Update on CLSI and EUCAST

Transcription

1 Update on CLSI and EUCAST 1

2 Completed work» Cephalosporin breakpoints for Enterobacteriaceae ESBL screens MIC versus resistance mechanism» Carbapenem breakpoints for Enterobacteriaceae Modified Hodge Test» Fluoroquinolone breakpoints for Salmonella» Ceftaroline breakpoints» Cefepime breakpoints (revisited) for Enterobacteriaceae» Carbapenem breakpoints for Acinetobacter» Cephalothin vs cefazolin surrogate testing Work in Progress» Azithromycin breakpoints for Salmonella» Polymyxins breakpoints (jointly with EUCAST) Gram-negative activity 2

3 Completed work» Cephalosporin breakpoints for Enterobacteriaceae MIC versus resistance mechanism» Carbapenem breakpoints for Enterobacteriaceae» Fluoroquinolone breakpoints for Salmonella» Ceftaroline breakpoints» Carbapenem breakpoints for Acinetobacter Gram-negative activity» Oral cephalosporins and Enterobacteriaceae breakpoints (16 Feb 2012)» Stenotrophomonas maltophilia (1 Feb 2012)» Burkholderia cepacia group (20 July, 2013) Work in Progress» Detection of resistance mechanisms guidance» Polymyxins breakpoints (jointly with EUCAST) 3

4 A Consensus Issue «Report as Tested» For Enterobacteriaceae with β-lactamases 4

5 A Consensus Issue «Report as Tested» EUCAST:» The cephalosporin breakpoints for Enterobacteriaceae will detect all clinically important resistance mechanisms (including ESBL and plasmid mediated AmpC). Some isolates that produce beta-lactamases are susceptible or intermediate to 3rd or 4th generation cephalosporins with these breakpoints and should be reported as tested, i.e. the presence or absence of an ESBL does not in itself influence the categorisation of susceptibility. In many areas, ESBL detection and characterisation is recommended or mandatory for infection control purposes. CLSI:» When using the current interpretive criteria, ESBL testing is not longer necessary before reporting results (i.e. it is no longer necessary to edit results for cephalosporins, aztreonam or penicillins from susceptible to resistant).however, ESBL testing may still be useful for epidemiological or infection control purposes 5

6 A Consensus Issue «Report as Tested» CAN THIS REALLY BE TRUE AFTER ALL THESE YEARS? CAN I REALLY TRUST THE PIPERACILLIN- TAZOBACTAM RESULT? 6

7 In muride

8 Andes & Craig, CMI 2005 Multiple ESBL-negative and ESBL-positive strains of E. coli, Klebsiella spp., Enterobacter spp. and Serratia spp. ESBLs: TEM-3, TEM-7, TEM-12, TEM-26, SHV-2, SHV-4, SHV-5, SHV-7, CTX-M2, CTX-M3

9 Andes & Craig, CMI 2005 Justifiable Conclusions %T above MIC is predictive of bacterial kill in vivo» Independent of presence of an ESBL» Independent of type of ESBL It is the MIC that is predictive of kill, not the gene per se The MIC is related to level of gene expression If the ESBL is present, but expressed at a level such that MIC exceeds wild-type but is below the clinical breakpoint, the strain will respond normally to treatment using standard dosing regimens

10 In homine

11 The problem of proof Prospective controlled clinical studies (registration trials) usually have pre-determined breakpoints, and tend to either» exclude patients whose isolates have higher MICs or» recruit insufficient patients whose isolates have MICs around the near the breakpoint Real-world observational studies encounter problems too, e.g.:» Multiple agents used during treatment» Formal recording of MICs not done

12 The Wrong Breakpoints Experiment The CLSI breakpoints for cephalosporins prior to January 2010 allowed us to conduct a natural experiment:» Treatment of ESBL-producing Enterobacteriaceae with extended-spectrum generation cephalosporins whose MICs were at or below breakpoint ( 8 mg/l)

13 Outcome versus 3GC MIC Septicaemia from Klebsiella spp and E. coli with ESBLs Failure 100% 14 Success Failure 80% Success % % 4 20% 2 0 0% MIC (mg/l) MIC (mg/l) Data from Paterson et al JCM 2001; 39:2206; Kim et al AAC 2002; 46:1481; Wong-Beringer et al CID 2002; 34:135; Kang et al AAC 2004; 48:4574; Bhavnani et al DMID 2006; 54:231 Number of cases Number of cases Andes & Craig, CMI 2005; 11 (Suppl 6):10-17

14 Outcome versus Cefepime MIC Gram-negative Septicaemia treated with Cefepime 1-2g 12-hrly Number of cases Died Survived MIC (mg/l) Number of cases 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Died Survived MIC (mg/l) Bhat et al, AAC 2007; 51:4390-5

15 Daikos et al, AAC patients with bacteraemia Treatments were frequently combinations Data on single agent carbapenem treatment not given > 4 µg/ml used in analysis to both imipenem and meropenem despite different activities of the two drugs MIC not significant in Cox multivariate regression (>0.1)

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18 In the end... The MIC tells you all you need to know to treat patients An MIC is an MIC is an MIC (Apologies to Gertrude Stein, 1913) It s the MIC, stupid (Kahlmeter, 2007)

19 The Modified Hodge Test Old breakpoints only Only worked well for KPC

20 The Modified Hodge Test New Breakpoints

21 Breakpoints Carbapenemase detection Screening

22 Interpretation Carbapenemase detection

23 WorldCAST?