Pharmacodynamics of Fosfomycin: Insights into Clinical Use for Antimicrobial Resistance

Abstract

The aim of this study was to improve the understanding of the pharmacokinetic-pharmacodynamic relationships of fosfomycin against extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli strains that have different fosfomycin MICs. Our methods included the use of a hollow fiber infection model with three clinical ESBL-producing E. coli strains. Human fosfomycin pharmacokinetic profiles were simulated over 4 days. Preliminary studies conducted to determine the dose ranges, including the dose ranges that suppressed the development of drug-resistant mutants, were conducted with regimens from 12 g/day to 36 g/day. The combination of fosfomycin at 4 g every 8 h (q8h) and meropenem at 1 g/q8h was selected for further assessment. The total bacterial population and the resistant subpopulations were determined. No efficacy was observed against the Ec42444 strain (fosfomycin MIC, 64 mg/liter) at doses of 12, 24, or 36 g/day. All dosages induced at least initial bacterial killing against Ec46 (fosfomycin MIC, 1 mg/liter). High-level drug-resistant mutants appeared in this strain in response to 12, 15, and 18 g/day. In the study arms that included 24 g/day, once or in a divided dose, a complete extinction of the bacterial inoculum was observed. The combination of meropenem with fosfomycin was synergistic for bacterial killing and also suppressed all fosfomycinresistant clones of Ec2974 (fosfomycin MIC, 1 mg/liter). We conclude that fosfomycin susceptibility breakpoints (<64 mg/liter according to CLSI [for E. coli urinary tract infections only]) should be revised for the treatment of serious systemic infections. Fosfomycin can be used to treat infections caused by organisms that demonstrate lower MICs and lower bacterial densities, although relatively high daily dosages (i.e., 24 g/day) are required to prevent the emergence of bacterial resistance. The ratio of the area under the concentration-time curve for the free, unbound fraction of fosfomycin versus the MIC (fAUC/MIC) appears to be the dynamically linked index of suppression of bacterial resistance. Fosfomycin with meropenem can act synergistically against E. coli strains in preventing the emergence of fosfomycin resistance.

Alternatives to antibiotics—a pipeline portfolio review

“…Revisiting past programmes and applying new methods of PK/PD modelling could indicate improvements in dose regimens that could alter the outcome of new clinical trials. 116 Regulatory approaches to antibacterials also continue to evolve and may in the future permit narrowly focused programs in which some of these agents might better succeed. 117…”

Pharmacodynamic and pharmacokinetic considerations in the treatment of critically Ill patients infected with carbapenem-resistant Enterobacteriaceae

“…[76][77][78] The emergence of resistance to fosfomycin has been demonstrated in vitro in studies in both Enterobacteriaceae and Pseudomonas species. [76][77][78] This resistance may be suppressed by combining fosfomycin with other agents. [76][77][78][79][80] Though it is generally well tolerated, it should be noted that the intravenous formulation (fosfomycin disodium) contains 330 mg of sodium per gram of fosfomycin, which could be problematic in patients with heart failure.…”

“…[76][77][78] This resistance may be suppressed by combining fosfomycin with other agents. [76][77][78][79][80] Though it is generally well tolerated, it should be noted that the intravenous formulation (fosfomycin disodium) contains 330 mg of sodium per gram of fosfomycin, which could be problematic in patients with heart failure. 70 A study of IV fosfomycin for UTIs for approval in the United States is currently being conducted (NCT02753946).…”

“…74,75 Optimal pharmacodynamic targets for fosfomycin are unclear; historically it has been considered a time-dependent agent, but some recent pharmacodynamic studies with fosfomycin against E. coli have shown the fAUC/MIC ratio to be most predictive of efficacy. 76,77 The pharmacodynamics of fosfomycin may differ by species. [76][77][78] The emergence of resistance to fosfomycin has been demonstrated in vitro in studies in both Enterobacteriaceae and Pseudomonas species.…”

“…76,77 The pharmacodynamics of fosfomycin may differ by species. [76][77][78] The emergence of resistance to fosfomycin has been demonstrated in vitro in studies in both Enterobacteriaceae and Pseudomonas species. [76][77][78] This resistance may be suppressed by combining fosfomycin with other agents.…”