@article{3020832,
    title = "Efficacy of single and multiple oral doses of fosfomycin against Pseudomonas aeruginosa urinary tract infections in a dynamic in vitro bladder infection model",
    author = "Abbott, I.J. and Van Gorp, E. and Wijma, R.A. and Dekker, J. and Croughs, P.D. and Meletiadis, J. and Mouton, J.W. and Peleg, A.Y.",
    journal = "The Journal of antimicrobial chemotherapy",
    year = "2020",
    volume = "75",
    number = "7",
    pages = "1879-1888",
    publisher = "Oxford University Press",
    doi = "10.1093/jac/dkaa127",
    keywords = "bacterial DNA;  fomicyt;  fosfomycin;  antiinfective agent;  fosfomycin, antibiotic resistance;  Article;  AUC (0-24 h);  bacterial count;  bacterial growth;  bacterium culture;  bladder disease;  broth dilution;  chemical composition;  controlled study;  disease model;  disk diffusion;  drug efficacy;  in vitro study;  kidney concentrating capacity;  minimum inhibitory concentration;  multiple drug dose;  nonhuman;  Pseudomonas aeruginosa;  Pseudomonas infection;  single drug dose;  urinary tract infection;  bladder;  human;  microbial sensitivity test;  Pseudomonas aeruginosa;  Pseudomonas infection;  urinary tract infection, Anti-Bacterial Agents;  Fosfomycin;  Humans;  Microbial Sensitivity Tests;  Pseudomonas aeruginosa;  Pseudomonas Infections;  Urinary Bladder;  Urinary Tract Infections",
    abstract = "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 3 g oral fosfomycin were simulated, comparing single and multiple (daily for 7 days) doses. Pharmacodynamic response of 16 P. aeruginosa (MIC range 1 to >1024 mg/L) were examined. Baseline disc diffusion susceptibility, broth microdilution MIC and detection of heteroresistance were assessed. Pathogen kill and emergence of resistance over 72 h following a single dose, and over 216 h following daily dosing for 7 days, 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 72 h and 7 day-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 7 days. Emergence of resistance was observed in the majority of isolates and worsened following prolonged therapy. Detection of a baseline resistant subpopulation predicted treatment failure. © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved."
}