A Large, Refractory Nosocomial Outbreak of Klebsiella pneumoniae Carbapenemase-Producing Escherichia coli Demonstrates Carbapenemase Gene Outbreaks Involving Sink Sites Require Novel Approaches to Infection Control

Abstract

Carbapenem-resistant Enterobacteriaceae (CRE) represent a health threat, but effective control interventions remain unclear. Hospital wastewater sites are increasingly being highlighted as important potential reservoirs. We investigated a large Klebsiella pneumoniae carbapenemase (KPC)-producing Escherichia coli outbreak and wider CRE incidence trends in the Central Manchester University Hospital NHS Foundation Trust (CMFT) (United Kingdom) over 8 years, to determine the impact of infection prevention and control measures. Bacteriology and patient administration data (2009 to 2017) were linked, and a subset of CMFT or regional hospital KPC-producing E. coli isolates (n = 268) were sequenced. Control interventions followed international guidelines and included cohorting, rectal screening (n = 184,539 screens), environmental sampling, enhanced cleaning, and ward closure and plumbing replacement. Segmented regression of time trends for CRE detections was used to evaluate the impact of interventions on CRE incidence. Genomic analysis (n = 268 isolates) identified the spread of a KPC-producing E. coli outbreak clone (strain A, sequence type 216 [ST216]; n = 125) among patients and in the environment, particularly on 2 cardiac wards (wards 3 and 4), despite control measures. ST216 strain A had caused an antecedent outbreak and shared its KPC plasmids with other E. coli lineages and Enterobacteriaceae species. CRE acquisition incidence declined after closure of wards 3 and 4 and plumbing replacement, suggesting an environmental contribution. However, ward 3/ward 4 wastewater sites were rapidly recolonized with CRE and patient CRE acquisitions recurred, albeit at lower rates. Patient relocation and plumbing replacement were associated with control of a clonal KPC-producing E. coli outbreak; however, environmental contamination with CRE and patient CRE acquisitions recurred rapidly following this intervention. The large numbers of cases and the persistence of bla_KPC in E. coli, including pathogenic lineages, are of concern.

Keywords: antimicrobial resistance; carbapenemase-producing Enterobacteriaceae; genome sequencing; infection control; molecular epidemiology.

FIG 1

(A) Numbers of individuals in MHC wards with first CRE-positive detection, by week, stratified by genus group and species of the organism isolated. The bla_KPC-positive Enterobacteriaceae strains detected in environmental samples over the same time frame are also shown. The MHC outbreak was declared by the IPC team in the first week in 2015 (arrow). (B) Timeline of IPC measures instituted.

FIG 2

(A and B) Counts of individuals with first CR E. coli detection by ward location. Detections on days 0 and 1 of admission are excluded. Faint vertical lines correspond to the boundaries of the 4 time periods, as follows: period 1 (P1), prior to implementation of a systematic CPE rectal screening policy; period 2 (P2), implementation of a CPE rectal screening policy consistent with national guidance; period 3 (P3), closure of wards 3 and 4 and replacement of plumbing infrastructure; period 4 (P4), reopening of wards 3 and 4 to patient admissions. (C) Incidence rate ratios for rates of first positive CR E. coli detection, carbapenem-resistant K. pneumoniae detection, and any CRE detection ≥2 days postadmission, relative to period 2 in the same location (MHC versus the rest of CMFT). An incidence rate ratio is not shown for period 3 in the MHC due to unit closure during this period, to facilitate plumbing replacement.

FIG 3

Recombination-corrected phylogeny of 259 sequenced KPC-producing E. coli isolates (and 9 E. coli isolates that were bla_KPC negative on sequencing) from CMFT and other regional hospitals in northwest England, annotated with collection date, ward/center location, Tn4401 type, and outbreak plasmid types. The earliest available sequences per patient are denoted “first carbapenem-resistant E. coli from patient” if the stored isolate collection date was ≤7 days from the first isolation date in the TRACE database or “sequential carbapenem-resistant E. coli from patient” if the stored isolate date was after that. KPC-producing E. coli isolates from a Public Health England (PHE) project that sequenced the first 10 KPC-producing Enterobacteriaceae strains from hospitals in northwest England (2009 to 2014) are denoted “regional study isolate.” “Environmental isolate” denotes KPC-producing E. coli strains cultured during an initial environmental prevalence survey on wards 3 and 4 (10 March 2015), any KPC-producing E. coli strain isolated as part of subsequent, intermittent, IPC-associated environmental sampling (9 April 2015 to 17 November 2015), and isolates available at the time of analysis from environmental and patient samples from a separate ongoing study (commenced January 2016).

FIG 4

(A) Alignments of the 2012 MHC outbreak KPC plasmid pKPC-CAD2 (wards 45 and 46; Tn4401a plus bla_KPC) and the 2015 MHC KPC plasmid pKPC-CAD1 (Tn4401a plus bla_KPC), highlighting the recombination of the Tn4401a- and bla_KPC-harboring 48-kb segment from pKPC-CAD2 with pCAD3 to generate pKPC-CAD1. Regions of sequence homology are represented by pink links drawn between alignments. pKPC-272 (GenBank accession no. CP008825.1), a plasmid identified in an isolate from a sink drain at the National Institutes of Health Clinical Centre in Maryland in 2012, demonstrates significant sequence homology with pKPC-CAD2. (B) Incidence plot of different E. coli STs and likely MHC-related KPC plasmid types across hospital locations.