The role of carbapenems in the hospital

Transcription

1 The role of carbapenems in the hospital Matteo Bassetti, MD, PhD Infectious Diseases Division Santa Maria Misericordia University Hospital Udine, Italy

2 Rationale for Antibiotic Optimizaton: Balancing The Needs of Patient and Society Inappropriate antibiotic therapy associated with higher mortality Indiscriminate use of broad-spectrum antibiotics driving resistance Richards GA. Clin Microbiol Infect. 2005;11(suppl):18-S22.

3 Impact of inappropriate initial empiric antibiotic selection Appropriate antimicrobial treatment Mortality (% of patients) p < p < 0.05 Inappropriate antimicrobial treatment p < p < 0.02 p = Bacteraemia 1 Communityacquired bacteraemia 2 S. aureus bacteremia 3 Ventilatoracquired pneumonia 4 Bacteraemia in ICU patients 5 1. Ibrahim EH, et al. Chest. 2000; 118:146 55; 2. Valles J, et al. Chest 2003; 123: ; 3. Khatib R, et al. Eur J Clin Microbiol Infect Dis 2006; 25:181 5; 4. Teixeira PJZ, et al. J Hosp Infect 2007; 65:361 7; 5. Garnacho-Montero J, et al. J Antimicrobial Chemother 2008; 61:436 41

4 How to be appropriate?

5 Optimal Empiric Therapy h Choice 1 - Patient factors including safety - Local resistance patterns (antibiogram) - Prior antimicrobial exposure h Appropriate - All suspected pathogens susceptible to 1 of the administered antibiotics h Timely 1 - In one study, patients were 2.1% more likely to die for each 30 minute delay in administration 2 h Adequate dosage 1 - Consistent with pk/pd parameters The important decision in antibiotic treatment turns out to be the choice between present and future patients 3 1 Deresinski S. Clin Infect Dis. 2007;45:S177-S Barie PS, et al. Surg Infect. 2005;6: Leibovici L, et al. BMJ. 1999;318:

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7 Risk factors for ESBL-producing Enterobacteriaceae isolation within 48h of hospital Multivariate analysis Risk factor OR (95% CI) P-value Recent hospitalization a 5.69 ( ) Admission from another health care facility 5.61 ( ) Charlson comorbidity index > ( ) Previous therapy with beta -lactams and/or 3.68 ( ) fluoroquinolones b History of urinary catheterization c 3.52 ( ) Age >70 years 3.20 ( ) a During the 12 months preceding index hospitalization. b Includes treatment with -lactam/-lactamase inhibitor combinations, oxyiminocephlosporins, and/or fluoroquinolones during the 3 months preceding index admission. c During the 30 days preceding index blood culture. Tumbarello M, Bassetti M et al. Antimicrob Agents Chemother Jul 2011;55:

8 Predictors of ESBL Pathogens in Patients with Community-Acquired Infections Variable All patients (n=983) Odds Ratio (95% CI) P Male sex 2.5 ( ) <0.001 Age 65 years 2.4 ( ) <0.001 Admission from LTCF 7.5 ( ) <0.001 Recent hospitalization a 2.9 ( ) <0.001 Recent use of any antibiotic a 1.8 ( ) Patients with no recent health care contact (n=795) Male sex 2.9 ( ) <0.001 Age 65 years 3.5 ( ) <0.001 Recent use of a cephalosporin a 3.6 ( ) <0.001 Ben-Ami R, et al. Clin Infect Dis. 2009;49:

9 ESBL-producing K. pneumoniae Bacteraemia Beta-lactam inhibitor 50% Cephalosporin 40% Crude 14-day mortality (%) Multivariate analysis of mortality (attributed to bacteraemia) Carbapenem during the first 5 days 36.3% : OR ( 95% CI )= 0.06 ( ); p < Quinolone Carbapenem 3.7% Survivors Non-survivors Paterson D et al. Clin Infect Dis 2004;39:31 37

10 Effect of initial antibiotic therapy on mortality in patients with BSI by ESBL-producing Enterobacteriaceae Mortality (%) n=186 59,5 Inadequate initial therapy (n=89) p< ,5 Adequate initial therapy (n=97) Tumbarello et al. Antimicrob Agents Chemother 2007;51:

11 Effect of switching initial antimicrobial therapy on mortality 70 p<0.001 Mortality (%) Switching after susceptibility results Adequate treatment within a few hours n=75 Tumbarello et al. Antimicrob Agents Chemother 2007;51:

12 OR 0.14* ** P =*0.01 **< day mortality (%) 97 ESBL-BSI patients initially treated with potentially active agents Tumbarello M et al Antimicrob Agents Chemother 2007; 51:

13 ESBL-Producing Gram-Negative Bacilli: A Global Problem Europe E. coli 8.1% K. pneumoniae 16.3% North America E. coli 4.9% K. pneumoniae 9.6% Africa/Middle East E. coli 12.2% K. pneumoniae 37.6% K. oxytoca 5.3% Asia/Pacific E. coli 34.9% K. pneumoniae 29.8% K. oxytoca 27.6% Latin America E. coli 21.6% K. pneumoniae 41.6% Data from SMART (Study for Monitoring Antimicrobial Resistance Trends) Hawser et al. Int J Antimicrob Agents. 2009;34:585-8.

14 ESBL Prevalence in Nosocomial Enterobacteriaceae in Russia RosNet Study Group Species Number (%) Number (%) Klebsiella pneumoniae 341 (47.5) 332 (46.3) Escherichia coli 191 (26.6) 205 (28.6) Proteus mirabilis 51 (7.1) 40 (5.6) Enterobacter species 45 (6.3) 75 (10.9) Serratia marcescens 45 (6.3) 29 (4.0) Citrobacter species 16 (2.2) 11 (1.5) Klebsiella oxytoca 8 (1.1) 11 (1.5) Morganella morganii 7 (1.0) 5 (0.7) Other Enterobacteriaceae 14 (1.9) 6 (0.8) Sukhorukova M et al. 20 th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). Vienna, Austria, April 10 13, Abstract P716

15 Mortality with ESBL Production in Enterobacteriaceae Bacteremia A Systematic Review and Meta-Analysis Lead Author (year) Schwaber (2006) Tumbarello (2006) Marra (2005) Endimiani (2005) Zaoutis (2005) Blomberg (2005) Panhotra (2004) Kang (2004) Kim BN (2002) Du (2002) Kim YK (2002) Borer (2002) Ho (2002) Menashe (2001) Pena (2001) Ariffin (2000) Pooled Relative Risk of Mortality (95% confidence interval) Schwaber MJ, Carmeli Y. J Antimicrob Chemother 2007;60:

16 TREATMENT OPTIONS FOR INFECTIONS DUE TO ESBL+ Urinary tract infection FIRST CHOICE CARBAPENEM SECOND CHOICE Amoxycillin/clavulanate QUINOLONE Ventilatorassociated pneumonia CARBAPENEM TIGECYCLINE Bacteremia CARBAPENEM TYCECICLINE Intra-abdominal infection CARBAPENEM TYGECICLINE Quinolone Possibility of using piperacillin-tazobactam for ESLB-producing E. coli bloodstream infections originating from the urinary tract

17 Clinical Guidelines for Intra-Abdominal Infections Recommendations for single-agent therapy Recommendations for combination regimens Mild-tomoderate severity* Cefoxitin Ertapenem Moxifloxacin Tigecycline Ticarcillin/clav High risk or severity** Imipenem/cil Meropenem Doripenem Piperacillin/tazo Mild-to moderate severity* Cefazolin, cefuroxime, ceftriaxone, cefotaxime, ciprofloxacin, or levofloxacin, each in combination with metronidazole High risk or severity** Cefepime, ceftazidime, ciprofloxacin, or levofloxacin, each in combination with metronidazole *including perforated or abscessed appendicitis **severe physiologic disturbance, advanced age, or immunocompromised state Solomkin JS et al. Clin Infect Dis 2010;50:

18 Carbapenems Group 1 Group 2 Group 3 Nonfermentants No Yes Yes MRSA No No Yes Carbapenems Ertapenem Panipenem Tebipenem Imipenem Meropenem Doripenem Biapenem Tomopenem Razupenem

19 Newer carbapenems Bassetti M et al. Curr Med Chem. 2009;16:564-75

20 Relative activity of Carbapenems Gram-Positive Activity Gram-Negative Activity Imipenem Ertapenem Meropenem Doripenem

21 Spectrum of Carbapenems Organism Ertapenem Imipenem Meropenem MIC 50 MIC 90 MIC 50 MIC 90 MIC 50 MIC 90 E. faecalis E. faecium > MSSA MRSA > S. pneumoniae Acinetobacter spp Citrobacter spp Enterobacter spp E. coli P. aeruginosa

22 In vitro Activity of Antibiotics (% Susceptible) Against ESBL-Producing Organisms Kozlov RS et al. Final report of IISP No. MK-0826 RUSLS1292, 2009

23 Ertapenem h New 1-ß-methyl carbapenem licensed in 2003 h Significantly different properties from existing carbapenems h Significantly different uses

24 Carbapenem properties Stable to renal DHP1 Metabolism Renal Protein bound Ertapenem Imipenem - Cilastatin Yes No Yes I: Hepatic C: Renal Meropenem Renal ~94% 20% <10% Half life 4h 1h 1h

25 Ertapenem Human Pharmacokinetics [Total Ertapenem] PL (mg/l) Healthy Volunteers Single 1g dose 1 Bioavailability of IM Ertapenem > 90% Half-life ~ 4h 2 mg/l Time, hr IV IM

26 Ertapenem free concentration Spneumo pen-r Anaerobic bacteria ESBL Burkhardt O et al. J Antimicrob Chemother. 2007;59(2):277-84

27 RCTs involving Ertapenem Context Comparator Equivalence Intra-abdominal infection Pip/Taz 3.375g 6h Ceftriaxone 2g od + Metronidazole 500mg 8h Yes Yes Pelvic infection Pip/Taz 3.375g 6h Yes Complicated SSTI Pip/Taz 3.375g 6h Yes Community - acquired pneumonia Ceftriaxone 2g od Yes Complicated UTI Ceftriaxone 2g od Yes

28 Ertapenem: efficacy in intra-abdominal infections (mata-analysis) Clinical efficacy Adverse effects Falagas ME et al. Aliment Pharmacol Ther 2008; 27,

29 Bassetti M et al JAC 2007 Ertapenem in ESBL early VAP h 20 pts treated with ertapenem Respiratory culture Eradicated Persisted Klebsiella pneumoniae 12/14 [86%] 2/14 [14%] Enterobacter cloacae 2/2 [100%] 0 Proteus mirabilis 1 / 2 [50%] 1 / 2 [50%] Citrobacter freundii 0/2 2/2 [100%] Total 15/20 [75%] 5/20 [25%]

30 The Primary Goal Espoused in the IDSA/ SHEA Antibiotic Stewardship Guideline The primary goal of antimicrobial stewardship is to optimize clinical outcomes while minimizing unintended consequences of antimicrobial use, including toxicity, the selection of pathogenic organisms (such as Clostridium difficile), and the emergence of resistance. Dellit TH. Clin Infect Dis 2007;44:

31 Correlation Between Antibiotic Consumption and Resistance in P. aeruginosa Antibiotic class!hazard ratios! Ceftazidime!0.8! Piperacillin!5.2! Ciprofloxacin!9.2! Imipenem!44! Carmeli Y et al. Antimicrobial Agents Chemother. 1999;43:

32 Correlation Between Imipenem Consumption and Resistance of P. aeruginosa to Imipenem Imipenem resistance (%) Imipenem consumption (DDDs) Lepper PM et al. Antimicrob Agents Chemother. 2002;46:

33 Risk Factors for Imipenem-Resistant P. aeruginosa h A total of 779 isolated resulting in an incidence of 5.6 cases per 1,000 patient admissions (with an average % resistance of 21.6%) h Associated with a high incidence of imipenem-resistant P. aeruginosa by univariate analysis - Group 2 carbapenems (P <0.0001) - Aminoglycosides (P = 0.034) - Penicillins (P = 0.05) h Group 1 carbapenems not associated with imipenemresistant P. aeruginosa (P = 0.2) Carmeli Y et al. Diagn Microbiol Infect Dis 2011;70:

34 Impact of Ertapenem on Susceptibility of P. aeruginosa to Imipenem Retrospective analysis in a 344-bed community teaching hospital on the effect of ertapenem on susceptibility * *Autosubstitution of ertapenem for ampicillin-sulbactam in months 19 to 48 of the study Goldstein EJC et al. Antimicrob Agents Chemother 2009;53:

35 An Example of Optimizing Antibiotic Use Through an ASP: Carbapenem Stewardship* Suggestion that ertapenem best used as either empirical or directed therapy for infections due to aerobic gramnegative and mixed anaerobic bacteria where coverage of non-fermentative gram-negatives including Pseudomonas is not typically necessary or desirable Suspected infections due to ESBL-producing bacteria Polymicrobial complicated intra-abdominal infections where the probability of Pseudomonas is unlikely based on the medication history, clinical course, and demographics of the patient Potential role in de-escalation or step-down therapy from carbapenems when possible, with therapy being changed as necessary once culture data become available *Nicolau DP et al. Int J Antimicrob Agents 2012;39:11-15

36 Carbapenems in VAP h ICU carbapenembased regimen h After D3 therapy based on susceptibility results h Better empirical cover (81 vs 46%; p<0.01) Soo Hoo GW et al. Chest 2005;128:

37 When to Expect P. aeruginosa h Retrospective analysis from 4 hospitals patients and 152 controls h P. aeruginosa caused 6.8% of 4,114 episodes of Gram-negative bacteremia h Risk factors: severe immunodeficiency, OR: age >90, antimicrobials within 30 days, presence of central venous catheter or a urinary device - If 2 had over 25% risk for P. aeruginosa V Schechner et al, CID 48:580-6, 2009

38 An Approach to Clinical Therapeutics Centered on the Consideration of P. aeruginosa Pseudomonas Likely Pseudomonas Unlikely Penicillins Piperacillin Ampicillin Cephalosporins Carbapenems Ceftazidime Cefepime Imipenem Meropenem Doripenem Ceftriaxone Cefotaxime Ertapenem Fluoroquinolones Ciprofloxacin Moxifloxacin

39 Potential Benefits of a De-escalation Strategy: Recent Evidence ICU-acquired pneumonia in 137 patients: Safe when the patient is clinically stable by day 5 Patients in the de-escalation group showed a significantly lower mortality rate compared to patients in the non-de-escalation group o o Day 14, p=0.08 Day 30, p=0.03 (Days) Joung MK, et al. Crit Care. 2011:15;R79.

40 De-escalation in the ICU: A Retrospective Study All consecutive patients treated with empiric therapy in the ICU for 72 hours over a period of 16 months 116 patients with 133 infections All infections were examined, not just VAP De-escalation in 60 (45%) of cases De-escalation therapy was associated with a significant reduction of recurrent infection 15% vs. 5% (p = 0.02) De-escalation had no effect on mortality Morel J, et al. Crit Care. 2010:14;R225.

41 Potential Benefits of a De-escalation Strategy A reduction in overall antimicrobial costs Beneficial impacts on the antimicrobial resistance profile of the institution Decreased antibiotic-related adverse events Superinfection with resistant bacteria Clostridium difficile No alteration in treatment outcomes Masterton RG. Crit Care Clin. 2011:27;

42 Carbapenem Uses Ertapenem Imipenem Meropenem Doripenem h 1 st line for complicated community-acquired infection h Low risk of Pseudomonas/ Acinetobacter infection h Intra-abdominal infections h Directed therapy h De-escalation drug h Serious hospital-acquired infection h High risk of Pseudomonas/ Acinetobacter infection h Directed therapy