciprofloxacin for 3 days.

Mortality and the length of ICU stay were similar. Drug resistance and superinfection rates were lower in the short-course regimen.

Singh N, Rogers P, et al. Am J respir Crit Care Med 2000.

COPD exacerbation

• In a report analyzing 36 studies related to antibiotic therapy in acute bacterial exacerbations of chronic bronchitis, treatment with– Cephalosporines, new fluoroquinolons,

telithromycin and dirithromycin (5 days) and– Azithromycin (3 days)

were shown to be superior or equal to standard treatment for 14 days.

Guay DRP. Drugs 2003.