INTRODUCTION: Daptomycin is commonly used for vancomycin-resistant enterococcal bloodstream infections (VRE-BSIs); however, its optimal dosing remains uncertain. Although doses > 12 mg/kg may improve attainment of pharmacodynamic targets, clinical outcomes and safety data for very-high-dose daptomycin are limited. METHODS: This multicenter cohort study included adults with a VRE-BSI treated with daptomycin doses > 12 mg/kg, between 2011 and 2024. The primary outcome was 28-day all-cause mortality. Daptomycin-associated adverse events, including creatine kinase (CK) elevation, were assessed, and multivariable logistic regression models were used to identify factors associated with mortality and an elevated CK level. RESULTS: Among 101 patients, the median age was 70.2 years, and 67.3% had an underlying malignancy. The 28-day mortality was 41.6% and was primarily associated with host factors and illness severity. Daptomycin dose was not associated with mortality when modeled as a continuous variable; however, in exploratory post hoc analysis, doses > 13 mg/kg were associated with lower mortality compared with 12-13 mg/kg adjusted odds ratio (aOR), 0.22; 95% confidence interval (CI) 0.05-0.98; p = 0.047. CK elevation occurred in 13.9% and was independently associated with higher daptomycin dose (aOR, 2.99; 95% CI 1.05-8.50). Eosinophilic pneumonia was identified in 10.9% of patients. CONCLUSIONS: In patients with VRE-BSI treated with daptomycin doses > 12 mg/kg, mortality remained high and was primarily driven by host factors and severity of illness. Although exploratory findings suggest a potential mortality benefit at doses > 13 mg/kg, this must be balanced against a significantly increased risk of dose-related toxicity, including a notably high incidence of eosinophilic pneumonia.
Lin et al. (2026) studied this question.