{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T19:37:56Z","timestamp":1791401876841,"version":"4.3.3"},"reference-count":30,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The aim of this study was to improve the understanding of the pharmacokinetic-pharmacodynamic relationships of fosfomycin against extended-spectrum beta-lactamase (ESBL)-producing\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Escherichia coli<\/jats:named-content>\n            strains that have different fosfomycin MICs. Our methods included the use of a hollow fiber infection model with three clinical ESBL-producing\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">E. coli<\/jats:named-content>\n            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 (\u226464 mg\/liter according to CLSI [for\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">E. coli<\/jats:named-content>\n            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 (\n            <jats:italic>f<\/jats:italic>\n            AUC\/MIC) appears to be the dynamically linked index of suppression of bacterial resistance. Fosfomycin with meropenem can act synergistically against\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">E. coli<\/jats:named-content>\n            strains in preventing the emergence of fosfomycin resistance.\n          <\/jats:p>","DOI":"10.1128\/aac.00752-15","type":"journal-article","created":{"date-parts":[[2015,6,30]],"date-time":"2015-06-30T02:44:58Z","timestamp":1435632298000},"page":"5602-5610","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":101,"title":["Pharmacodynamics of Fosfomycin: Insights into Clinical Use for Antimicrobial Resistance"],"prefix":"10.1128","volume":"59","author":[{"given":"F.","family":"Docobo-P\u00e9rez","sequence":"first","affiliation":[{"name":"Unidad Intercentros de Enfermedades Infecciosas, Microbiolog\u00eda Cl\u00ednica y Medicina Preventiva, Hospital Universitario Virgen de Macarena, Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. L.","family":"Drusano","sequence":"additional","affiliation":[{"name":"Institute for Therapeutic Innovation, College of Medicine, University of Florida, Lake Nona, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Goodwin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Whalley","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"Ramos-Mart\u00edn","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Ballestero-Tellez","sequence":"additional","affiliation":[{"name":"Unidad Intercentros de Enfermedades Infecciosas, Microbiolog\u00eda Cl\u00ednica y Medicina Preventiva, Hospital Universitario Virgen de Macarena, Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. M.","family":"Rodriguez-Martinez","sequence":"additional","affiliation":[{"name":"Departmento de Microbiolog\u00eda, Universidad de Sevilla, Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. C.","family":"Conejo","sequence":"additional","affiliation":[{"name":"Departmento de Microbiolog\u00eda, Universidad de Sevilla, Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"van Guilder","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Pharmacokinetics, School of Medicine, University of Southern California, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Rodr\u00edguez-Ba\u00f1o","sequence":"additional","affiliation":[{"name":"Unidad Intercentros de Enfermedades Infecciosas, Microbiolog\u00eda Cl\u00ednica y Medicina Preventiva, Hospital Universitario Virgen de Macarena, Seville, Spain"},{"name":"Departamento de Medicina, Universidad de Sevilla, Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Pascual","sequence":"additional","affiliation":[{"name":"Unidad Intercentros de Enfermedades Infecciosas, Microbiolog\u00eda Cl\u00ednica y Medicina Preventiva, Hospital Universitario Virgen de Macarena, Seville, Spain"},{"name":"Departmento de Microbiolog\u00eda, Universidad de Sevilla, Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. W.","family":"Hope","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/649537"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/508877"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2010.03089.x"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(08)70041-0"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.05035-11"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2014-007363"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-2126(96)00153-0"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.1.368-370.2006"},{"key":"e_1_3_2_10_2","volume-title":"Performance standards for antimicrobial susceptibility testing, 23rd informational supplement","author":"Clinical and Laboratory Standards Institute","year":"2013","unstructured":"Clinical and Laboratory Standards Institute. 2013. 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Spanish Agency of Medicines and Medical Devices, Madrid, Spain. http:\/\/www.aemps.gob.es\/cima\/pdfs\/es\/ft\/54165\/FT_54165.pdf."},{"key":"e_1_3_2_26_2","volume-title":"MHRA","author":"Medicines and Healthcare Products Regulatory Agency","year":"2015","unstructured":"Medicines and Healthcare Products Regulatory Agency. 2015. Fosfomycin sodium. MHRA, London, England. http:\/\/www.mhra.gov.uk\/home\/groups\/par\/documents\/websiteresources\/con309596.pdf."},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1974.tb43277.x"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01648937"},{"key":"e_1_3_2_29_2","volume-title":"Breakpoint tables for interpretation of MICs and zone diameters, version 5.0","author":"European Committee on Antimicrobial Susceptibility Testing","year":"2015","unstructured":"European Committee on Antimicrobial Susceptibility Testing. 2015. 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