Daptomycin for enterococcal bloodstream infections and endocarditis: reconciling clinical evidence, susceptibility testing, and regulatory frameworks.

Despite the absence of US Food and Drug Administration or European Medicines Agency approval, randomised trials, and harmonised susceptibility guidance, daptomycin has become indispensable for the treatment of serious enterococcal bloodstream infections and endocarditis. The Clinical and Laboratory Standards Institute assigns Enterococcus faecium a susceptible dose-dependent category (≤4 mg/L, 8-12 mg/kg per day) and Enterococcus faecalis a susceptible breakpoint (≤2 mg/L, 6 mg/kg per day), whereas the European Committee on Antimicrobial Susceptibility Testing sets no clinical breakpoint, citing insufficient evidence. We argue that this misalignment between evidence and regulation is itself a potential source of patient harm, through persistent underdosing and inconsistent interpretive guidance. Observational data link 10-12 mg/kg per day with lower mortality in patients infected with vancomycin-resistant E faecium. Even so, appropriate dosing frequently does not attain the pharmacodynamic target, because target attainment depends less on the administered dose than on the isolate's minimum inhibitory concentration (MIC), which current methods cannot reliably determine. Any-grade creatine phosphokinase elevation rises modestly with dose in the largest registry but is inconsistent elsewhere, with a clearer signal of marked elevation at the highest doses. We propose a pragmatic framework (≥8 mg/kg per day for E faecium, 10-12 mg/kg per day in vancomycin-resistant disease, MIC-informed dose selection, β-lactam combination in endocarditis, and weekly creatine phosphokinase monitoring) and call for therapeutic drug monitoring, harmonised breakpoints, prospective studies, and molecular resistance detection.