Antibiotic Treatment Duration for Uncomplicated Monomicrobial Enterococcal Bloodstream Infection: A Multicenter Target Trial Emulation

BACKGROUND: Enterococcal bloodstream infection (BSI) is common with 30-day mortality rates approaching 25-30%, yet evidence guiding optimal antibiotic treatment duration, particularly for patients with uncomplicated infection, is limited. METHODS: We conducted a retrospective cohort study using a target trial emulation framework across eight hospitals in Israel (2013-2023) of adults hospitalized with uncomplicated monomicrobial enterococcal BSI. Treatment strategies were defined as short (7±2 days) vs long (14±2 days) antibiotic therapy. A cloning-censoring-weighting framework with inverse probability of censoring weights was applied to account for immortal time bias and potential confounders. The primary outcome was 30-day all-cause mortality; secondary outcomes included 90-day all-cause mortality, recurrence, length of stay, readmission and Clostridioides difficile infection. Analyses were performed using pooled logistic regression and negative binomial regression models, with prespecified subgroup and sensitivity analyses. RESULTS: Of 3,450 patients with enterococcal bacteremia screened, 870 were eligible, and 485 received treatment durations consistent with the study treatment strategies (short n=283, long n=202). Mean age was 74 years (±15.0); 87/485 (18%) had pre-existing cardiac hardware, 164/485 (34%) a urinary source and 180/485 (37%) had nosocomial BSI. Adjusted analyses demonstrated no difference in 30-day mortality between short and long therapy (21.6% vs 21.3%; adjusted risk ratio 1.01, 95% confidence intervals [CI] 0.84 to 1.22). There was no evidence of differences across the secondary outcomes. Results were consistent across subgroup and sensitivity analyses. CONCLUSIONS: Short-course antibiotic treatment was associated with comparable clinical outcomes to long-course treatment in uncomplicated monomicrobial enterococcal BSI, supporting the use of short treatment durations in appropriately selected patients.