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dc.creatorRodríguez Martínez, José Manueles
dc.creatorConejo Gonzalo, Mª Carmenes
dc.creatorRodríguez-Baño, Jesúses
dc.creatorPascual Hernández, Álvaroes
dc.creatorDocobo Pérez, Fernando Manueles
dc.date.accessioned2017-07-25T10:48:20Z
dc.date.available2017-07-25T10:48:20Z
dc.date.issued2015-09-01
dc.identifier.citationRodríguez Martínez, J.M., Conejo Gonzalo, M.C., Rodríguez Baño, J., Pascual Hernández, Á. y Docobo Pérez, F.M. (2015). Pharmacodynamics of fosfomycin: Insights into clinical use for antimicrobial resistance. Antimicrobial Agents and Chemotherapy, 59 (9), 5602-5610.
dc.identifier.issn0066-4804 (impreso)es
dc.identifier.issn1098-6596 (electrónico)es
dc.identifier.urihttp://hdl.handle.net/11441/63080
dc.description.abstractThe 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.es
dc.description.sponsorshipConsejería de Igualdad, Salud y Políticas Sociales Junta de Andalucía PI-0044-2013es
dc.description.sponsorshipFEDER REIPI RD12/0015es
dc.formatapplication/pdfes
dc.language.isoenges
dc.publisherAmerican Society for Microbiologyes
dc.relation.ispartofAntimicrobial Agents and Chemotherapy, 59 (9), 5602-5610.
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.titlePharmacodynamics of fosfomycin: Insights into clinical use for antimicrobial resistancees
dc.typeinfo:eu-repo/semantics/articlees
dc.type.versioninfo:eu-repo/semantics/publishedVersiones
dc.rights.accessrightsinfo:eu-repo/semantics/openAccesses
dc.contributor.affiliationUniversidad de Sevilla. Departamento de Microbiologíaes
dc.contributor.affiliationUniversidad de Sevilla. Departamento de Medicinaes
dc.relation.projectIDPI-0044-2013es
dc.relation.projectIDRD12/0015es
dc.relation.publisherversionhttp://dx.doi.org/10.1128/AAC.00752-15es
dc.identifier.doi10.1128/AAC.00752-15es
idus.format.extent9 p.es
dc.journaltitleAntimicrobial Agents and Chemotherapyes
dc.publication.volumen59es
dc.publication.issue9es
dc.publication.initialPage5602es
dc.publication.endPage5610es
dc.contributor.funderJunta de Andalucía
dc.contributor.funderEuropean Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)

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