Abstract
BackgroundEnterococcus faecium is a leading cause of hospital-acquired infection, particularly in the immunocompromised. Here, we use whole genome sequencing of E. faecium to study within-host evolution and the transition from gut carriage to invasive disease.MethodsWe isolated and sequenced 180 E. faecium from four immunocompromised patients who developed bloodstream infection during longitudinal surveillance of E. faecium in stool and their immediate environment.ResultsA phylogenetic tree based on single nucleotide polymorphisms (SNPs) in the core genome of the 180 isolates demonstrated several distinct clones. This was highly concordant with the population structure inferred by Bayesian methods, which contained four main BAPS (Bayesian Analysis of Population Structure) groups. The majority of isolates from each patient resided in a single group, but all four patients also carried minority populations in stool from multiple phylogenetic groups. Bloodstream isolates from each case belonged to a single BAPS group, which differed in all four patients. Analysis of 87 isolates (56 from blood) belonging to a single BAPS group that were cultured from the same patient over 54 days identified 30 SNPs in the core genome (nine intergenic, 13 non-synonymous, eight synonymous), and 250 accessory genes that were variably present. Comparison of these genetic variants in blood isolates versus those from stool or environment did not identify any variants associated with bloodstream infection. The substitution rate for these isolates was estimated to be 128 (95% confidence interval 79.82 181.77) mutations per genome per year, more than ten times higher than previous estimates for E. faecium. Within-patient variation in vancomycin resistance associated with vanA was common and could be explained by plasmid loss, or less often by transposon loss.ConclusionsThese findings demonstrate the diversity of E. faecium carriage by individual patients and significant within-host diversity of E. faecium, but do not provide evidence for adaptive genetic variation associated with invasion.
Highlights
Enterococcus faecium is a leading cause of hospital-acquired infection, in the immunocompromised
The majority of isolates from each patient resided in a single BAPS group, the four patients carried minority populations in stool that belonged to multiple BAPS groups, a diversity that was maintained over time (Additional file 3: Figure S2)
Bloodstream isolates from each patient belonged to a single BAPS group that differed in each individual (Fig. 1a, b)
Summary
Enterococcus faecium is a leading cause of hospital-acquired infection, in the immunocompromised. Bacterial characterisation using multilocus sequence typing (MLST) has demonstrated that hospital-adapted E. faecium are genetically distinct from commensal isolates [2] and cluster within clonal complex (CC) 17, designated as clade A1 [3]. Isolates belonging to this clade are globally disseminated and have been linked to numerous healthcare-associated outbreaks [4,5,6]. We extend these findings through the study of four patients who developed E. faecium bloodstream infection while undergoing longitudinal surveillance of stool carriage, and from whom multiple colonies were sequenced from stool, blood cultures and their environment
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