3 years ago

High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers

Fosfomycin is increasingly being prescribed for the treatment of uncomplicated urinary tract infections in an era of emerging drug resistance. Surprisingly, little is known of the urinary concentrations of fosfomycin and its interindividual variation after the standard single 3 gram oral dose. We aimed to gain more insight into urinary fosfomycin pharmacokinetics to evaluate its effectiveness. Methods Three grams of fosfomycin trometamol was administered to 40 healthy female volunteers with an estimated mean glomerular filtration rate of > 90 mL/min/1.73m2. Urine samples were collected from every urination during 48 hours, and then twice daily for up to 7 days. Time, volume and pH were recorded. Concentrations were quantified with UPLC-MS/MS. Effectiveness was evaluated based on urinary concentrations and the target MIC of E. coli, the most common uropathogen. Results A high interindividual variability was found. Peak concentration was 1982.0 ± 1257.4 mg/L, urinary half-life 12.4 ± 5.7 hours and excretion rate over 48 hours 29.9 ± 7.1 mg/h. Recovery was 44.5 ± 12.6% after 48 h and 47.0 ± 10.4% after 7 days. Concentrations remained above the EUCAST breakpoint of 32 mg/L in 100% of the volunteers over the first 24 h, 67.5% for 48 h and 30% for 72 h. A high urinary output was associated with low urinary concentrations and consequently reduced time > MIC, AUC0-7days/MIC and Cmax/MIC values. Conclusions Considerable interindividual variability observed in the pharmacokinetics of fosfomycin signifies a risk for inadequate drug exposure in a significant proportion of the population. The current dosing regimen should therefore be reevaluated.

Publisher URL: www.sciencedirect.com/science

DOI: S1198743X17304810

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