Fosfomycin efficacy and emergence of resistance among Enterobacteriaceae in an in vitro dynamic bladder infection model

Abstract

Background

Urinary tract infections (UTIs) are among the most common bacterial infections and a frequent indication for antibiotic use. Fosfomycin, an important oral antibiotic for outpatient UTIs, remains a viable option for MDR uropathogens. We aimed to perform pharmacodynamic profiling simulating urinary concentrations to assess the adequacy of the current dosing regimen.

Methods

A dynamic in vitro bladder infection model was developed, replicating urinary fosfomycin concentrations after gastrointestinal absorption, systemic distribution and urinary elimination. Concentrations were measured by LC-MS/MS. Twenty-four Enterobacteriaceae strains (Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae; MIC range 0.25–64 mg/L) were examined. Pathogen kill and emergence of resistance was assessed over 72 h.

Results

Observed in vitro fosfomycin concentrations accurately simulated urinary fosfomycin exposures (T_max 3.8 ± 0.5 h; C_max 2630.1 ± 245.7 mg/L; AUC_0-24 33 932.5 ± 1964.2 mg·h/L). Fifteen of 24 isolates regrew, with significant rises in fosfomycin MIC (total population MIC₅₀ 4 to 64 mg/L, MIC₉₀ 64 to > 1024 mg/L, P = 0.0039; resistant subpopulation MIC₅₀ 128 to > 1024 mg/L, MIC₉₀ >1024 mg/L, P = 0.0020). E. coli and E. cloacae isolates were killed with pharmacokinetic/pharmacodynamic EI₅₀ of fAUC_0-24/MIC = 1922, fC_max/MIC = 149 and fTime>4×MIC = 44 h. In contrast, K. pneumoniae isolates were not reliably killed.

Conclusions

Using dynamic in vitro simulations of urinary fosfomycin exposures, E. coli and E. cloacae isolates with MIC >16 mg/L, and all K. pneumoniae isolates, were not reliably killed. Emergence of resistance was significant. This challenges fosfomycin dosing and clinical breakpoints, and questions the utility of fosfomycin against K. pneumoniae. Further work on in vitro dose optimization is required.

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