Urinary tract infections (UTIs) are one of the most common conditions for which antimicrobials are prescribed worldwide. This, in turn, represents a significant driver for the emergence of antimicrobial resistance (AMR) in the community. Therefore, the optimisation of UTI treatment is paramount for improved clinical outcomes and the preservation of the activity of antimicrobials for the future. 

Despite oral fosfomycin being recommended as a first-line agent in many international guidelines, the comprehensive pharmacodynamic profiling of fosfomycin efficacy in UTIs has never been done. Approaches to susceptibility testing and the licensed dose recommendations have remain unchanged since the 1970s.

This research program was undertaken to develop a preclinical in vitro model that mimics infections of the urinary bladder, simulate the dynamically changing antimicrobial concentrations and replicate the normal urodynamics of bladder filling and intermittent voiding. Furthermore, this model enables the study of pathogen response in the biomatrix of pooled human urine and the validation of a synthetic alternative. 

The key findings of this research are as follows. Fosfomycin demonstrated good activity against a range of Escherichia coli isolates, although treatment failure and emergence of resistance was not predicted by standard susceptibility testing and current clinical breakpoints. Fosfomycin activity against Klebsiella pneumoniae was limited, with this species having an almost universal presence of a fosfomycin-resistant subpopulation at baseline. When comparing different dosing and urinary exposures, compared to a single dose with average exposure, there was no improvement in fosfomycin efficacy against Enterobacterales when urinary concentrations were high, or prolonged following multiple administered doses. The in vitro testing environment was found to impact upon the activity of fosfomycin, with a reduced propensity for isolates to develop emergence of resistance when comparing pooled human urine and synthetic alternatives with nutrient-rich standard laboratory media. The activity against Pseudomonas aeruginosa in synthetic human urine was limited, with the majority of isolates demonstrating emergence of resistance that was promoted by the administration of multiple doses over 7-days of simulated therapy. In contrast, fosfomycin activity against Enterococcus spp. was reasonable, albeit bacteriostatic, without any emergence of resistance when tested in synthetic human urine. 

This research has contributed the in vitro data regarding fosfomycin susceptibility testing, spectrum of activity and clinical dosing recommendations. The development of the preclinical bladder infection model has proven to be a powerful tool for the pharmacodynamic profiling of oral fosfomycin for the treatment of UTIs. Furthermore, this research provides a strong basis for the future study of other antimicrobials to inform UTI-specific clinical breakpoints, optimised dosing schedules in human studies and for the study of new agents.