Fosfomycin efficacy and emergence of resistance among Enterobacteriaceae in an in vitro dynamic bladder infection model. (14th December 2017)

• Record Type: Journal Article
• Authors: Abbott, Iain J; Meletiadis, Joseph; Belghanch, Imane; Wijma, Rixt A; Kanioura, Lamprini; Roberts, Jason A; Peleg, Anton Y; Mouton, Johan W
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 73:Number 3(2018)
• Page Start: 709
• Page End: 719
• Publication Date: 2017-12-14
• Subjects: Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dkx441
• Languages: English
• ISSNs: 0305-7453

Abstract

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; AUC0-24 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 f AUC0-24 /MIC = 1922, fC max /MIC = 149 and f Time>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.