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Screening Criteria for Carbapenem Resistant Enterobacteriaceae

Screening Criteria for Carbapenem Resistant Enterobacteriaceae. Fernando Baquero, Rafael Cantón Department of Microbiology Ramón y Cajal University Hospital, IRYCIS 28034 Madrid, Spain. Screening Criteria for Carbapenem Resistant Enterobacteriaceae.

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Screening Criteria for Carbapenem Resistant Enterobacteriaceae

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  1. Screening Criteria for Carbapenem Resistant Enterobacteriaceae Fernando Baquero, Rafael Cantón Department of Microbiology Ramón y Cajal University Hospital, IRYCIS 28034 Madrid, Spain

  2. Screening Criteria for Carbapenem Resistant Enterobacteriaceae Carbapenem-resistant………………For Therapy? Carbapenem-resistant….. = Carbapenemase producers?

  3. Carbapenem resistance and carbapenemases • Most carbapenemase producing Enterobacteriaceae are R to carbapenems but can be also S or I Carbapenemase producingEnterobacteriaceae (CPE) Susceptible (S) Intermediate (I) Resistant (R) Categories for clinical response to carbapenems

  4. Carbapenemase producingEnterobacteriaceae • MICs associated with carbapenemases might be below current breakpoints (… even below the ECCOFs)

  5. Carbapenemase producingEnterobacteriaceae carbapenemases The carbapenem breakpoints for Enterobacteriaceae will detect all clinically important resistance mechanisms (including the majority of carbapenemases). Some isolates that produce carbapenemase are categorised as susceptible with these breakpoints and should be reported as tested, i.e. the presence or absence of a carbapenemase does not in itself influence the categorisation of susceptibility. In many areas, carbapenemase detection and characterisation is recommended or mandatory for infection control purposes. EUCAST breakpoint tables v4.0, 2014

  6. Imipenem MIC distributions EUCAST

  7. Meropenem MIC distributions EUCAST

  8. Ertapenem MIC distributions EUCAST

  9. A) Imipenem ECOFF Clinicalbreakpoints S R Kp/Ecl Eco E. coli K. pneumoniae E. cloacae Carbapenems susceptibility criteria EUCAST mg/L B) Meropenem ECOFF Clinicalbreakpoints S R Eco/Kp/Ecl mg/L C) Ertapenem ECOFF Clinicalbreakpoints S R Eco/Kp/Ecl mg/L

  10. Carbapenem breakpoint (mg/L) evolution in Enterobacteriaceae over time FDA: Food and Drug Administration; CLSI: Clinical and Laboratory Standards Institute; EUCAST: European Committee on Antimicrobial Susceptibility Testing; EMA: European Medicines Agency; ECOFF: epidemiological cut-off values; S: susceptible; R: resistant; ND: not defined. Bold numbers indicate currently identical breakpoints for CLSI and EUCAST.

  11. The concept of resistance … pharmacologists Probabilities of Target Attainment (PTA) for Meropenem fAUC/MIC currently use by EUCAST and carbapenems Pharmacokinetic parameters used to obtain the PTA: - Volume of distribution (Vd): 20.8 L,CV 13% - Fraction unbound (Fu): 91% - Elimination half-life (t): 1.04 h, CV 19% - Infusion time: 0.5 h Eucast Rationale Document, 1.5, June 2009

  12. Carbapenems pharmacokinetic criteria

  13. Carbapenemase producingEnterobacteriaceae • Survival probability (Kaplan-Meier curves) of patients with VIM-producing • K. pneumoniaebloodstream infections according with susceptibility • to carbapenems (imipenem or meropenem): • Patients infected with a VIM-(+) • organism for which the MICs of • both imipenem and meropenem • were >4 mg/L were more likely • to die than those infected with a • VIM-(+) carbapenem-susceptible • of VIM-negativeorganisms • (P 0.044) VIM (+) and (-) MIC <4 VIM (+) MIC>4 … butnotallpatientsweretreatedwith carbapenems Daikos et al. Antimicrob Agents Chemother 2009; 53:1868-73

  14. Interpretive reading of AST results • Interpretative reading: do we have to apply to carbapenemase producing Enterobacteriaceae (CRE)? Carbapenemase positive isolate expert rule* resistant to all carbapenems (irrespective of MICs) *Currenty, both CLSI and EUCAST recommend to “report as tested” an do not have specific expert rules for CRE

  15. Carbapenemase producingEnterobacteriaceae • Bactericidal activity against CPE (VIM-1-producing K. pneumoniae) MIC: imipenem, meropenem, doripenem = 8 mg/L, ertapenem = 1 mg/L Morosini et al. 2011 • Presence of KPC in Enterobacteriaceae with carbapenem MICs 1-16 mg/L had no impact on the PD (%T>MIC) necessary for bacteriostasis by carbapenems Craig et al. 48th ICAAC, 2008, abstract A-029 • Animal models corroborates in vitro studies with MBL or KPC producing isolates Tzouvelekis et al. Clin Microbiol Infect 2014 May 29 [Epub ahead of print]

  16. Carbapenemase producing K. pneumoniae Inapropriate therapy Combinationtherapywith 2 active drugs, Monotherapy with A: oneof which was a carbapenem B: not including a carbapenem C: aminoglycoside D: carbapenem E: tigecycline F: colistin Tzouvelekis et al. Clin Microbiol Rev 2012; 25: 682-707

  17. Carbapenemase producing K. pneumoniae Results of carbapenem monotherapy in 50 infected patients with K. pneumoniae harboring carbapenemases from 15 studies (most VIM producers) 75.0% P = 0.02 % of failures 28.6% 5/17 3/12 2/7 2/6 6/8 MIC (mg/L) Tzouvelekis et al. Clin Microbiol Rev 2012; 25: 682-707

  18. Mortality in bloodstream infections and KPC-K. pneumoniae • Higher 30-day mortality rate in patients treated with monotherapy (54.3%) that those with combination (34.1%) therapy (P=0.02) • Significant decreased of mortality in patients treated with combination therapy including meropenem • Mortality (%): monotherapy • Kaplan-Meier curves (survival) Combination therapy Monotherapy Tumbarello et al. Clin Infect Dis 2012; 55: 943-50

  19. Mortality in bloodstream infections and KPC-K. pneumoniae • Higher 30-day mortality rate in patients treated with monotherapy (54.3%) that those with combination (34.1%) therapy (P=0.02) • Significant decreased of mortality in patients treated with combination therapy including meropenem • Mortality (%): combination therapy • Kaplan-Meier curves (survival) Combination therapy Monotherapy Tumbarello et al. Clin Infect Dis 2012; 55: 943-50

  20. Carbapenem resistance for clinicians: MIC, mechanisms, what matters? • Carbapenem MICs should be determined if clinically necessary • Do not use the clinical breakpoints to detect resistance mechanisms but the ECOFFs (or screening cut-off values) • Combine adequate susceptibility testing methods and go beyond MIC values to infer resistance mechanisms (interpretive reading) • In carbapenemase producing Enterobacteriaceae MIC values seem to be necessary to better define combination therapies • New clinical data are waiting for further supporting EUCAST and CLSI views • There are still unresolved problems in susceptibility testing of carbapenemase producing Enterobacteriaceae

  21. EUCAST created a subcommittee in 2012 to establish guidelines for the detection of resistance mechanisms of clinical and/or epidemiological importance www.eucast.org

  22. Guidelines for detection of resistance mechanisms and specific resistances of clinical and/or epidemiological importance Clinical breakpoints and screening cut-off valuesfor carbapenemase-producing Enterobacteriaceae

  23. Acknowledgments Breakpoints for carbapenemase-producing Enterobacteriaceae: Is the problem solved? Rafael Cantón,a,b Andrés Canut,c María Isabel Morosini,a,b Antonio Oliverb,d (submitted) www.eucast.org

  24. Problems with carbapenem susceptibility and CPE • Carbapenemase genes in isolates within the wild type population • Common hetero-resistance: difficulties to define MICs when using different and even the same inoculum Tato et al. J Clin Microbiol 2010; 48:4089-93 • Difficult correlation of MICs and outcome due to MIC variation when using different methods Weisenberg et al. Diagn Microbiol Infect Dis 2009; 64:233-5 • Difficult detection of certain carbapenemases (OXA-48) by commercial automatic systems when using MIC values Woodford et al. J Clin Microbiol 2010; 48: 2999-3002 . Failure . MIC (mg/L) Vitek Etest . ≤2 1 / 2 2 / 4 4 4 / 7 --- 8 --- 3 / 4 ≥16 2 / 2 2 / 3 Outcome in patients treated with carbapenems in monotherapy

  25. Mortality in bloodstream infections and KPC-K. pneumoniae • 30-day mortality rate in patients treated with combination therapy including meropenem stratified by meropenem MIC values Nonsurvivors Survivors 1/10 6/17 2/10 1/1 4/4 8/10 3/4 11/17 MIC (mg/L) Tumbarello et al. Clin Infect Dis 2012; 55: 943-50

  26. PK/PD breakpoints (expressed as mg/L) based on Monte Carlo simulations in healthy volunteers and in critically ill patients without renal dysfunction Bhavnani SM, Dudley MN, Landersdorfer L, Drusano GL, Craig WA, Jones RN, et al. Pharmacokinetic-pharmacodynamic basis for CLSI carbapenem susceptibility breakpoint changes, abstr A-1382. Abstr. 50th Intersci. Conf. Antimicrob. Agents Chemother, Boston, MA. 2010

  27. Clin Microbiol Infect 2011; 17: 1135-41 Efficacy of antimicrobial regimens used to treat infections caused by carbapenemase-producing Klebsiella pneumoniae

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