Efficacy of single and multiple oral doses of fosfomycin against Pseudomonas aeruginosa urinary tract infections in a dynamic in vitro bladder infection model.

Objectives: We used a dynamic bladder infection in vitro model with synthetic human urine (SHU) to examine fosfomycin exposures to effectively kill, or prevent emergence of resistance, among Pseudomonas aeruginosa isolates. Methods: Dynamic urinary fosfomycin concentrations after 3g oral fosfomycin were simulated, comparing single and multiple (daily for 7days) doses. Pharmacodynamic response of 16 P. aeruginosa (MIC range 1 to >1024mg/L) were examined. Baseline disc diffusion susceptibility, broth microdilution MIC and detection of heteroresistance were assessed. Pathogen kill and emergence of resistance over 72h following a single dose, and over 216h following daily dosing for 7days, were investigated. The fAUC(0-24)/MIC associated with stasis and 1, 2 and 3log(10) kill were determined. Results: Pre-exposure high-level resistant (HLR) subpopulations were detected in 11/16 isolates after drug-free incubation in the bladder infection model. Five of 16 isolates had >2log(10) kill after single dose, reducing to 2/16 after seven doses. Post-exposure HLR amplification occurred in 8/16 isolates following a single dose and in 11/16 isolates after seven doses. Baseline MIC >= 8mg/L with an HLR subpopulation predicted post-exposure emergence of resistance following the multiple doses. A PK/PD target of fAUC(0-24)/MIC >5000 was associated with 3log(10) kill at 72h and 7day-stasis. Conclusions: Simulated treatment of P. aeruginosa urinary tract infections with oral fosfomycin was ineffective, despite exposure to high urinary concentrations and repeated daily doses for 7days. Emergence of resistance was observed in the majority of isolates and worsened following prolonged therapy. Detection of a baseline resistant subpopulation predicted treatment failure.