Carbapenemases in Enterobacteriaceae: Prof P. Nordmann Bicêtre hospital, South-Paris Med School

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1 Carbapenemases in Enterobacteriaceae: 2012 Prof P. Nordmann Bicêtre hospital, South-Paris Med School

2 March 21, 2012

3 Trends in Molecular Medecine NDM IMP OXA-48 KPC VIM ALERT VI M KPC KPC NDM I MP OXA- 48 OXA- 181 KPC Carbapenemase producing Enterobacteriaceae : Here is the storm! April, 2012, Volume XX, Issue YY Nordmann, Dortet, Poirel

4 Defining a Carbapenemase Definition debated... β-lactamases able to hydrolyse carbapenems; imipenem, meropenem, ertapenem. Enzymes with imipenemase activity; Most, but not all, hydrolyse many β- lactams i.e cephalosporins Not all carbapenemases confer clinically significant carbapenem resistance.

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8 E. coli, et E. cloacae (Petrella, AAC, 2008) E. Cloacae KPC-3 (JAC, 2009) Naas, Nordmann, Vedel, Poyart AAC 2005, 49 ;

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12 Combined Mechanisms of Resistance IMP IMP + EDTA AMC ATM ESBL (SHV-12) and metallo-ß-lactamase (IMP-4) Poirel et al., Pathology, 2004, 36, 366-8

13 EID, Nordmann et al. 2011

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18 Resistance genes including -9 ß-lactamase genes including -3 carbapenemase gene and 1 ESBL gene -16S RNA methylase gene -Rifampicin ribosylation gene -Chloramphenicol acetylase -Point mutation in gyrases

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20 NDM Canada EUROPE USA Morocco Algeria Cameroon Egypt Israel Pakistan Bangladesh Iraq Oman Kenya India China South-Korea Taiwan Hong Kong Singapore Japan South Africa Mauritius Australia STAR SIZE 1-5 cases 6-50 cases >50 cases

21 NDM Canada USA Ireland Spain Morocco Algeria Cameroon Egypt Switzerland Israel China Pakistan Bangladesh Iraq Oman Kenya India South Korea Taiwan Hong Kong Singapore Japan South Africa Mauritius Australia STAR SIZE 1-5 cases 6-50 cases >50 cases

22 Infections with NDM producers E. coli, Klebsiella, Enterobacter, Serratia, Citrobacter, Pseudomonas, Acinetobacter Asymptomatic colonisation Wound infection / Diabetic foot Lower urinary tract infection Upper urinary tract infection SEVERITY Nosocomial pneumonia / VAP Intra-abdominal / pelvic infection Bacteraemia / septicaemia Neurosurgical meningitis

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32 in India

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37 The Netherlands Switzerland Germany Belgium UK Ireland France Spain Morocco Algeria Tunisia Italy Russia Slovenia Turkey Georgia Lebanon Israel Jordan Egypt Lybia Senegal Single OXA-48-like-producing isolates Outbreaks of OXA-48-like-producing isolates Nationwide distribution of OXA-48-like-producing isolates Sultanate of Oman Kuwait India

38 The Netherlands Switzerland Germany Belgium UK Ireland France Spain Morocco Algeria Tunisia Italy Russia Slovenia Turkey An unique ca. 62 kb OXA-48 plasmid Georgia Lebanon Israel Jordan Egypt Lybia Senegal Single OXA-48-like-producing isolates Outbreaks of OXA-48-like-producing isolates Nationwide distribution of OXA-48-like-producing isolates Sultanate of Oman Kuwait India

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41 Carbapenemases- Enterobactericeae reservoirs VIM? KPC KPC OXA-48? IMP-VIM OXA-48 NDM-1? KPC? KPC OXA-48/OXA181

42 Spread of carbapenemase producers in Enterobacteriacae in Europe Endemic Interregional spread Regional spread Independent hospital outbreaks Single hospital outbreaks Sporadic occurrence Not reported / no data Canton R et al. CMI in press

43 Non-susceptibility rates of Klebsiella pneumoniae in Europe % of isolates Canton R et al. CMI in press

44 Case number (single case + outbreaks) of carbapenemases reported in France since 2004

45 Carbapenemase producers according to carbapenemase type and origin - France

46 Transfer of OXA-48-like producers to France

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48 However Carbapenem non-susceptible isolates do not necessary produce carbapenemases ESBL production + permeability defects may lead to resistance, in particular to ertapenem AmpC production + permeability defects may lead to resistance, including to imipenem

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50 Conclusion - Increase prevalence of carbapenemase producers worldwide - Carbapenemase producers; multiplicity of clones and of genetic vectors - Spread of carbapenemase producers (NDM, OXA-48) in the community (++ E. coli) is an important source of concern - Difficult detection; a need for rapid identification techniques - Multidrug resistance and pandrug resistance: reversion of multidrug resistance in Gram negatives is rare

51 Antibiotics in the pipeline Number of compounds Focus of activity U. Theuretzbacher: IJAA, Feb. 2012

52 Our medical duty in 2012; preventing the SPREAD of carbapenemase producers in Enterobacteriacae

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55 Detection of carbapenemase producers as colonizers of the intestinal flora CHROMagar KPC (carbapenemase producers) contains a carbapenem Oxoid Brillance CRE agar (Thermo Fisher) contains a carbapenem ESBL ID biomérieux (Carbapenemase and ESBL producers) contains a cephalosporin

56 A novel screening medium (SUPER CARBA medium) Combines many advantages Excellent sensitivity for OXA-48 producers thanks to a low concentration of the carbapenem for MBL producers (especially NDM) thanks to the addition of zinc ions Excellent specificity supplemented with a carbapenem, not a cephalosporin (no growth of an ESBL+ and carbapenem susceptible strain) supplemented with cloxacillin (no growth of an AmpC-mediated carbapenem non-susceptible strain) Nordmann, Girlich, and Poirel, J. Clin Microbiol. 2012, in press

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