Genomic investigation of multi-species and multi-variant blaNDM outbreak reveals key role of horizontal IncN and IncX3 plasmid transfer

Abstract

Objectives: New Delhi metallo-beta-lactamases (NDMs) are major contributors to the spread of carbapenem resistance globally. In Australia, NDMs were previously associated with international travel but from 2019 we noted increasing NDM episodes. We conducted an investigation to determine the clinical and genomic epidemiology of NDM-carriage at a tertiary Australian hospital from 2016-2021. Methods: We identified 49 patients with 84 NDM-carrying isolates in an institutional database and collected clinical data from electronic medical records. Short- and long-read whole genome sequencing was performed on all isolates. Completed genome assemblies were used to assess the genetic setting of blaNDM genes and compare NDM plasmids. Results: Of 49 patients, 38 (78%) were identified in 2019-2021 and only 11/38 (29%) reported prior travel compared with 9/11 (82%) in 2016-2018 (P=0.037). In patients with NDM infection, crude 7-day mortality was 0% and 30-day mortality was 14% (2/14 patients). NDMs were noted in 41 bacterial strains (i.e. species/sequence type combinations). Four NDM variants (blaNDM-1, blaNDM-4, blaNDM-5, blaNDM-7) were detected across 13 plasmid groups. We noted a change from a diverse NDM plasmid repertoire in 2016-2018 to the emergence of conserved blaNDM-1 IncN and blaNDM-7 IncX3 epidemic plasmids with inter-strain spread in 2019-2021. These plasmids were noted in 19/38 (50%) patients and 35/68 (51%) genomes in 2019-2021. Conclusions: Increased NDM case numbers were due to local circulation of two epidemic plasmids with extensive inter-strain transfer. Our study underscores the challenges of outbreak detection when horizontal transmission of plasmids is the primary mode of spread.