In-host intra- and inter-species transfer of bla and bla in Serratia marcescens and its local and global epidemiology.

Objectives: The aim of this study was to investigate interspecies transfer of resistance gene bla and intraspecies transfer of resistance gene bla 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- or bla were identified by antimicrobial susceptibility testing, plasmid conjugation and curing, discovery of transposable units (TUs), outer membrane vesicles (OMVs), qPCR, whole-genome sequencing (WGS) 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 and bla on one plasmid, was isolated from the blood of a patient with acute pancreatitis and could generate TUs carrying either bla or bla. The interspecies transfer of bla-carrying plasmid from Providencia rettgeri P50213, producing the identical bla-carrying TUs, to S. marcescens S50079K, an S50079 variant via plasmid curing, was identified through bla-harbouring plasmid conjugation and OMVs transfer. Moreover, the intraspecies transfer of bla, mediated by IS26 from plasmid to chromosome in S50079, was also identified. In another patient, who underwent lung transplantation, interspecies transfer of bla carried by IncX3 plasmid was 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 to both bla and bla, was found in the 8 CPSM across 4 years. Finally, the analysis of 236 global CPSM from 835 non-repetitive S. marcescens genomes, retrieved from the 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 and intraspecies transfer of resistance gene bla in CPSM were identified. Nosocomial and global dissemination of CPSM were revealed and more urgent surveillance was acquired.