Optimizing intravenous fosfomycin dosing in combination with carbapenems for treatment of Pseudomonas aeruginosa infections in critically ill patients based on pharmacokinetic/pharmacodynamic (PK/PD) simulation.

OBJECTIVE: The purpose of the study was to determine the optimal dosing regimen of intravenous fosfomycin for the treatment of Pseudomonas aeruginosa (PA) based on PK/PD targets.

METHOD: A total of 120 PA isolates were recovered from various clinical specimens at university hospital in Thailand. Minimum Inhibitory Concentrations (MICs) of all the isolates were determined by the E-test method. PK parameters were obtained from a published study. Monte Carlo simulation was performed to calculate the percentage of target attainment (PTA) and cumulative fraction of response (CFR).

RESULTS: MIC90 of fosfomycin alone, fosfomycin in combination with carbapenem, carbapenems alone and carbapenems in combination with fosfomycin were >1,024, 1,024, >32 and 32μg/ml, for multidrug resistant (MDR)-PA and 512, 128, 8 and 3μg/ml respectively, for non-MDR PA. Approximately 40% of the non-MDR PA were carbapenem-resistant strains. For non-MDR PA with CRPA, fosfomycin 16g continuous infusion in combination with carbapenems provided %PTA of approximately 80 and %CFR of > 88. While, %PTA and %CFR > 90 were achieved with fosfomycin 24g/day prolonged infusion in combination with carbapenem.

CONCLUSIONS: Prolonged infusion of fosfomycin 16 - 24g combined with extended carbapenem infusion could be used in non-MDR PA treatment with CRPA.