P. aeruginosa aeruginosa : : P. Present therapeutic options in Present therapeutic options in Intensive Care Intensive Care Y. Van Laethem Laethem Y. Van (CHU St- -Pierre & Universit Pierre & Université é libre de libre de (CHU St Bruxelles, Brussels, Belgium Belgium) ) Bruxelles, Brussels,
Activity vs vs Pseudomonas Pseudomonas aeruginosa aeruginosa Activity Pseudomonas aeruginosa - MYSTIC Belgium - 1998/2005 100 90 80 % susceptible strains 70 60 50 40 30 20 10 0 MER IMI CAZ CPM PTZ CIP AMU 1998 1999 2000 2001 2002 2003 2004 2005 n=263 n=211 n=233 n=264 n=214 n=204 n=242 n=260
Susceptibility Patterns for Pseudomonas Susceptibility Patterns for Pseudomonas aeruginosa : Total : Total vs vs non non- -CF strains CF strains aeruginosa 2002 2003 Total Non-CF Total Non-CF (n=175) (n=140) (n=237) P value (n=184) MEM 88.6 87.1 76.8 0.02 82.1 IPM 78.9 77.9 71.7 NS 77.2 CAZ 78.3 78.6 67.5 0.02 76.6 CPM 74.3 75.0 58.1 0.001 67.8 P+T 86.9 86.4 77.2 0.01 78.8 CIP 76.6 79.3 57.0 <0.001 68.5 AMK 80.0 87.9 68.2 0.01 76.0 ⇒ Increase in resistance: affected by CF isolates !
Multi Drug Resistant Isolates of Multi Drug Resistant Isolates of Pseudomonas aeruginosa aeruginosa 1997 1997 - - 2004 2004 Pseudomonas Country N° ° Centers Centers N° ° of isolates (%) of isolates (%) Country N N Ps.aeruginosa MDR Ps.aeruginosa MDR Belgium 8 1613 152 (9.4) Belgium 8 1613 152 (9.4) Czech Republic 1 164 39 (2.4) Czech Republic 1 164 39 (2.4) Germany 7 1799 172 (9.6) Germany 7 1799 172 (9.6) Italy 3 1111 252 (22.7) Italy 3 1111 252 (22.7) Poland Poland 1 1 178 178 3 (1.7) 3 (1.7) Russia 1 160 41 (25.6) Russia 1 160 41 (25.6) Sweden 4 267 5 (1.9) Sweden 4 267 5 (1.9) Turkey Turkey 9 9 1280 1280 383 (29.9) 383 (29.9) UK 5 1056 82 (7.8) UK 5 1056 82 (7.8)
MONOTHERAPY COMBINATION THERAPY
Sepsis (1) Sepsis (1) � Mica Paul et al BMJ 2004 Mica Paul et al BMJ 2004 � � Meta Meta- -analysis analysis of 64 of 64 randomized randomized trials trials � with 7586 non 7586 non neutropenic neutropenic patients patients with → betalactam → betalactam = = betalactam betalactam + aminoside + aminoside on the basis of all cause fatality fatality on the basis of all cause - No No advantage advantage among among patients patients with with - P. aeruginosa aeruginosa infection (426 patients) infection (426 patients) P.
Sepsis (2) Sepsis (2) � Clinical Clinical failure failure more more common common with with � combination treatment treatment combination � No No difference difference in the rate of in the rate of development development � of resistance resistance of ⇒ lack ⇒ lack of of compelling compelling data to support data to support the initial use of combination combination the initial use of therapy… … therapy
Combination versus versus monotherapy monotherapy Combination Bodey et al Bodey et al Arch Arch Int Med 1985 Int Med 1985 � Retrospective Retrospective study study in 410 cancer patients in 410 cancer patients � with P. P. aeruginosa aeruginosa septicemia septicemia with of MD Anderson Cancer Center of MD Anderson Cancer Center � 1/3 1/3 with with pneumonia pneumonia � → betalactam → betalactam monotherapy monotherapy = = combination combination ↔ 71% 72 ↔ 71% 72 � NB : NB : very very poor poor outcome outcome if if monotherapy monotherapy with with � an aminoglycoside aminoglycoside (29%) (29%) an
Combination versus versus monotherapy monotherapy Combination Hilf,Yu et al Am J Med 1989 et al Am J Med 1989 Hilf,Yu � � 200 patients with with P. P. aeruginosa aeruginosa septicemia septicemia 200 patients � � Prospective study study Prospective ↔ 47% (mono) ) ↔ � Mortality Mortality : 27% ( : 27% (combination combination) 47% (mono) � � BUT : BUT : less less potent potent AB AB than than now now � < 10% < 10% had had received received pipera, pipera, cefta cefta or or � � imipenem imipenem � Alternative conclusion : Alternative conclusion : � combination therapy therapy is is superior superior to an to an amino amino alone alone! ! combination
Combination versus versus monotherapy monotherapy Combination in P.aeruginosa P.aeruginosa septicemia septicemia in � Since Since 1989 : 1989 : several several studies studies : : � � same same outcome outcome � – Vidal Vidal Arch Arch Int Med 1996(189 pat) Int Med 1996(189 pat) – – Kuikka Kuikka Eur Eur J Clin J Clin Microb Microb Infect Dis 1998 Infect Dis 1998 – – Sigman Sigman Int J Int J Inf Inf Dis 1998 (123 pat) Dis 1998 (123 pat) – – Chatzinikolaou – Chatzinikolaou Arch Arch Int Med 2000(145 pat) Int Med 2000(145 pat) – Chamot Chamot AAC 2003 AAC 2003 – – BUT : BUT : majority majority of ID experts of ID experts still still favor favor use of a use of a – combination, , especially especially if S to the if S to the betalactam betalactam combination is ≤ ≤ 80% agent is 80% agent
Endovascular infections infections Endovascular � Rare cases of Rare cases of endocarditis endocarditis ( (esp.drug esp.drug addicts addicts) ) � � Case reports of Case reports of failure failure with with several several � mono/combination combination therapy therapy mono/ � Meropenem Meropenem and and tobra tobra sucessfull sucessfull in one case in one case � � Association of Association of rifampin rifampin with with carbenicillin carbenicillin / / � amino effective in 2 cases effective in 2 cases clinically clinically R to the R to the amino combination .( combination .(Yu Yu AAC 1984) AAC 1984)
Nosocomial pneumonia pneumonia (1) Nosocomial (1) � P. P. aeruginosa aeruginosa in the in the three three leading leading pathogens pathogens in in most most VAP VAP � studies studies - High High failure failure rate rate with with aminoglycosides aminoglycosides alone alone - (historic historic data) data) ( - No data for inclusion of No data for inclusion of amino amino for for fully fully S S - organisms(not (not optimally optimally active in the active in the lungs lungs at at organisms concentration obtained obtained with with IV administration) IV administration) concentration � No prospective No prospective study study of a of a betalactam betalactam with with � or without without a FQ a FQ or
Nosocomial pneumonia pneumonia (2) Nosocomial (2) � No data for No data for aerosolized aerosolized administration in administration in � ACUTE P. aeruginosa aeruginosa pneumonia pneumonia : : ACUTE P. - Small DBR Small DBR study study in VAP due to in VAP due to various various - pathogens ( ( Brown AAC 1990 ) but potential potential pathogens Brown AAC 1990 ) but efficacy in MDR in MDR P.aeruginosa P.aeruginosa pneumonia pneumonia efficacy (case reports) (case reports) � No data No data showing showing prevention prevention of of development development of R of R � to imipenem imipenem by the addition of an by the addition of an aminoglycoside aminoglycoside to (Cometta ( Cometta AAC 1994) AAC 1994)
Comparison of 8 versus 15 days of AB therapy for VAP in adults • Chastre et al , JAMA 2003 • Prospective, randomized, double-blind study (until day 8) • 51 ICU in France - From 6/99 to 6/02 • Either short course of AB : 8 days long (classic) course : 15 days with BAL at D1
Study Design Study Design 769 ineligible 1171 patients assessed for eligibility 180 had early-onset VAP 79 had inappropriate initial treatment 79 had SAPS II >65 77 had severe immunosuppression 77 had been enrolled in other studies 75 had extrapulmonary infections 402 randomised 70 died before Day 3 31 were aged <18 yr 21 refused consent 19 had DNR orders 61 were excluded for other reasons 197 assigned to 205 assigned to 15-day regimen 8-day regimen 1 patient excluded from analysis (Consent withdrawal) 197 included in 204 included in analysis analysis Chastre, Wolff, Fagon, et al. JAMA 2003 , Wolff, Fagon, et al. JAMA 2003 Chastre
Cumulative Survival Survival Estimates Estimates According According to to Cumulative Duration of of Antimicrobial Antimicrobial Treatment Treatment Duration 1.0 Probability of Survival 0.8 0.6 8-day 0.4 15-day 0.2 0.0 0 10 20 30 40 50 60 Days after bronchoscopy Chastre, Wolff, Fagon, et al. JAMA 2003 , Wolff, Fagon, et al. JAMA 2003 Chastre
Bacteriology Bacteriology % 8-day 100 15-day 80 p=0.613 p=0.973 p=0.913 60 43.2 40.2 40 32.9 30.9 20 11.2 11.3 0 Polymicrobial MRSA NF-GNB Chastre, Wolff, Fagon, et al. JAMA 2003 , Wolff, Fagon, et al. JAMA 2003 Chastre
Cumulative Survival Survival Estimates Estimates According According to to Cumulative Duration of of Antimicrobial Antimicrobial Treatment Treatment Duration 1 NF-GNB ,8 ,6 ,4 8-day ,2 15-day p=0.39 0 0 10 20 30 40 50 60 70 Days Chastre, Wolff, Fagon, et al. JAMA 2003 , Wolff, Fagon, et al. JAMA 2003 Chastre
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