Oral fosfomycin treatment for enterococcal urinary tract infections in a dynamic in vitro model

Iain J. Abbott, Elke van Gorp, Aart van der Meijden, Rixt A. Wijma, Joseph Meletiadis, Jason A. Roberts, Johan W. Mouton, Anton Y. Peleg

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article numbere00342-20
Number of pages14
JournalAntimicrobial Agents and Chemotherapy
Volume64
Issue number6
DOIs
Publication statusPublished - Jun 2020

Keywords

  • Enterococcus
  • Fosfomycin
  • In vitro modelling
  • Pharmacodynamics
  • Pharmacokinetics
  • Synthetic human urine
  • Urinary tract infection
  • Vancomycin resistance

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