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Published on: June 24, 2025
Oral Fosfomycin Treatment for Enterococcal Urinary Tract Infections in a Dynamic In Vitro Model
Iain J Abbott1,2, Elke van Gorp2, Aart van der Meijden2
1Department of Infectious Diseases, The Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Abstract:
There are limited treatment options for enterococcal urinary tract infections, especially vancomycin-resistant Enterococcus (VRE). Oral fosfomycin is a potential option, although limited data are available guiding dosing and susceptibility. We undertook pharmacodynamic profiling of fosfomycin against E. faecalis and E. faecium isolates using a dynamic in vitro bladder infection model. Eighty-four isolates underwent fosfomycin agar dilution susceptibility testing (E. faecalis MIC50/90 32/64 μg/ml; E. faecium MIC50/90 64/128 μg/ml). Sixteen isolates (including E. faecalis ATCC 29212 and E. faecium ATCC 35667) were chosen to reflect the MIC range and tested in the bladder infection model with synthetic human urine (SHU). Under drug-free conditions, E. faecium demonstrated greater growth restriction in SHU compared to E. faecalis (E. faecium maximal growth 5.8 ± 0.6 log10 CFU/ml; E. faecalis 8.0 ± 1.0 log10 CFU/ml). Isolates were exposed to high and low fosfomycin urinary concentrations after a single dose, and after two doses given over two days with low urinary concentration exposure. Simulated concentrations closely matched the target (bias 2.3%). E. faecalis isolates required greater fosfomycin exposure for 3 log10 kill from the starting inoculum compared with E. faecium The ƒAUC0-72/MIC and ƒ%T > MIC0-72 for E. faecalis were 672 and 70%, compared to 216 and 51% for E. faecium, respectively. There was no rise in fosfomycin MIC postexposure. Two doses of fosfomycin with low urinary concentrations resulted in equivalent growth inhibition to a single dose with high urinary concentrations. With this urinary exposure, fosfomycin was effective in promoting suppression of regrowth (>3 log10 kill) in the majority of isolates.
Insights
Oral fosfomycin shows promise for treating enterococcal urinary tract infections, including vancomycin-resistant strains. This study demonstrated fosfomycin
Area of Science:
- Pharmacology and Microbiology
- Infectious Diseases
- Urology
Background:
- Enterococcal urinary tract infections (UTIs) present limited therapeutic options, particularly vancomycin-resistant Enterococcus (VRE).
- Oral fosfomycin is a potential treatment, but data on dosing and susceptibility are scarce.
- Pharmacodynamic profiling is crucial for optimizing fosfomycin use in UTIs.
Purpose of the Study:
- To evaluate the pharmacodynamic properties of oral fosfomycin against Enterococcus faecalis and Enterococcus faecium in an in vitro bladder infection model.
- To determine the optimal fosfomycin exposure required for bacterial kill and suppression of regrowth.
- To assess the impact of different dosing regimens on fosfomycin efficacy.
Main Methods:
- Eighty-four enterococcal isolates were tested for fosfomycin susceptibility using agar dilution.
- Sixteen isolates were selected for pharmacodynamic profiling in a dynamic in vitro bladder infection model using synthetic human urine.
- Bacterial growth and kill were assessed under various simulated urinary fosfomycin concentrations and dosing regimens.
Main Results:
- Enterococcus faecium exhibited greater intrinsic growth restriction in synthetic urine compared to Enterococcus faecalis.
- Enterococcus faecalis required higher fosfomycin exposure (ƒAUC/MIC and %T > MIC) for a 3 log10 kill compared to Enterococcus faecium.
- Two doses of fosfomycin at low urinary concentrations achieved similar growth inhibition to a single high-dose exposure, with no observed increase in fosfomycin MIC postexposure.
- Fosfomycin effectively suppressed regrowth (>3 log10 kill) in most isolates under tested urinary exposures.
Conclusions:
- Oral fosfomycin demonstrates in vitro efficacy against Enterococcus species relevant to UTIs.
- Dosing strategies involving multiple administrations of fosfomycin can be effective in achieving bacterial suppression.
- Further clinical studies are warranted to confirm the efficacy of oral fosfomycin for enterococcal UTIs, especially VRE.
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