In-host intra- and inter-species transfer of blaKPC-2 and blaNDM-1 in Serratia marcescens and its local and global epidemiology.

Objectives: This study aimed to investigate interspecies transfer of resistance gene bla_NDM-1 and intraspecies transfer of bla_KPC-2 in Serratia marcescens, and explore the epidemical and evolutionary characteristics of carbapenemase-producing S. marcescens (CPSM) regionally and globally.

Methods: Interspecies and intraspecies transfer of bla_KPC-2- or bla_NDM-1 were identified by antimicrobial susceptibility testing, plasmid conjugation and curing, discovery of transposable units (TUs), outer membrane vesicles (OMVs), qPCR, whole-genome sequencing and bioinformatic analysis. The genomic evolution of CPSM strains was explored by cgSNP and maximum-likelihood phylogenetic tree.

Results: CPSM S50079 strain, co-carrying bla_KPC-2 and bla_NDM-1 on one plasmid, was isolated from the blood of a patient with acute pancreatitis and could generate TUs carrying either bla_KPC-2 or bla_NDM-1. We identified the interspecies transfer of bla_NDM-1-carrying plasmid from Providencia rettgeri P50213, producing the identical bla_NDM-1-carrying TUs, to S. marcescens S50079K, an S50079 variant via plasmid curing, through bla_NDM-1-harboring plasmid conjugation and OMVs transfer. Furthermore, the intraspecies transfer of bla_KPC-2, mediated by IS26 from plasmid to chromosome in S50079, was identified. Likely, in another lung transplant patient, interspecies transfer of bla_NDM-1 carried by IncX3 plasmid was also identified among S. marcescens and Citrobacter freundii as well as Enterobacter hormaechei via plasmid transfer. Furthermore, 11 CPSM from 349 non-repetitive S. marcescens strains were identified in the same hospital and clonal dissemination, with carbapenemase evolution from bla_KPC-2 to both bla_KPC-2 and bla_NDM-1 was found in the 8 CPSM across four years. Finally, the analysis of 236 global CPSM from 835 non-repetitive S. marcescens genomes, retrieved from NCBI database, revealed long-term spread and evolution worldwide, and would cause the convergence of more carbapenemase genes.

Conclusions: Interspecies transfer of resistance gene bla_NDM-1 and intraspecies transfer of resistance gene bla_KPC-2 in CPSM were identified. Nosocomial and global dissemination of CPSM were revealed and more urgent surveillance was acquired.