In Vitro Pharmacodynamics of Fosfomycin against Carbapenem-Resistant Enterobacter cloacae and Klebsiella aerogenes

Abstract

Objectives: The increase of carbapenem-resistant Enterobacterales (CRE) and lack of therapeutic options due to scarcity of new antibiotics has sparked interest towards the use of intravenous fosfomycin against systemic CRE infections. We aimed to investigate the in vitro pharmacodynamics of fosfomycin against carbapenem-resistant Enterobacter cloacae and Klebsiella aerogenes. Methods: Time-kill studies and population analysis profiles were performed with eight clinical CRE isolates, which were exposed to fosfomycin concentrations ranging from 0.25 to 2048mg/L. The 24h mean killing effect was characterized by an inhibitory sigmoid E_max model. Whole genome sequencing was performed to elucidate known fosfomycin resistance mechanisms. Results. Fosfomycin MICs ranged from 0.5–64mg/L. The isolates harbored a variety of carbapenemase genes including bla_IMP, bla_KPC and bla_NDM. Five out of eight isolates harbored the fosA gene while none harbored the recently discovered fosL-like gene. Heteroresistant subpopulations was detected in all isolates, with two out of eight isolates harboring heteroresistant subpopulations at up to 2048mg/L. In time-kill studies, fosfomycin exhibited bactericidal activity at 2-4h at several fosfomycin concentrations [one isolate, at ≥16 mg/L; two at ≥32mg/L; two at ≥64mg/L; two at ≥128 mg/L and one at ≥512 mg/L]. At 24h, bactericidal activity was only observed in two isolates (MICs 0.5 and 4mg/L) at 2048mg/L. From the E_max model, no significant bacterial killing was observed beyond 500mg/L. Conclusions. Our findings suggest that the use of fosfomycin monotherapy may be limited against CRE due to heteroresistance and rapid bacterial regrowth. Further optimization of intravenous fosfomycin dosing regimens is required to increase efficacy against such infections.