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

• MICs90 of fosfomycin for MDR PA and non MDR PA were high in this study.
• Approximately 40% of the non-MDR PA was carbapenem-resistant strains.
• The combination of fosfomycin and carbapenems decreased the MICs of both drugs.
• Prolonged infusion of fosfomycin combination provided the best PK/PD targets.

ObjectiveThe 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.MethodA 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).ResultsMIC90 of fosfomycin alone, fosfomycin in combination with carbapenem, carbapenems alone and carbapenems in combination with fosfomycin were >1,024, 1,024, >32 and 32 μg/ml, for multidrug resistant (MDR)-PA and 512, 128, 8 and 3 μg/ml respectively, for non-MDR PA. Approximately 40% of the non-MDR PA were carbapenem-resistant strains. For non-MDR PA with CRPA, fosfomycin 16 g continuous infusion in combination with carbapenems provided %PTA of approximately 80 and %CFR of > 88. While, %PTA and %CFR > 90 were achieved with fosfomycin 24 g/day prolonged infusion in combination with carbapenem.ConclusionsProlonged infusion of fosfomycin 16 - 24 g combined with extended carbapenem infusion could be used in non-MDR PA treatment with CRPA.