Emulating a Target Trial to Evaluate the Impact of Empiric Antimicrobial Strategies on Mortality in Enterococcal Bloodstream Infections

Enterococcal bloodstream infections (BSI) caused by Enterococcus faecalis and Enterococcus faecium present significant public health concerns, particularly with rising vancomycin resistance (VRE). This study aimed to estimate the causal effect of two empiric strategies-- immediate VRE coverage (daptomycin or linezolid) versus initial vancomycin or ampicillin with potential escalation--by emulating a target trial in electronic health records. We identified adult patients with positive blood cultures for E. faecalis or E. faecium from January 2017 to January 2023. Patients were assigned to immediate VRE coverage or initial VSE-active therapy with escalation within three days if clinical deterioration or new microbiologic data warranted. Using inverse probability weighting, we adjusted for baseline factors (e.g., age, comorbidities, prior antibiotic use) and time-varying confounders (changes in severity). Our intention-to-treat (ITT) and per-protocol analyses estimated 30-day all-cause mortality, with additional sensitivity analyses at 10 and 15 days. Among 799 patients, 45 (5.6%) received VRE-targeted therapy at baseline. The ITT analysis indicated a 1.35 percentage point mortality reduction (95% CI: -7.2% to 7.9%) with universal immediate VRE coverage, and the per-protocol analysis showed a risk difference of -3.76 points (95% CI: -14.9% to 20.4%). Sensitivity analyses yielded similar findings. In this population, immediate VRE coverage did not confer a clear survival advantage over standard therapy with potential escalation, supporting clinical equipoise and highlighting the need for larger trials (randomized or target trials) to evaluate optimal empiric regimens for enterococcal BSI.