Oral Fosfomycin Efficacy with Variable Urinary Exposures following Single and Multiple Doses against Enterobacterales: the Importance of Heteroresistance for Growth Outcome.

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 various MICs of fosfomycin (8 Escherichia coli, 4 Enterobacter cloacae, and 4 Klebsiella pneumoniae isolates). Baseline fosfomycin high-level-resistant (HLR) subpopulations were detected prior to drug exposure in half of the isolates (2 E. coli, 2 E. cloacae, and 4 K. pneumoniae isolates; proportion, 1 × 10-5 to 5 × 10-4% of the total population). Fosfomycin exposures were accurately reproduced compared to mathematical modeling (linear regression slope, 1.1; R2, 0.99), with a bias of 3.8% ± 5.7%. All 5/5 isolates with MICs of ≤1 μg/ml had no HLR and were killed, whereas 8/11 isolates with higher MICs regrew regardless of exposure to high or low urinary concentrations. A disk diffusion zone of <24 mm was a better predictor for baseline HLR and regrowth. Administering 3 doses with average exposures provided very limited additional kill. These results suggest that baseline heteroresistance is important for treatment response, while increased drug exposure and administering multiple doses may not be better than standard single-dose fosfomycin therapy.

• Authors: Iain J Abbott, Elke van Gorp, Rixt A Wijma, Joseph Meletiadis, Jason A Roberts, Johan W Mouton, Anton Y Peleg
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 64 Issue 3 (02 21 2020) ISSN: 1098-6596 [Electronic] United States
• PMID: 31907184 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 American Society for Microbiology.

Chemical References

• Anti-Bacterial Agents
• Fosfomycin

Topics

• Anti-Bacterial Agents (administration & dosage, therapeutic use)
• Escherichia coli (drug effects, metabolism, pathogenicity)
• Escherichia coli Infections (drug therapy, virology)
• Fosfomycin (administration & dosage, therapeutic use)
• Humans
• Klebsiella Infections (drug therapy, virology)
• Klebsiella pneumoniae (drug effects, metabolism, pathogenicity)
• Microbial Sensitivity Tests
• Urinary Tract Infections (drug therapy, virology)