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Carbapenemases in Enterobacteriaceae: getting closer?
Date: 2009-01-07  Read: 7858

Dr. David M. Livermore

Health Protection Agency
Centre for Infections
Antibiotic Resistance Monitoring & Reference Laboratory
London, UK

Carbapenems are the sole b-lactams (except, perhaps, temocillin) retaining activity against Enterobacteriaceae with ESBLs and/or high-level AmpC enzymes. In the UK, carbapenem resistance is mostly confined to Pseudomonas aeruginosa with permeability mutations and Acinetobacter baumannii clones with OXA-carbapenemases, although there is also a scatter of Enterobacter and Klebsiella spp. isolates with combinations of an ESBL or AmpC enzyme and impermeability, conferring resistance to ertapenem and reducing susceptibility to other carbapenems. Whilst troublesome in individual patients these latter organisms have not spread and may be relatively unfit, with their impermeability also impairing nutrient uptake.  
In several other countries there has been recent substantial spread of Enterobacteriaceae with carbapenemases Klebsiella pneumoniae (mostly) with KPC enzymes in the USA and Israel, K. pneumoniae with VIM-1 in Greece and K. pneumoniae (mostly) with OXA-48 in Turkey.   Many KPC+ K. pneumoniae in both the US and Israel belong to one clone (ST, sequence type, 258); the Greek K. pneumoniae with VIM-1 enzyme, by contrast, are non-clonal and the problem is one of gene spread.   Metallo-carbapenemases of the VIM, IMP and (in Brazil) SPM families have been a greater problem in non-fermenters, principally P. aeruginosa, where there have been numerous large if localised clonal outbreaks worldwide whilst OXA carbapenemases are widespread in Acinetobacter spp.
Up to 1st Jan 2008, ARMRL, which is the national antibiotic resistance reference laboratory - to which any UK hospital can send resistant isolates, free gratis, for investigation - had received just four UK Enterobacteriaceae (three K. pneumoniae and one E. coli) with IMP metallo-carbapenemases (MBL), all of them lacking obvious overseas links and one K. pneumoniae with a VIM-type MBL, imported with a patient hospitalized in Greece; also two isolates (one Enterobacter and one K. pneumoniae) with KPC carbapenemases and one K. pneumoniae with OXA-48 enzyme (from a patient previously hospitalized in Turkey). During 2008 we received 17 more carbapenemase producers, thus doubling the total for all previous year combined. These comprised:
  • Five more K. pneumoniae with KPC carbapenemases. One was from a patient previously hospitalized in Israel and two were from those hospitalized in Greece, while the others had no apparent overseas links. At least five of the total of six K. pneumoniae producers to date belong to a single strain by PFGE and have a profile related to ST258; they are from five hospitals, with no obvious cross infection, though two in Scotland are potentially linked.
  • Nine K. pneumoniae with OXA-48 enzyme, none with defined overseas links. These isolates were from three patients at two hospitals, and, worryingly, from two residents at a nursing home; only the latter showed evidence of cross-infection; the other patients all had different strains.
  • Two K. pneumoniae with a VIM-type MBL, both linked to travel to Greece, and a Pantoea sp. with an IMP-type enzyme and no overseas link.
These totals are far fewer than the c. 150 referred ertapenem-resistant Enterobacteriaceae with combinations of ESBL or AmpC and impermeability, but the potential risk is greater since: (i) carbapenemase production is a more efficient resistance mechanism than the combination of impermeability and an ESBL, and (ii) overseas data, particularly, for the ST258 KPC-3+ K. pneumoniae illustrate the potential for major spread.  
Producers can be difficult to recognize. The ST258 strain typically is susceptible only to gentamicin, tigecycline and polymyxin and has clear resistance to all carbapenems, but (i) some US KPC+ isolates are obviously resistant only to ertapenem among carbapenems; (ii)  some MBL producers are not consistently resistant to carbapenems and, whilst EDTA-imipenem synergy tests can be used for confirmation, these are prone to give false positive results, though perhaps more often with non-fermenters than with Enterobacteriaceae; (iii) the resistance profiles of OXA-48-positive isolates are very variable.
UK advice -surely valid internationally- is that laboratories should be alert to the increase in carbapenemase-producing Enterobacteriaceae, to the threat posed, to the diversity of producers and enzymes, and to the detection issues.   They should be especially alert to carbapenem-resistant isolates from patients with a history of hospitalization in countries where carbapenemase-producing Enterobacteriaceae are prevalent particularly Greece, Turkey, Israel and the USA. Wherever possible, suspected producers should be sent to a reference laboratory for confirmation of resistance and identification of the enzyme involved. Where carbapenemase producers are confirmed, fullest infection control procedures should be followed.
Treatment presents major challenges.  Polymyxin is usually active in vitro, but of uncertain efficacy in pneumonia whilst tigecycline -also often active in vitro- has low serum levels and is of unproven efficacy in severe single pathogen infections. Aminoglycosides retain strain-variable activity and aztreonam is active against some, but not all, MBL producers.

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