Population pharmacokinetics of intravenous fosfomycin: dose optimization for critically ill patients with and without kidney replacement therapy

Abstract

We investigated the pharmacokinetics (PK) of intravenous fosfomycin in critically ill patients undergoing different types of kidney replacement therapy (KRT) to identify optimized dosing regimens for patient care. Four prospective, observational studies contributed data of critically ill patients with prolonged-intermittent KRT (PIKRT, n=18), continuous KRT (CKRT, n=15), or without KRT (n=12) for population PK analysis. Subsequently, licensed daily dosages (12–24 g), varying estimated glomerular filtration rates (eGFR, 0–120 mL/min/1.73 m2 ), and scenarios with or without KRT were simula ted for comparison against minimum inhibitory concentrations (MICs, 32–256 mg/L). A dosing regimen was considered “effective” if the ratio of area under the concentra tion–time curve from 24–48 hours and MIC (AUC24-48/MIC ratio) exceeded 22.7 or 83.3, respectively, and if the percentage of time above MIC between 24 and 48 hours (%T24-48>MIC) was greater than 69.0. The probability of target attainment (PTA) was assessed using Monte Carlo simulations (n = 2,000) for each scenario. A two-compart ment model incorporating body (1.6 L/h) and dialysis (2.0 L/h) clearance identified eGFR, dialyzate flow rate (QD), and time after first dose as significant covariates. Considering the AUC24-48/MIC ratio, 8 g three times daily (TID) was bactericidal (PTA≥90%) in all scenarios at MIC32, 5 g TID was bacteriostatic (PTA≥90%) at MIC64, and 8 g TID was also effective (PTA≥90%) at MIC128. Based on the %T24-48>MIC, 4 g TID and 8 g TID were bactericidal (PTA≥90%) at MIC32 and MIC64, respectively. In conclusion, a dosage of 12–24 g/d intravenous fosfomycin is plausible for critically ill patients undergoing CKRT or PIKRT.