title: 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 fosfomycin-resistant 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.
authors.affiliation: Unidad Intercentros de Enfermedades Infecciosas, Microbiología Clínica y Medicina Preventiva, Hospital Universitario Virgen de Macarena, Seville, Spain fdocobop@yahoo.es.
authors.forename: F
authors.initials: F
authors.lastname: Docobo-Pérez
authors.affiliation: Institute for Therapeutic Innovation, College of Medicine, University of Florida, Lake Nona, Florida, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Drusano
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Goodwin
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Whalley
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: V
authors.initials: V
authors.lastname: Ramos-Martín
authors.affiliation: Unidad Intercentros de Enfermedades Infecciosas, Microbiología Clínica y Medicina Preventiva, Hospital Universitario Virgen de Macarena, Seville, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Ballestero-Tellez
authors.affiliation: Departmento de Microbiología, Universidad de Sevilla, Seville, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Rodriguez-Martinez
authors.affiliation: Departmento de Microbiología, Universidad de Sevilla, Seville, Spain.
authors.forename: M C
authors.initials: MC
authors.lastname: Conejo
authors.affiliation: Laboratory of Applied Pharmacokinetics, School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: van Guilder
authors.affiliation: Unidad Intercentros de Enfermedades Infecciosas, Microbiología Clínica y Medicina Preventiva, Hospital Universitario Virgen de Macarena, Seville, Spain Departamento de Medicina, Universidad de Sevilla, Seville, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Rodríguez-Baño
authors.affiliation: Unidad Intercentros de Enfermedades Infecciosas, Microbiología Clínica y Medicina Preventiva, Hospital Universitario Virgen de Macarena, Seville, Spain Departmento de Microbiología, Universidad de Sevilla, Seville, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Pascual
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: W W
authors.initials: WW
authors.lastname: Hope
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects*; D005578:Fosfomycin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D009154:Mutation; D013845:Thienamycins / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D013845:Thienamycins; D005578:Fosfomycin; D000077731:Meropenem