Expert rules. for Gram-negatives

Transcription

1 Academic Perspective in Expert rules Emerging Issues of Resistance in Gram-ve Bacteria for Gram-negatives Trevor Winstanley Sheffield Teaching Hospitals Presented on behalf of David Livermore University of East Anglia & Health Protection Agency

2 Inherent resistance we can agree on, Enterobacteriaceae All except E. coli & P. mirabilis - ampicillin Klebsiella - ticarcillin AmpC-inducible species - ampicillin, co-amoxiclav, 1-gen cephs Serratia, Proteeae - colistin and nitrofurantoin Proteeae - tetracyclines & tigecycline

3 Inherent resistance we mostly agree on - non-fermenters Pseudomonas, Acinetobacter - ampicillin, cephs except ceftazidime, tetracycline, chloramphenicol, ertapenem S. maltophilia - all -lactams except ticar-clav, aminoglycosides, trimethoprim alone Burkholderia - aminoglycosides & colistin Elizabethkingella - -lactams except pip-tazo

4 Exceptional resistance Enterobacteriaceae meropenem / imipenem P. aeruginosa, Acinetobacter colistin Bacteroides metronidazole & carbapenems I d add, in UK context E. coli tigecycline P. mirabilis ESBL Bacteroides co-amoxiclav / pip-tazo

5 AmpC-inducible species --- not too contentious If S to cefotaxime, ceftriaxone or ceftazidime THEN use as monotherapy should be discouraged owing to the risk of selecting resistance, or suppress these results risk is absent or diminished for cefepime and cefpirome...may still fail with aminoglycoside added BUT... combination with quinolone has been found protective

6 EUCAST rules. Quinolones & G-ves Enterobacteriaceae R to ciprofloxacin Report R to all fluoroquinolones Salmonella with cipro MIC >0.06 mg/l Report R to all fluoroquinolones Leclercq et al., CMI 2011 epub 21 Oct

7 Reporting for ESBL producers EUCAST Cephalosporin breakpoints for Enterobacteriaceae will detect clinically-important resistance mechanisms (including ESBLs) Some strains that produce -lactamases are susceptible or intermediate to third- or fourth- generation cephalosporins with these breakpoints, and should be reported as found. Leclercq et al., CMI 2011 epub 21 Oct

8 Don t seek ESBLs just have a low breakpoint Better ceph outcomes vs. ESBL producers if MICs <1-2 mg/l -Lactamase vulnerability does not guarantee resistance Pharmacodynamic modelling suggests activity Animal experiments suggest that ceph efficacy reflects MIC Not presence of a ESBL Omitting ESBL tests saves time and money Andes, Craig. CMI 2005; 11 Suppl 6: 10 Maglio et al. AAC 2004; 48: 1941

9 Outcome & MIC bacteraemias with ESBL-klebsiellae Patient Source Ceph MIC Outcome (mg/l M72 VAP Ceftazidime 16 Fail M76 Central line Ceftriaxone 16 Fail M58 HAP Ceftriaxone 12 Fail, 48h M39 Central line Ceftriaxone 8 Fail, F35 Surg wound Cefotaxime 4 Fail M48 Unknown Cefepime 2 Fail M49 Peritonitis Ceftriaxone 1.5 Cure F73 VAP Cefepime 1.5 Cure M25 VAP Cefepime 0.5 Fail, died septic F25 Central line Ceftazidime 0.5 Cure Paterson et al., J Clin Microbiol 2001; 39: 2206

10 Why we think EUCAST (& CLSI) ESBL advice is wrong Pharmacokinetics more variable than we admit Outcomes are inconsistent vs. low-mic ESBL & carbapenemase producers Inoculum effect (TW) Susceptibility tests less precise than we wish Mechanism detection will become faster than susceptibility testing Livermore et al. JAC 2012;67:1569

11 Pharmacodynamics integrates MICs & pk Serum peak = C max AUC MIC T>MIC Monte Carlo simulation models the population scatter on the time curves

12 Sepsis & antibiotic pk Conc interstitium (mg/l) Muscle of healthy volunteers Adipose tissue of healthy volunteers Muscle of septic patients Adipose tissue of septic patients Piperacillin 4 g in 10 min APACHE II score (36-66) Time after infusion (min) Joukhadar et al. Crit Care Med 2001;29:385

13 CTX-M extended-spectrum -lactamases worldwide CTX-M-15 / 3 CTX-M came late CTX-M-15 now spreading CTX-M-15 / 3 CTX-M-9 / 14 CTX-M-15 / 3 CTX-M-9 / 14 CTX-M- 15 / 3 CTX-M-2 CTX-M-2 Israel 13 Hawkey, Jones. JAC 2009;64 (Suppl 1):i3

14 MICs for ESBL producers R- TEM-1 TEM-12 TEM-10 CTX- M-15 CTX- M-14 Ceftazidime Cefotaxime Ceftriaxone Livermore et al. JAC 2012;67:1569 Worldwide East Asia Spain Burnout of ST131 CTX-M-15 Strain A Ceftazidime 1-4 (UK) CTX-M-2 Ceftazidime 2 (Israel, Argentina) [TW]

15 Ceftazidime MICs for Enterobacteria with CTX-M-9/14 ESBLs Livermore et al. JAC 2012;67:1569

16 Outcome & MIC in bacteraemias with CTX-M-3/-14 E. coli; ceftazidime 2g q8h Patient Source MIC (mg/l Outcome M62 UTI 8 Cure F49 Peritonitis 1 Responded, but drainage needed F36 UTI 2 Cure M45 Biliary infection 2 Cure M67? 2 Cure F76 HAP 8 Cure F38 UTI 0.5 Cure Bin et al., DMID 2006; 56: 351

17 ESBL E coli infections treated with ceftazidime: all zones >18 mm Patient Infection Ceftazidime MIC (mg/l) Outcome F70 Peritonitis 1 Died, Sepsis F72 UTI 1 Died, Despite switch to imipenem F69 UTI 0.75 Fail, Resolved on gentamicin M49 Liver abscess >16, not CTX-M Died, Persistent infection F82 UTI 0.06 Cured M67 1 o bacteraemia 0.5 Cured F83 UTI 0.25 Cured Initial response to amoxclav Hong Kong; CTX-M-14; MICs determined subsequently Ho et al., Scand JID 2002; 34:567 Livermore et al. JAC 2012;67:1569

18 Carbapenem R x in infections with KPC Klebsiella Patient Site MIC imipenem Days Outcome Vitek Etest imipenem M76 Respiratory mero Failed M82 Blood Cure M92 Respiratory Cure F64 Respiratory Failed F69 Respiratory Failed F46 Blood Cure M77 Respiratory 4 >32 7 Failed F61 UTI 2 >32 7 Cure M52 UTI Failed F60 Blood > mero Failed M60 Respiratory > mero Cure Weisenberg et al., DMID 2009;64:233

19 In short. It s not so clear that cephalosporin & carbapenem MICs of 1-4 mg/l are associated with satisfactory outcomes. Next key point The lab doesn t determine precise MICs anyway

20 E. coli NCTC K-12 derivative with TEM-10, a ceftazidimase MIC mg/l Ceftazidime >128 Cefotaxime 1-2 Ceftriaxone 1-2 Cefepime labs each did disc tests 10 times Livermore et al. JAC 2012;67:1569-7

21 NCTC13352: ceftazidime 30 g discs: 10 tests/lab Mean zone (mm) SD (mm) > <25 Lab Lab Lab Lab S I R Livermore et al. JAC 2012;67:1569-7

22 NCTC13352: cefotaxime 30 g discs: 10 tests/lab Mean zone (mm) SD (mm) > <23 Lab Lab Lab Lab S I R Livermore et al. JAC 2012;67:1569-7

23 NCTC13352: cefepime 30 g discs: 10 tests/lab Mean zone (mm) SD (mm) > <26 Lab Lab Lab Lab S I R Livermore et al. JAC 2012;67:1569-7

24 Carbapenem R x in infections with KPC Klebsiella Patient Site MIC imipenem Days Outcome Vitek Etest imipenem M76 Respiratory mero Failed M82 Blood Cure M92 Respiratory Cure F64 Respiratory Failed F69 Respiratory Failed F46 Blood Cure M77 Respiratory 4 >32 7 Failed F61 UTI 2 >32 7 Cure M52 UTI Failed F60 Blood > mero Failed M60 Respiratory > mero Cure Weisenberg et al., DMID 2009;64:233

25 Next (& say it in whispers ) For the seriously-ill patient, fast microbiology is more valuable than precise microbiology And, mostly, microbiology moves at the pace it did in Fleming s time: 48h from specimen to susceptibility result Far more potential to accelerate seeking resistance genes than phenotypes

26 EUCAST rules. Aminoglycosides & G-ves Gent Tobra Amik Netil Action Logic S I/R S - Amik to I AAC(6 )-I I S S - Gent to R low AAC(3)-I R I S - Tobra to R ANT(2 ) I/R I/R - I Netil to R AAC(3 )-II or AAC(3 )-IV Leclercq et al., CMI 2011 epub 21 Oct

27 Summary Good reminder of intrinsic and exceptional resistance Inconsistent on phenotype implications Brave on ESBLs & carbapenemases