Oral fosfomycin efficacy with variable urinary exposures following single and multiple doses against Enterobacterales: the importance of heteroresistance on growth outcome.

Oral fosfomycin efficacy with variable urinary exposures following single and multiple doses against Enterobacterales: the importance of heteroresistance on growth outcome. Antimicrob Agents Chemother. 2020 Jan 06;: Authors: Abbott IJ, van Gorp E, Wijma RA, Meletiadis J, Roberts JA, Mouton JW, Peleg AY Abstract Oral fosfomycin trometamol is licensed as a single oral dose for the treatment of uncomplicated urinary tract infections, with activity against multidrug resistant uropathogens. The impact of interindividual variability in urinary concentrations on antimicrobial efficacy, and any benefit of giving multiple doses, is uncertain. We therefore performed pharmacodynamic profiling of oral fosfomycin, using a dynamic bladder infection in vitro model, to assess high and low urinary exposures following a single oral dose, and three repeat doses given every 72 h, 48 h and 24 h against 16 clinical isolates with varied MICs of fosfomycin (8 Escherichia coli, 4 Enterobacter cloacae, 4 Klebsiella pneumoniae). Baseline fosfomycin high-level resistant (HLR) subpopulations were detected prior to drug exposure in half of the isolates (2 E. coli, 2 E. cloacae, 4 K. pneumoniae; proportion 1×10-5 - 5×10-4% of total population). Fosfomycin exposures were accurately reproduced compared to mathematical modelling (linear regression slope 1.1, R2 0.99) and bias of 3.8 ± 5.7%. All 5/5 isolates with MICs ≤ 1 μg/mL had no HLR and were killed, wherea...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research