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

摘要: Objectives We used a dynamic bladder infection in vitro model with synthetic human urine (SHU) to examine fosfomycin exposures effectively kill, or prevent emergence of resistance, among Pseudomonas aeruginosa isolates. Methods Dynamic urinary concentrations after 3 g oral were simulated, comparing single and multiple (daily for 7 days) doses. Pharmacodynamic response 16 P. (MIC range 1 >1024 mg/L) examined. Baseline disc diffusion susceptibility, broth microdilution MIC detection heteroresistance assessed. Pathogen kill resistance over 72 h following dose, 216 daily dosing days, investigated. The fAUC0-24/MIC associated stasis 1, 2 log10 determined. Results Pre-exposure high-level resistant (HLR) subpopulations detected 11/16 isolates drug-free incubation the model. Five had >2 reducing 2/16 seven Post-exposure HLR amplification occurred 8/16 dose ≥8 mg/L an subpopulation predicted post-exposure A PK/PD target >5000 was at day-stasis. Conclusions Simulated treatment tract infections ineffective, despite exposure high repeated doses days. Emergence observed majority worsened prolonged therapy. Detection baseline failure.