Population pharmacokinetics and monte carlo simulation for dosage optimization of fosfomycin in the treatment of osteoarticular infections in patients without renal dysfunction

Fosfomycin is gaining interest in the treatment of complex osteoarticular infections (OI) due to multidrug-resistant (MDR) pathogens. Our aims were to conduct population pharmacokinetics of fosfomycin in a cohort of OI patients receiving 16 g daily by intermittent (II) or continuous (CI) infusion and to carry out Monte Carlo simulations for dosage optimization in the treatment of these infections. Patients underwent blood sampling on day 5 of therapy (2 to 3 serial samples). Population pharmacokinetics and Monte Carlo simulations were performed to define the probability of target attainment (PTA) of 70% T.MIC and the cumulative fraction of response (CFR) against common OI pathogens with dosages of 8, 12, 16, and 20 g/day administered by II, extended infusion (EI), or CI. Forty-eight patients were recruited. A two-compartment open model with infusion input and first-order elimination was developed. Estimated creatinine clearance (CLCR) was included as a covariate in the final model. Monte Carlo simulations showed that optimal PTAs and CFRs ($90%) can be achieved in three different classes of renal function by administering a daily dosage of 2 g every 6 h (q6h) by II against Staphylococcus aureus, Escherichia coli, expanded-spectrum beta-lactamase (ESBL)- producing E. coli, and methicillin-resistant S. aureus; 8 g by CI against coagulasenegative staphylococci, K. pneumoniae, and ESBL-producing K. pneumoniae; 12 g by CI against P. aeruginosa; and 16 g by CI against KPC-producing K. pneumoniae. Our study provides a strong rationale for considering fosfomycin dosages of 8 to 16 g daily by CI in several clinical scenarios for OI patients. The feasibility of administration by CI in an elastomeric pump makes fosfomycin a candidate for OPAT programs.