We assessed the activity of fosfomycin simulating urinary concentrations achieved after a single 3 gram 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 × 106 cfu/mL). Fosfomycin was administered to simulate maximum free (ƒ) urine (U) concentrations and a t1/2 obtained after a standard single 3 gram oral dose in healthy volunteers (ƒUmax, 4000 mg/L; t1/2, 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 three carbapenemase-producing E. coli demonstrated a fosfomycin MIC of 2 μg/mL. Fosfomycin ƒT>MIC of 100% (ƒAUC0–24/MIC, ≥ ~ 7250) resulted in bacterial killing (reductions in log10 CFU assessed relative to the starting inoculum at 2, 4, 6, 12, 24, and 48 hours 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 gram 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 gram oral dose to treat patients with acute uncomplicated cystitis.
Zhanel George G., Parkinson Kate, Higgins Sean, Denisuik Andrew, Adam Heather, Pitout Johann, Noreddin Ayman, Karlowsky James A., Pharmacodynamic Activity of Fosfomycin Simulating Urinary Concentrations Achieved After a Single 3 Gram Oral Dose versus Escherichia coli Using an In Vitro Model, Diagnostic Microbiology and Infectious Disease (2017), doi: 10.1016/j.diagmicrobio.2017.04.007
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