Integrated analysis of patient networks and plasmid genomes reveals a regional, multi-species outbreak of carbapenemase-producing Enterobacterales carrying bothbla_IMPandmcr-9genes

Abstract

The incidence of carbapenemase-producing Enterobacterales (CPE) is rising globally, yet Imipenemase (IMP) carbapenemases remain relatively rare. This study describes an investigation of the emergence of IMP-encoding CPE amongst diverse Enterobacterales species between 2016 and 2019 in patients across a London regional hospital network.A network analysis approach to patient pathways, using routinely collected electronic health records, identified previously unrecognised contacts between patients who were IMP CPE positive on screening, implying potential bacterial transmission events. Whole genome sequencing of 85 Enterobacterales isolates from these patients revealed that 86% (73/85) were diverse species (predominantly Klebsiella spp, Enterobacter spp, E. coli) and harboured an IncHI2 plasmid, which carried both blaIMP and the putative mobile colistin resistance gene mcr-9. Detailed phylogenetic analysis identified two distinct IncHI2 plasmid lineages, A and B, both of which showed significant association with patient movements between four hospital sites and across medical specialities.Combined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-mediated outbreak of blaIMPCPE, which remained unidentified during standard microbiology and infection control investigations. With whole genome sequencing (WGS) technologies and large-data incorporation, the outbreak investigation approach proposed here provides a framework for real-time identification of key factors causing pathogen spread. Analysing outbreaks at the plasmid level reveals that resistance may be wider spread than suspected, allowing more targetted interventions to stop the transmission of resistance within hospital networks.

Genomic dissection of endemic carbapenem resistance: metallo-beta-lactamase gene dissemination through clonal, plasmid and integron transfer pathways

“…To study this emergence, we demonstrated that bla IMP-4 IncHI2A plasmids were highly similar to non- bla IMP-4 IncHI2A plasmids in E. hormaechei ST93, ST114 and ST190 that may have served as acceptors for the bla IMP-4 integron. In addition, there was possible importation from outside sources: bla IMP-4 has been found in both IncHI2A and IncL/M plasmids in Australian isolates 2, 4, 9, 26 and bla IMP-4 -harbouring IncHI2A plasmids are emerging as a global issue, having been noted in a recent multi-hospital outbreak in the United Kingdom 27 .…”

“…In addition to pathogen factors, we were able to analyse patient factors. While genomic surveillance previously focused on lineage-level analysis, long-read sequencing technologies have improved analysis of plasmids and other mobile genetic elements 12, 27, 33 . In our study, these insights proved informative both for understanding within-patient and between-patient bla IMP-4 spread.…”