Penkevich, A. | Search bioRxiv

bioRxiv2026

Population genetic structure of disease-causing vancomycin-resistant Enterococcus faecium in a hospital closely reflects the dynamics of colonizing populations in patients

Vancomycin-resistant Enterococcus faecium (VREfm) is a common nosocomial pathogen that can lead to severe and difficult-to-treat infections. VREfm effectively exploits healthcare environments because transmission chains are difficult to prevent and eradicate. VREfm also readily acquires antimicrobial resistance (AMR), strongly reducing the likelihood of treatment success. Here we compare the genetic population structure and antimicrobial resistance load of VREfm strains that are typically associated with patient colonization, and those found to cause disease. We use two separate but contemporaneous collections of clinical bacterial isolates in a tertiary care medical center: one consisting of Enterococcus from blood samples, and a second originating from a hospital wide surveillance strategy screening for VREfm in perirectal swabs of incoming patients. Using whole-genome sequencing and analysis of 2061 VREfm clones, we found that the genetic structure of colonizing and disease-causing VREfm closely resemble each other, and that sequence type 117 (ST117) played an important role in shaping these populations. The population structures of strains acquired at the hospital and those present on arrival are also remarkably similar. We further observed a high likelihood that the colonizing clone genetically resembles the disease-causing strain in patients who are both colonized and infected. Finally, the AMR gene load and distribution did not vary significantly between the blood isolates and the gut-associated strains. Altogether, our results highlight the similarities between colonizing and infectious VREfm populations and further emphasize the need to focus infection prevention strategies to minimize gut colonization. Author SummaryVancomycin-resistant Enterococcus faecium (VREfm) often lives harmlessly in the human gut but can cause life-threatening infections when it enters the bloodstream. Hospitals struggle with is pathogen because it spreads easily and tends to resist many antibiotics. We compared bacteria collected from patients guts and from their blood to ask whether the strains that cause infection are different from those that only colonize. Studying more than 2,000 bacterial genomes, we found that the two groups look remarkably similar: the same genetic types dominate in both, patients are usually infected by the same strain already living in their gut, an both groups also carried similar sets of resistance genes. Overall, this is important because it suggests that preventing colonization--not just treating infection--may therefore be the most effective way to reduce VREfm disease in hospitals.

microbiology↗

bioRxiv2022

Oral cholestyramine prevents enrichment of diverse daptomycin-resistance mutations in intestinal Enterococcus faecium

Background and ObjectivesPreviously, we showed proof-of-concept in a mouse model that oral administration of cholestyramine prevented enrichment of daptomycin-resistant Enterococcus faecium in the gastrointestinal (GI) tract during daptomycin therapy. Cholestyramine binds daptomycin in the gut, which removes daptomycin selection pressure and so prevents the enrichment of resistant clones. Here, we investigated two open questions related to this approach: 1) can cholestyramine prevent the enrichment of diverse daptomycin mutations emerging de novo in the gut? 2) how does the timing of cholestyramine administration impact its ability to suppress resistance? MethodologyMice with GI E. faecium were treated with daptomycin with or without cholestyramine, and E. faecium was cultured from feces to measure changes in daptomycin susceptibility. A subset of clones was sequenced to investigate the genomic basis of daptomycin resistance. ResultsCholestyramine prevented the enrichment of diverse resistance mutations that emerged de novo in daptomycin-treated mice. Whole-genome sequencing revealed that resistance emerged through multiple genetic pathways, with most candidate resistance mutations observed in the clsA gene. Additionally, we observed that cholestyramine was most effective when administration started prior to the first dose of daptomycin. However, beginning cholestyramine after the first daptomycin dose reduced the frequency of resistant E. faecium compared to not using cholestyramine at all. Conclusions and ImplicationsCholestyramine prevented the enrichment of diverse daptomycin-resistance mutations in intestinal E. faecium populations during daptomycin treatment, and it is a promising tool for managing transmission of daptomycin-resistant E. faecium.

microbiology↗