Evaluation of Fosfomycin-Sulbactam Combination Therapy against Carbapenem-Resistant Acinetobacter baumannii Isolates in a Hollow-Fibre Infection Model

Abstract

Static concentration in vitro studies have demonstrated that fosfomycin- or sulbactam-based combinations may be efficacious against carbapenem-resistant Acinetobacter baumannii (CRAB). In the present study, we aimed to evaluate the bacterial killing and resistance suppression potential of fosfomycin-sulbactam combination therapies against CRAB isolates in a dynamic infection model. We simulated clinically relevant dosing regimens of fosfomycin (8 g every 8 h, 1 h infusion) and sulbactam (12 g continuous infusion or 4 g every 8 h, 4 h infusion) alone and in combination for 7 days in a hollow-fibre infection model (HFIM) against three clinical isolates of CRAB. The simulated pharmacokinetic profiles in the HFIM were based on fosfomycin and sulbactam data from critically ill patients. Fosfomycin monotherapy resulted in limited bacterial killing. Sulbactam monotherapies resulted in ~ 3 to 4 log10 kill within the first 8 to 32 h followed by regrowth of up to 8 to 10 log10 CFU/mL. A combination of fosfomycin and continuous infusion of sulbactam led to a ~2 to 4 log10 reduction in bacterial burden within the first 24 h, which was sustained throughout the duration of the experiments. A combination of fosfomycin and extended infusion of sulbactam produced a ~4 log10 reduction in colony count within 24 h. This study demonstrated that fosfomycin in combination with sulbactam is a promising option for the treatment of MDR A. baumannii. Further studies are needed to further assess the potential clinical utility of this combination.