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. 2025 Jul 8:jiaf358.
doi: 10.1093/infdis/jiaf358. Online ahead of print.

Clinical and Genomic Characterization of Recalcitrant Enterococcal Bacteremia: A Multicenter Prospective Cohort Study (VENOUS)

Shelby R Simar  1 , Truc T Tran  2   3 , Kirsten B Rydell  2   3 , Rachel L Atterstrom  2   3 , Pranoti V Sahasrabhojane  4 , An Q Dinh  2   3 , Marissa G Schettino  2   3 , Haley S Slanis  2   3 , Alex E Deyanov  2   3 , Andie M DeTranaltes  2   3 , Dierdre B Axell-House  2   3 , William R Miller  2   3 , Jose M Munita  5 , David Tobys  6   7 , Harald Seifert  6   7   8 , Lena M Biehl  7   9 , Marcus Zervos  10 , Geehan Suleyman  10 , Jagjeet Kaur  10 , Victoria Warzocha  10 , Rossana Rosa  11 , Renzo O Cifuentes  11 , Lilian M Abbo  11 , Luis Shimose  12 , Catherine Liu  13   14 , Katherine Nguyen  13   14 , Ashleigh Miller  13   14 , Samuel A Shelburne  4 , Blake M Hanson  1 , Cesar A Arias  2   3   15
Affiliations

Clinical and Genomic Characterization of Recalcitrant Enterococcal Bacteremia: A Multicenter Prospective Cohort Study (VENOUS)

Shelby R Simar et al. J Infect Dis. .

Abstract

Background: Patients with recalcitrant enterococcal bloodstream infections are at greater risk of adverse outcomes. We identified patients in the 2016-2022 Vancomycin-Resistant Enterococcal Bacteremia Outcomes Study (VENOUS) cohort experiencing recalcitrant bloodstream infections for further clinical and genomic characterization.

Methods: Bacteremia episodes were considered "persistent" if there was a lack of clearance on day four while receiving ≥ 48 hours of active therapy and recurrent if there was clearance during hospitalization with a subsequent positive culture (collectively, "recalcitrant" bacteremia). A matched comparison group of non-recalcitrant bacteremia patients was chosen in a 2:1 control:case ratio. Isolates were subjected to short- and long-read whole-genome sequencing. Hybrid assemblies were created using a custom pipeline.

Findings: A total of 46 recalcitrant infections from 41 patients were identified. Patients with persistent bacteremia were more often admitted to the ICU upon admission relative to controls. E. faecalis strains causing persistent infections had a significantly higher proportion of genes associated with carbohydrate utilization relative to controls. Representation of functional groups associated with mutated genes was disparate between E. faecium and E. faecalis index and persistent isolates, suggesting species-specific adaptation.

Discussion: Enterococcal isolates causing recalcitrant bacteremia were genomically diverse, indicating that strain-specific signatures are not drivers of persistence. However, comparisons of index vs. persistent isolates revealed that E. faecium may be genetically pre-adapted to cause persistent infection, and site-specific structural variation during infection suggests the role of differential gene expression in adaptation and persistence. This data lays groundwork for future studies to define signatures of enterococcal adaptation during bacteremia.

Keywords: Enterococcus; bacteremia; genomic adaptation; persistent infection.

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