Pharmacokinetic and pharmacodynamic evaluations of oral moxifloxacin for Enterococcus faecalis endocarditis

OBJECTIVES: Enterococcus faecalis is a challenging cause of endocarditis and often occurs in elderly, frail patients. The aim of this study was to evaluate the use of moxifloxacin for treating E. faecalis endocarditis by determining the probability of target attainment (PTA) and to investigate potential synergistic effects of moxifloxacin in combination therapy. METHODS: Population pharmacokinetic modelling was performed using moxifloxacin data from patients in the Partial Oral Endocarditis Treatment (POET) trial who were infected with E. faecalis, staphylococci, or streptococci. The PTA was estimated from model-based simulations across a range of MICs and dosing regimens. Synergy testing of moxifloxacin in combination with amoxicillin or linezolid was conducted using checkerboard assays and time-kill assays with E. faecalis isolates. RESULTS: Seventy-seven patients were included. Standard dosing (400 mg every day) achieved PTA >90% for MIC values ≤0.125 mg/L. At an MIC of 0.25 mg/L, PTA was 80.8% (90% CI: 73.4-87.5%) and increased to >90% with simulated doses of 600-800 mg every day. At an MIC of 0.5 mg/L, no regimen reached PTA >90%. Among 23 tested isolates, moxifloxacin MICs were 0.125 mg/L (3 of 23, 13%), 0.25 mg/L (17 of 23, 73.9%), and 0.5 mg/L (3 of 23, 13%). Checkerboard assays showed no synergy or antagonism with amoxicillin or linezolid. However, fractional inhibitory concentration indices were ≤1 in 18 isolates (18 of 23, 78.3%) for amoxicillin. Time-kill assays revealed synergistic activity of amoxicillin-moxifloxacin in seven strains (7 of 23, 30%). CONCLUSIONS: Standard moxifloxacin dosing (400 mg every day) achieved high PTA against E. faecalis at MIC ≤0.125 mg/L, whereas higher doses or alternative strategies may be needed at MIC ≥0.25 mg/L. The findings support the need for combination therapy in E. faecalis endocarditis. Time-kill assays revealed synergistic activity of amoxicillin and moxifloxacin in some isolates, suggesting a potential benefit of this combination.