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

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 (similar to 1 x 10(6) cfu/mL). Fosfomycin was administered to simulate maximum free (f) urine (U) concentrations and a t(1/2) obtained after a standard single 3-g oral dose in healthy volunteers (fU(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 mu g/mL for ESBL producers, while all 3 carbapenemase-producing E. coli demonstrated a fosfomycin MIC of 2 mu g/mL. Fosfomycin fT(>MIC) of 100% (fAUC(0-24)/MIC, >=similar to 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. coll. 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. (C) 2017 Elsevier Inc. All rights reserved.