Pharmacokinetics and Pharmacodynamics of Fosfomycin and its Activity against ESBL-, Plasmid-mediated AmpC- and Carbapenemase-Producing Escherichia coli in a Murine Urinary Tract Infection Model [PublishAheadOfPrint]

Fosfomycin has become an attractive treatment alternative for urinary tract infections (UTIs) due to increasing multidrug-resistance (MDR) in Escherichia coli. In this study, we evaluated the pharmacokinetic and pharmacodynamic (PK/PD) indices of fosfomycin and its in vivo activity in an experimental murine model of ascending UTI. Subcutaneous administration of fosfomycin showed that the mean peak plasma concentrations of fosfomycin were 36, 280, and 750 mg/L following administration of a single dose of 0.75, 7.5, and 30 mg/mouse, respectively, with an elimination half-life of 28 min; and urine peak concentrations of 1100, 33400, and 70000 mg/L expected to sustain above the MIC of the test strain (NU14, 1 mg/L) for 5, 8 and 9.5 h, respectively. The optimal PK/PD indices for reducing urine colony counts (CFU/ml) were determined to be AUC/MIC_0-72h and C_max/MIC based on the dose-dependent bloodstream PK and evaluation of six dosing regimens. With a dosing regimen of 15 mg/mouse twice (q36h), fosfomycin significantly reduced the CFU/ml in urine of susceptible strains, including clinical MDR strains, except for one clinical strain (p = 0.062). A variable degree of reduction was observed in the bladder and kidneys. No significant reduction in CFU/ml were observed with the resistant strains. In conclusion, fosfomycin shows concentration-dependent in vivo activity and the results suggest that fosfomycin is an effective alternative to carbapenems in treating MDR E. coli in uncomplicated UTIs. The data for effectiveness on the MDR isolates along with PK/PD modeling should facilitate further development of improved recommendations for clinical use.

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