顽固性肠球菌血症的临床与基因组特征：一项多中心前瞻性队列研究（VENOUS）

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

作者信息

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

机构信息

Center for Infectious Diseases, UTHealth-Houston School of Public Health, Houston, TX, USA.

Division of Infectious Diseases, Houston Methodist Hospital, Houston, TX, USA.

出版信息

J Infect Dis. 2025 Jul 8. doi: 10.1093/infdis/jiaf358.

DOI:10.1093/infdis/jiaf358

PMID:40629152

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.

摘要

背景

难治性肠球菌血流感染患者出现不良结局的风险更高。我们在2016 - 2022年耐万古霉素肠球菌菌血症结局研究（VENOUS）队列中识别出经历难治性血流感染的患者，以进行进一步的临床和基因组特征分析。

方法

如果在接受≥48小时的积极治疗后第4天仍未清除菌血症，则认为菌血症发作是“持续性的”；如果住院期间菌血症清除后随后的培养结果为阳性，则认为是复发性的（统称为“难治性”菌血症）。以2:1的对照：病例比例选择非难治性菌血症患者的匹配比较组。对分离株进行短读长和长读长全基因组测序。使用定制流程创建混合组装。

结果

共识别出41例患者的46例难治性感染。与对照组相比，持续性菌血症患者入院时更常入住重症监护病房。与对照组相比，导致持续性感染的粪肠球菌菌株中与碳水化合物利用相关的基因比例显著更高。屎肠球菌和粪肠球菌指数株及持续性分离株之间与突变基因相关的功能组表现不同，表明存在物种特异性适应。

讨论

导致难治性菌血症的肠球菌分离株在基因组上具有多样性，这表明菌株特异性特征不是持续性的驱动因素。然而，指数株与持续性分离株的比较显示，屎肠球菌可能在基因上预先适应导致持续性感染，感染期间的位点特异性结构变异表明差异基因表达在适应和持续性中的作用。这些数据为未来研究确定肠球菌在菌血症期间的适应特征奠定了基础。