Pharmacodynamic activity of fosfomycin simulating urinary concentrations achieved after a single 3-g oral dose versus Escherichia coli using an in vitro model

Abstract We assessed the activity of fosfomycin simulating urinary concentrations achieved after a single 3-g oral dose against Escherichia coli using an in vitro pharmacodynamic model. Eleven urinary isolates of E. coli were studied. Isolates were ESBL-producing or carbapenemase-producing. The in vitro pharmacodynamic model was inoculated with an inoculum of (~1 × 10 6  cfu/mL). Fosfomycin was administered to simulate maximum free (ƒ) urine (U) concentrations and a t 1/2 obtained after a standard single 3-g oral dose in healthy volunteers (ƒU max , 4000 mg/L; t 1/2 , 6 h). Sampling was performed over 48 h to assess the rate and extent of bacterial reduction as well as resistance selection. Complete bacterial eradication from the model was defined by no regrowth over the 48 h study period. Fosfomycin MICs ranged from 1 to 4 μg/mL for ESBL producers, while all 3 carbapenemase-producing E. coli demonstrated a fosfomycin MIC of 2 μg/mL. Fosfomycin ƒT >MIC of 100% (ƒAUC 0–24 /MIC, ≥~7250) resulted in bacterial killing (reductions in log 10 CFU assessed relative to the starting inoculum at 2, 4, 6, 12, 24, and 48 h of ≥3.0) at each time-point versus all isolates of ESBL-producing and carbapenemase-producing E. coli . We conclude that fosfomycin urinary concentrations obtained after a single 3-g oral dose were bactericidal as early as 1 h after dosing with complete bacterial eradication at all time-points over the 48 h testing period against urinary isolates of E. coli (including MDR ESBL- and/or carbapenemase-producing strains). Our data help to explain the high (>90%) microbiological and clinical cure rates achieved with fosfomycin when used as a single 3-g oral dose to treat patients with acute uncomplicated cystitis.