R A Wijma1, B C P Koch2, T van Gelder2, J W Mouton3. 1. Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: r.wijma@erasmusmc.nl. 2. Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands. 3. Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands.
Abstract
OBJECTIVES: Fosfomycin is increasingly being prescribed for 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-g 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 hours 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 hours, 67.5% for 48 hours, and 30% for 72 hours. 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.
OBJECTIVES:Fosfomycin is increasingly being prescribed for 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-g 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 hours 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 hours, 67.5% for 48 hours, and 30% for 72 hours. 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.
Authors: Iain J Abbott; Elke van Gorp; Aart van der Meijden; Rixt A Wijma; Joseph Meletiadis; Jason A Roberts; Johan W Mouton; Anton Y Peleg Journal: Antimicrob Agents Chemother Date: 2020-05-21 Impact factor: 5.191
Authors: Eric Wenzler; Susan C Bleasdale; Monica Sikka; Kristen L Bunnell; Matthew Finnemeyer; Susan L Rosenkranz; Larry H Danziger; Keith A Rodvold Journal: Antimicrob Agents Chemother Date: 2018-07-27 Impact factor: 5.191
Authors: Iain J Abbott; Elke van Gorp; Rixt A Wijma; Joseph Meletiadis; Jason A Roberts; Johan W Mouton; Anton Y Peleg Journal: Antimicrob Agents Chemother Date: 2020-02-21 Impact factor: 5.191
Authors: Thijs Ten Doesschate; Suzan P van Mens; Cees van Nieuwkoop; Suzanne E Geerlings; Andy I M Hoepelman; Marc J M Bonten Journal: BMC Infect Dis Date: 2018-12-05 Impact factor: 3.090
Authors: Sander G Kuiper; Anneke C Dijkmans; Erik B Wilms; Ingrid M C Kamerling; Jacobus Burggraaf; Jasper Stevens; Cees van Nieuwkoop Journal: J Antimicrob Chemother Date: 2020-11-01 Impact factor: 5.758