Fosfomycin as a potential therapy for the treatment of systemic infections: a population pharmacokinetic model to simulate multiple dosing regimens

Abstract

Fosfomycin has emerged as a potential therapy for multidrug‐resistant bacterial infections. In most European countries, the oral formulation is only approved as a 3 g single dose for treatment of uncomplicated cystitis. However, for the treatment of complicated systemic infections, this dose regimen is unlikely to reach efficacious serum and tissue concentrations. This study aims to investigate different fosfomycin‐dosing regimens to evaluate its rationale for treatment of systemic infections. Serum concentration‐time profiles of fosfomycin were simulated using a population pharmacokinetic model based on published pharmacokinetic parameter values, their uncertainty, inter‐individual variability and covariates. The model was validated on published data and used to simulate a wide range of dosing regimens for oral and intravenous administration of fosfomycin. Finally, based on the minimum inhibitory concentration for E. coli, surrogate pharmacodynamic indices were calculated for each dosing regimen. This is the first population pharmacokinetic model to describe the oral pharmacokinetics of fosfomycin using data from different literature sources. The model and surrogate pharmacodynamic indices provide quantitative evidence that a dosing regimen of 6–12 g per day divided in 3 doses is required to obtain efficacious exposure and may serve as a first step in the treatment of systemic multi‐drug‐resistant bacterial infections.

Fosfomycin Vs Ciprofloxacin as Oral Step-Down Treatment for Escherichia coli Febrile Urinary Tract Infections in Women: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial

“…It is unclear to what extent plasma and/or urine levels are decisive for efficacy in the step-down treatment of fUTIs. Higher oral doses up to 6–12g per day are expected to be needed for the empiric treatment of systemic infections [ 26 , 27 ]. We decided to dose fosfomycin at 3g every 24 hours because we anticipated that higher doses would not be tolerated [ 27 ].…”

Performance of Four Fosfomycin Susceptibility Testing Methods against an International Collection of Clinical Pseudomonas aeruginosa Isolates

“…pathogens (5,6). Fosfomycin is an old antibiotic developed in the 1960s prior to modern methods for new antibiotic approval (7). It has a broad spectrum of activity that includes excellent activity against MDR Gram-negative pathogens such as extendedspectrum ␤-lactamase (ESBL)-producing organisms and carbapenem-resistant Enterobacterales (CRE) (8)(9)(10)(11).…”

Population plasma and urine pharmacokinetics and the probability of target attainment of fosfomycin in healthy male volunteers

“…The model showed a good ability to characterise fosfomycin PK based on model diagnostics and validation. Most other recent studies also confirmed that the two-compartment model was the best fit to describe the fosfomycin plasma PK [17][18][19][20]. The second exponential decay suggests a distribution into deeper tissue, which leads to a slower release into plasma.…”

“…Although a number of studies on the population PK of fosfomycin have been conducted, most of these focused on plasma PK. Consequently, urinary PK is not fully understood [17][18][19][20]. Only a limited number of PK studies have evaluated plasma and urine samples simultaneously in healthy volunteers, utilising conventional PK analyses that did not include a covariate analysis [21][22][23].…”