Oral Fosfomycin Treatment for Enterococcal Urinary Tract Infections in a Dynamic <i>In Vitro</i> Model

Abstract

There are limited treatment options for enterococcal urinary tract infections, especially vancomycin-resistant <i>Enterococcus</i> (VRE). Oral fosfomycin is a potential option, although limited data are available guiding dosing and susceptibility. We undertook pharmacodynamic profiling of fosfomycin against <i>E. faecalis</i> and <i>E. faecium</i> isolates using a dynamic <i>in vitro</i> bladder infection model. Eighty-four isolates underwent fosfomycin agar dilution susceptibility testing (<i>E. faecalis</i> MIC_50/90 32/64 μg/ml; <i>E. faecium</i> MIC_50/90 64/128 μg/ml). Sixteen isolates (including <i>E. faecalis</i> ATCC 29212 and <i>E. faecium</i> 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, <i>E. faecium</i> demonstrated greater growth restriction in SHU compared to <i>E. faecalis</i> (<i>E. faecium</i> maximal growth 5.8 ± 0.6 log₁₀ CFU/ml; <i>E. faecalis</i> 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%). <i>E. faecalis</i> isolates required greater fosfomycin exposure for 3 log₁₀ kill from the starting inoculum compared with <i>E. faecium</i> The ƒAUC_0-72/MIC and ƒ%T > MIC_0-72 for <i>E. faecalis</i> were 672 and 70%, compared to 216 and 51% for <i>E. faecium</i>, 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.