Defining nosocomial transmission of and antimicrobial resistance genes: a genomic surveillance study.

Background: is a leading cause of bloodstream infections. Developing interventions to reduce infections requires an understanding of the frequency of nosocomial transmission, but the available evidence is scarce. We aimed to detect and characterise transmission of and associated plasmids in a hospital setting.

Methods: In this prospective observational cohort study, patients were admitted to two adult haematology wards at the Cambridge University Hospitals NHS Foundation Trust in England. Patients aged 16 years and older who were treated for haematological malignancies were included. Stool samples were collected from study participants on admission, once per week, and at discharge. We sequenced multiple isolates (both extended spectrum β-lactamase [ESBL]-producing and non-ESBL-producing) from each stool sample. A genetic threshold to infer transmission was defined by maximum within-host single nucleotide polymorphism (SNP) diversity and the probability of drawing observed pairs of between-patient isolates at different SNP thresholds. Putative transmission clusters were identified when sequences were less than the genetic threshold. Epidemiological links for each transmission event were investigated. We sequenced all positive blood samples from the two adult haematology wards.

Findings: We recruited 174 (51%) of 338 adult patients admitted to the wards between May 13 and Nov 13, 2015. We obtained and cultured 376 stool samples from 149 patients, of which 152 samples from 97 (65%) patients grew . Whole-genome sequencing was done on 970 isolates. We identified extensive diversity in the bacterial population (90 sequence types) and mixed sequence type carriage. 24 (26%) patients carried two sequence types, 12 (13%) carried three, and six (6%) patients carried four or more sequence types. Using a 17 SNP cutoff we identified ten clusters in 20 patients. The largest cluster contained seven patients, whereas four patients were included in multiple clusters. Strong epidemiological links were found between patients in seven clusters. 17 (11%) of 149 patients had stool samples positive for ESBL-producing , the most common of which was associated with (12 [71%] of 17). Long-read sequencing revealed that was often integrated into the chromosome, with little evidence for plasmid transmission. Seven patients developed bloodstream infection, four with identical strains to those in their stool; two of these had documented nosocomial acquisition.

Interpretation: We provide evidence of bacterial transmission and endogenous infection during routine care by integrating genomic and epidemiological data and by determining a genetic cutoff informed by within-host diversity in the studied population. Our findings challenge single colony-based investigations, and the widely accepted notion of plasmid spread.

Funding: UK Department of Health, Wellcome Trust, UK National Institute for Health Research.