P. aeruginosa aeruginosa : : P. Present therapeutic options in - - PowerPoint PPT Presentation

P.

• P. aeruginosa

aeruginosa: : Present therapeutic options in Present therapeutic options in Intensive Care Intensive Care

• Y. Van
• Y. Van Laethem

Laethem (CHU St (CHU St-

• Pierre & Universit

Pierre & Université é libre de libre de Bruxelles, Brussels, Bruxelles, Brussels, Belgium Belgium) )

Activity Activity vs vs Pseudomonas Pseudomonas aeruginosa aeruginosa

Pseudomonas aeruginosa - MYSTIC Belgium - 1998/2005

10 20 30 40 50 60 70 80 90 100 MER IMI CAZ CPM PTZ CIP AMU % susceptible strains

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 aeruginosa : Total : Total vs vs non non-

• CF strains

CF strains

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 Pseudomonas aeruginosa aeruginosa 1997 1997 -

• 2004

2004

Country Country N N° ° Centers Centers N N° ° of isolates (%)

• f isolates (%)

Ps.aeruginosa Ps.aeruginosa MDR MDR Belgium Belgium 8 8 1613 1613 152 (9.4) 152 (9.4) Czech Republic Czech Republic 1 1 164 164 39 (2.4) 39 (2.4) Germany Germany 7 7 1799 1799 172 (9.6) 172 (9.6) Italy Italy 3 3 1111 1111 252 (22.7) 252 (22.7) Poland Poland 1 1 178 178 3 (1.7) 3 (1.7) Russia Russia 1 1 160 160 41 (25.6) 41 (25.6) Sweden Sweden 4 4 267 267 5 (1.9) 5 (1.9) Turkey Turkey 9 9 1280 1280 383 (29.9) 383 (29.9) UK UK 5 5 1056 1056 82 (7.8) 82 (7.8)

MONOTHERAPY COMBINATION THERAPY

Sepsis Sepsis(1)

(1)

• Mica Paul et al BMJ 2004

Mica Paul et al BMJ 2004

• Meta

Meta-

• analysis

analysis of 64

• f 64 randomized

randomized trials trials with with 7586 non 7586 non neutropenic neutropenic patients patients → → betalactam betalactam = = betalactam betalactam + aminoside + aminoside

• n the basis of all cause
• n the basis of all cause fatality

fatality

• No

No advantage advantage among among patients patients with with P.

• P. aeruginosa

aeruginosa infection (426 patients) infection (426 patients)

Sepsis Sepsis(2)

(2)

• Clinical

Clinical failure failure more more common common with with combination combination treatment treatment

• No

No difference difference in the rate of in the rate of development development

• f
• f resistance

resistance ⇒ ⇒ lack lack of

• f compelling

compelling data to support data to support the initial use of the initial use of combination combination therapy therapy… …

Combination Combination versus versus monotherapy monotherapy

Bodey Bodey et al et al Arch Arch Int Med 1985 Int Med 1985

• Retrospective

Retrospective study study in 410 cancer patients in 410 cancer patients with with P.

• P. aeruginosa

aeruginosa septicemia septicemia

• f MD Anderson Cancer Center
• f MD Anderson Cancer Center
• 1/3

1/3 with with pneumonia pneumonia → → betalactam betalactam monotherapy monotherapy = = combination combination 72 72↔ ↔71% 71%

• NB :

NB : very very poor poor outcome

• utcome if

if monotherapy monotherapy with with an an aminoglycoside aminoglycoside (29%) (29%)

Combination Combination versus versus monotherapy monotherapy

• Hilf,Yu

Hilf,Yu et al Am J Med 1989 et al Am J Med 1989

• 200 patients

200 patients with with P.

• P. aeruginosa

aeruginosa septicemia septicemia Prospective Prospective study study

• Mortality

Mortality : 27% ( : 27% (combination combination) ) ↔ ↔ 47% (mono) 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

• r

imipenem imipenem

• Alternative conclusion :

Alternative conclusion : combination combination therapy therapy is is superior superior to an to an amino amino alone alone! !

Combination Combination versus versus monotherapy monotherapy in in P.aeruginosa P.aeruginosa septicemia septicemia

• Since

Since 1989 : 1989 : several several studies studies : :

• same

same outcome

• utcome

– – 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

• f ID experts still

still favor favor use of a use of a combination combination, , especially especially if S to the if S to the betalactam betalactam agent agent is is ≤ ≤80% 80%

Endovascular Endovascular infections infections

• 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/ mono/combination combination therapy therapy

• 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 amino effective in 2 cases effective in 2 cases clinically clinically R to the R to the combination combination.(

.(Yu Yu AAC 1984) AAC 1984)

Nosocomial Nosocomial pneumonia pneumonia (1)

(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

• rganisms
• rganisms(not

(not optimally

• ptimally active in the

active in the lungs lungs at at concentration concentration obtained

• btained with

with IV administration) IV administration)

• No prospective

No prospective study study of a

• f a betalactam

betalactam with with

• r
• r without

without a FQ a FQ

Nosocomial Nosocomial pneumonia pneumonia (2)

(2)

• No data for

No data for aerosolized aerosolized administration in administration in ACUTE P. ACUTE P. aeruginosa aeruginosa pneumonia pneumonia : :

• Small DBR

Small DBR study study in VAP due to in VAP due to various various pathogens pathogens ( (Brown AAC 1990

Brown AAC 1990) but

) but potential potential efficacy efficacy in MDR in MDR P.aeruginosa P.aeruginosa pneumonia pneumonia (case reports) (case reports)

• No data

No data showing showing prevention prevention of

• f development

development of R

• f R

to to imipenem imipenem by the addition of an by the addition of an aminoglycoside aminoglycoside

( (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

1171 patients assessed for eligibility

769 ineligible

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 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 8-day regimen 205 assigned to 15-day regimen 197 included in analysis 204 included in analysis 1 patient excluded from analysis

(Consent withdrawal)

402 randomised

Chastre Chastre, Wolff, Fagon, et al. JAMA 2003 , Wolff, Fagon, et al. JAMA 2003

Probability of Survival

Cumulative Cumulative Survival Survival Estimates Estimates According According to to Duration Duration of

• f Antimicrobial

Antimicrobial Treatment Treatment

1.0 10 20 30 40 50 60 Days after bronchoscopy 0.0 0.2 0.4 15-day 8-day 0.8 0.6

Chastre Chastre, Wolff, Fagon, et al. JAMA 2003 , Wolff, Fagon, et al. JAMA 2003

Bacteriology Bacteriology

%

p=0.613 p=0.973 p=0.913

43.2 11.2 32.9 40.2 11.3 30.9

20 40 60 80 100 Polymicrobial MRSA NF-GNB 8-day 15-day

Chastre Chastre, Wolff, Fagon, et al. JAMA 2003 , Wolff, Fagon, et al. JAMA 2003

Cumulative Cumulative Survival Survival Estimates Estimates According According to to Duration Duration of

• f Antimicrobial

Antimicrobial Treatment Treatment

8-day 15-day p=0.39

,2 ,4 ,6 ,8 1

NF-GNB

10 20 30 40 50 60 70 Days

Chastre Chastre, Wolff, Fagon, et al. JAMA 2003 , Wolff, Fagon, et al. JAMA 2003

Percentages Percentages of

• f Pulmonary

Pulmonary Infection Infection Recurrence Recurrence According According to to Antimicrobial Antimicrobial Therapy Therapy Duration Duration (NF (NF-

• GNB)

GNB)

50 40.6% 25.4% “8-day” (n=64) “15-day” (n=63)

p=0.09

40 30 20 10

Chastre Chastre, Wolff, Fagon, et al. JAMA 2003 , Wolff, Fagon, et al. JAMA 2003

Febrile Febrile neutropenia neutropenia (1)

(1)

• Historically

Historically : : leading leading pathogen pathogen → → less less common common ( (prophylaxis prophylaxis, ,… …) )

• IDSA Guidelines :

IDSA Guidelines :

• ceftazidime

ceftazidime or

• r cefepime

cefepime or

• r

carbapenem carbapenem +/ +/-

• aminoglycoside

aminoglycoside

• antipseudomonal

antipseudomonal penicillin penicillin + + aminoglycoside aminoglycoside also also valid valid option

• ption

Febrile Febrile neutropenia neutropenia (2)

(2)

• Mica Paul et al BMJ 2003

Mica Paul et al BMJ 2003

Meta Meta-

• analysis

analysis of 47

• f 47 randomized

randomized trials/7807 p trials/7807 p → → no no significant significant difference difference in in all cause all cause fatality fatality

• significant

significant advantage advantage with with monotherapy monotherapy for for success success

• similar

similar rate of rate of superinfection superinfection

• more adverse

more adverse events events in the in the combination combination treatment treatment group group (not (not reduced reduced by OD by OD amino amino dosing dosing) )

MENINGITIS MENINGITIS(1)

(1)

• Secondary

Secondary to a to a neurosurgical neurosurgical procedure procedure, , head head trauma or trauma or bacteremia bacteremia

• Few

Few published published experience experience: :

• ceftazidime

ceftazidime has the has the « « largest largest » »published published data data

» » Fong Fong Rev Rev Inf Inf Dis 1985 Dis 1985 » » Marove Marove Chemotherapia Chemotherapia 1985 1985 » » Norrby Norrby Am J Med 1985 Am J Med 1985

MENINGITIS MENINGITIS (2)

(2)

• Less

Less data data with with : : cefepime cefepime meropenem meropenem (

(Chmelik

Chmelik JAC 1993 JAC 1993)

)

• Data in Gram (

Data in Gram (-

• )

)meningitis meningitis with with aztreonam aztreonam ( (not

not specifically specifically with with P.

• P. aeruginosa

aeruginosa ) )

Kilpatrick Kilpatrick Scand Scand J J Inf Inf Dis 1981 Dis 1981

with with ciprofloxacin ciprofloxacin

Wong CID 1997 Wong CID 1997

MENINGITIS MENINGITIS(3)

(3)

• Unproved

Unproved necessity necessity of an

• f an aminoglycoside

aminoglycoside, , unless unless betalactam betalactam R R organism

• rganism

( (then then by by intrathecal intrathecal administration) administration)

• Length

Length of

• f therapy

therapy : : empiric empiric! ! ≥ ≥ 2 2 weeks weeks( (with with removal removal of

• f any

any foreign foreign bodies) bodies)

UTI UTI

• (

(Nearly)by

Nearly)by definition definition a a « «complicated complicated UTI UTI» » stone, stone, stent stent, , catheter catheter, instrumentation, , instrumentation,… …

• No comparative data on

No comparative data on specific specific therapies therapies : :

• antipseudomonal

antipseudomonal betalactams betalactams

• aminoglycosides

aminoglycosides

• fluoroquinolones

fluoroquinolones(esp. (esp. ciprofloxacin ciprofloxacin) )

• Duration

Duration : 7 : 7-

• 14

14 days days (acute (acute pyelon pyelon.) .)

cSSTI cSSTI

• Burn

Burn wounds wounds, ,… … → → Extensive Extensive debridement debridement

• Ceftazidime

Ceftazidime(or (or cefepime cefepime, or , or aminopen aminopen or

• r

carbapenem carbapenem) )

• NB :

NB : rapid rapid development development of R in one

• f R in one study

study with with imipenem imipenem monotherapy monotherapy… …. .

Mode of administration Mode of administration

• Continuous

Continuous infusion of a infusion of a betalactam betalactam : : no no clinical clinical study study on P.

• n P. aeruginosa

aeruginosa infection infection

• OD or multiple doses of an

OD or multiple doses of an aminoglycoside aminoglycoside : : – – No prospective data No prospective data showing showing a a better better

• utcome
• utcome

Conclusion Conclusion

• Knowledge

Knowledge of LOCAL

• f LOCAL epidemiology

epidemiology

• Monotherapy

Monotherapy with with a a potentially potentially active active betalactam betalactam at at « « high high doses doses » » +/ +/-

• initial association in

initial association in severe severe infections infections with with : :

• an

an aminoglycoside aminoglycoside IF IF low low local R local R levels levels

non non pulm

• pulm. infect ?

. infect ?

• a FQ IF

a FQ IF low low local R local R levels levels/ /pulm pulm infect. infect. In In units units where where R to R to betalactam betalactam ≥ ≥ 15 15-

• 20%

20%