Τίτλος:
Efficacy of single and multiple oral doses of fosfomycin against Pseudomonas aeruginosa urinary tract infections in a dynamic in vitro bladder infection model
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Abbott, I.J.
Van Gorp, E.
Wijma, R.A.
Dekker, J.
Croughs, P.D.
Meletiadis, J.
Mouton, J.W.
Peleg, A.Y.
Περιοδικό:
The Journal of antimicrobial chemotherapy
Εκδότης:
Oxford University Press
Λέξεις-κλειδιά:
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
