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Evidence from a New York City hospital of rising incidence of genetically diverse carbapenem-resistant Enterobacter cloacae and dominance of ST171, 2007-14.

Sir, The proliferation of carbapenem-resistant Enterobacteriaceae (CRE) over the past two decades signifies an escalating threat to modern healthcare. CRE are typically resistant to most antibiotic classes and produce infections associated with high mortality. Carbapenem resistance mediated by blaKPC has been described in all major Enterobacteriaceae, but can also result from alterations in porins combined with overexpression of endogenous AmpC enzymes. However, clinical infections have been largely restricted to Klebsiella pneumoniae, especially epidemic blaKPC-harbouring ST258. Recent studies report the local emergence of carbapenemresistant Enterobacter cloacae (CREC) internationally and in the USA, suggesting accelerating carbapenem resistance acquisition in this organism. The prevalence and population structure of CREC remain incompletely understood. Here we report an increase in CREC incidence at a tertiary care hospital in New York City over a 7 year period and characterize its molecular epidemiology. We retrospectively reviewed the proportion of E. cloacae nonsusceptible to carbapenems from 2007 to 2014 at our hospital using antibiogram data. We then investigated the clinical and molecular epidemiology of CREC isolates since 2010 using MLST. Isolate susceptibilities were determined using Vitek 2 and interpreted using recent CLSI guidelines, accounting for 2010 revisions to carbapenem MIC breakpoints. We PCR-amplified carbapenemase genes blaKPC, blaVIM, blaIMP, blaNDM and blaOXA-48, ampC b-lactamase and ompC and ompF porin genes. PCR products were sequenced to differentiate subtypes or identify non-functional mutations. Our institutional review board approved this study. Between 2007 and 2014, we observed a hospital-wide increase in the proportion of carbapenem-non-susceptible E. cloacae from 1.6% to 8.7% of isolates (Figure 1a). This corresponded to a 5-fold absolute increase in incidence (Figure 1b), ranging from 4.6% to 19% in ICU inpatients, 1.3% to 10% in non-ICU inpatients and 0% to 2.6% in outpatients. During the same time period the incidence of carbapenem-resistant K. pneumoniae, Escherichia coli and Proteus mirabilis remained stable or decreased (Figure 1a). We obtained clinical data for 56 consecutive patients with CREC, of whom 53 had initial isolates available for molecular typing. CREC largely affected patients requiring prolonged or recurrent hospitalizations and most had multiple comorbidities. The most common culture source was the respiratory tract (n1⁄424), followed by blood (n1⁄411) and urine (n1⁄410). Most isolates (79%) had meropenem MICs of ≥16 mg/L. While susceptibility to amikacin (95%) and polymyxin B (100%) was preserved, most isolates were resistant to gentamicin (73%), tobramycin (82%), levofloxacin (77%) and trimethoprim/sulfamethoxazole (89%). Both 30 day mortality (29%) and hospital mortality (46%) were high. MLST revealed substantial clonal diversity, as CREC isolates belonged to 26 different STs. ST171 accounted for nearly half of all isolates (n1⁄423, 43%), followed in frequency by ST78 (n1⁄46) (Figure 1c). All other STs were singletons (n1⁄424), including 11 novel STs. blaKPC-3 (n1⁄430), blaKPC-2 (n1⁄412) and blaKPC-4 (n1⁄42) were the predominant putative mechanisms of carbapenem resistance, whereas blaNDM occurred in one isolate (Figure 1d). ST171 and ST78 were found to harbour blaKPC-3, while blaKPC-2, blaKPC-4 and blaNDM occurred in unique STs. All carbapenemase-negative isolates harboured ampC genes and four out of eight contained premature stop codons in the ompC porin (Table S1, available as Supplementary data at JAC Online). The mechanism of resistance remains undetermined in four isolates with lower meropenem MICs. Our data support a highly concerning diversification of CRE beyond K. pneumoniae. While many CREC isolates belonged to diverse lineages, suggesting sporadic acquisition of blaKPC-encoding plasmids, we also observed the emergence and rapid spread of two CREC clones, ST78 and ST171. ST171 was first detected at a Western Pennsylvania hospital and has spread in the Midwestern USA. ST78 and ST171 also accounted for the majority of 20 CREC isolates at a Boston hospital. Based on these findings and recent reports in the literature, we propose that ST171 is emerging as a dominant CREC clone in the USA. Research letters