AbstractThere is limited clinical evidence to support the combination of daptomycin and beta-lactam antibiotics (DAP + BLA) for treatment of vancomycin-resistant enterococci (VRE) bloodstream infections (BSI). We conducted a prospective observational cohort study of VRE-BSI during 2010–2015. The primary endpoint was mortality at the end of treatment. We included 114 patients who received DAP for VRE-BSI. Of these 87 (76.3%) received DAP + BLA. There were no significant differences in mortality between the DAP and DAP + BLA groups on univariable analysis (10/27 vs. 34/87, P = 0.85). A subgroup analysis of patients with enterococcal DAP minimum inhibitory concentrations (MICs) ≤2 mg/L, revealed that those treated with DAP + BLA had a lower mortality (adjusted hazard ratio [aHR], 0.23; 95% confidence interval [CI], 0.06–0.93; P = 0.04) after adjustment for other significant predictors of mortality, including the DAP dose. In addition, patients receiving high-dose (≥9 mg/kg) DAP + BLA independently had a better survival than those receiving low-dose DAP alone (aHR = 5.16), low-dose DAP + BLA (aHR = 5.39), and high-dose DAP alone (aHR = 19.01) (P < 0.05 for all comparisons). For patients with VRE-BSIs, the DAP MIC of the isolate and the DAP dose influence the effect of DAP + BLA on outcome. A high-dose DAP + BLA might improve survival. These findings support the use of high-dose DAP + BLA for treatment of VRE-BSI.