{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:23:52Z","timestamp":1787009032712,"version":"build-2736575974"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:00:00Z","timestamp":1738281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"InfectoPharm Arzneimittel und Consilium GmbH"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Intravenous fosfomycin is used in combination with other antimicrobials for the management of severe and\/or multidrug resistant Gram-negative infection. We used an in vitro pharmacokinetic model to study the combination of fosfomycin plus meropenem.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Six Klebsiella pneumoniae fosfomycin MICs 8\u20131024\u2005mg\/L, meropenem MICs 0.06\u2013&amp;gt;1024\u2005mg\/L were employed. A dilutional pharmacokinetic model was used to generate fosfomycin exposure ranges up to a fAUC\/MIC 500. Exposure-ranging experiments were repeated in the presence of meropenem at exposures associated with 2\u2005g 8-hourly human dosing for strains with meropenem MICs \u226532\u2005mg\/L and at half the bacteriostatic fT\u200a&amp;gt;\u200aMIC for strains with MICs &amp;lt;32\u2005mg\/L. The log change in bacterial burden from the initial inoculum after 24\u2005h drug exposure was taken as the primary endpoint and fAUC\/MIC ratios for antibacterial effects were calculated. The risk of emergence of resistance was assessed by measurement of the population profiles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fosfomycin fAUC\/MIC for bacteriostatic effect at 24\u2005h were &amp;gt;500 for 5\/6 K. pneumoniae strains. Meropenem fT\u200a&amp;gt;\u200aMIC for static effect were 16.6%\u201377.9% for the strains with meropenem MIC\u200a\u2264\u200a64\u2005mg\/L. Strains with MICs of &amp;gt;1024\u2005mg\/L were not tested. Fosfomycin fAUC\/MICs in the presence of meropenem were all reduced and for 5\/6 strains the fAUC\/MIC for static effect was &amp;lt;10 and &amp;lt;30 for a 2 log drop. Addition of meropenem suppressed changes in fosfomycin population profiles. There were no changes in meropenem population profiles exposed to the combination.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Addition of meropenem to fosfomycin had a dramatic impact on the fosfomycin fAUC\/MIC exposures required for bacteriostatic and bactericidal effects and suppressed emergence of fosfomycin resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jac\/dkaf020","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T07:15:48Z","timestamp":1736493348000},"page":"967-975","source":"Crossref","is-referenced-by-count":8,"title":["The pharmacodynamics of fosfomycin in combination with meropenem against\n                    <i>Klebsiella pneumoniae<\/i>\n                    studied in an\n                    <i>in vitro<\/i>\n                    model of infection"],"prefix":"10.1093","volume":"80","author":[{"given":"Alasdair P","family":"MacGowan","sequence":"first","affiliation":[{"name":"Severn Infection Sciences, Bristol Centre for Antimicrobial Research & Evaluation (BCARE), North Bristol NHS Trust, Southmead Hospital , Pathology Sciences Building, Westbury-on-Trym, Bristol BS10 5NB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pippa","family":"Griffin","sequence":"additional","affiliation":[{"name":"Severn Infection Sciences, Bristol Centre for Antimicrobial Research & Evaluation (BCARE), North Bristol NHS Trust, Southmead Hospital , Pathology Sciences Building, Westbury-on-Trym, Bristol BS10 5NB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1047-2098","authenticated-orcid":false,"given":"Marie L G","family":"Attwood","sequence":"additional","affiliation":[{"name":"Severn Infection Sciences, Bristol Centre for Antimicrobial Research & Evaluation (BCARE), North Bristol NHS Trust, Southmead Hospital , Pathology Sciences Building, Westbury-on-Trym, Bristol BS10 5NB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimee M","family":"Daum","sequence":"additional","affiliation":[{"name":"School of Cellular & Molecular Medicine, University Bristol , Biomedical Sciences Building, University Walk, Bristol BS8 1TD ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1454-8440","authenticated-orcid":false,"given":"Matthew B","family":"Avison","sequence":"additional","affiliation":[{"name":"School of Cellular & Molecular Medicine, University Bristol , Biomedical Sciences Building, University Walk, Bristol BS8 1TD ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan R","family":"Noel","sequence":"additional","affiliation":[{"name":"Severn Infection Sciences, Bristol Centre for Antimicrobial Research & Evaluation (BCARE), North Bristol NHS Trust, Southmead Hospital , Pathology Sciences Building, Westbury-on-Trym, Bristol BS10 5NB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,1,31]]},"reference":[{"key":"2025040208384727900_dkaf020-B1","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/j.cmi.2016.12.005","article-title":"Intravenous fosfomycin\u2014back to the future. Systematic review and meta-analysis of the clinical literature","volume":"23","author":"Grabein","year":"2017","journal-title":"Clin Microbiol Infect"},{"key":"2025040208384727900_dkaf020-B2","doi-asserted-by":"publisher","first-page":"971","DOI":"10.3390\/antibiotics12060917","article-title":"The use of intravenous fosfomycin in clinical practice: a 5-year retrospective study in a tertiary hospital in Italy","volume":"12","author":"Anastasia","year":"2023","journal-title":"Antibiotics (Basel)"},{"key":"2025040208384727900_dkaf020-B3","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1093\/cid\/ciz181","article-title":"Fosfomycin for injection (ZTI-01) versus piperacillin-tazobactam for the treatment of complicated urinary tract infection including acute pyelonephritis: ZEUS, a phase 2\/3 randomized trial","volume":"69","author":"Kaye","year":"2019","journal-title":"Clin Infect Dis"},{"key":"2025040208384727900_dkaf020-B4","doi-asserted-by":"publisher","first-page":"e2137277","DOI":"10.1001\/jamanetworkopen.2021.37277","article-title":"Effectiveness of fosfomycin for the treatment of multidrug-resistant Escherichia coli bacteremic urinary tract infections: a randomized clinical trial","volume":"5","author":"Sojo-Dorado","year":"2022","journal-title":"JAMA Netw Open"},{"issue":"Suppl 1","key":"2025040208384727900_dkaf020-B5","first-page":"19","article-title":"Deciphering pharmacokinetics and pharmacodynamics of fosfomycin","volume":"32","author":"Rodr\u00edguez-Gasc\u00f3n","year":"2019","journal-title":"Rev Esp Quimioter"},{"key":"2025040208384727900_dkaf020-B6","doi-asserted-by":"publisher","first-page":"e000476-17","DOI":"10.1128\/AAC.00476-17","article-title":"In vivo pharmacokinetics and pharmacodynamics of ZTI-01 (fosfomycin for injection) in the neutropenic murine thigh infection model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa","volume":"61","author":"Lepak","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"2025040208384727900_dkaf020-B7","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1093\/jac\/dkh158","article-title":"Concentrations of fosfomycin in the cerebrospinal fluid of neurointensive care patients with ventriculostomy-associated ventriculitis","volume":"53","author":"Pfausler","year":"2004","journal-title":"J Antimicrob Chemother"},{"key":"2025040208384727900_dkaf020-B8","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ijid.2016.06.017","article-title":"Optimizing intravenous fosfomycin dosing in combination with carbapenems for treatment of Pseudomonas aeruginosa infections in critically ill patients based on pharmacokinetic\/pharmacodynamic (PK\/PD) simulation","volume":"50","author":"Asuphon","year":"2016","journal-title":"Int J Infect Dis"},{"key":"2025040208384727900_dkaf020-B9"},{"key":"2025040208384727900_dkaf020-B10","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1093\/jac\/48.2.209","article-title":"In vitro activity of fosfomycin in combination with various antistaphylococcal substances","volume":"48","author":"Grif","year":"2001","journal-title":"J Antimicrob Chemother"},{"key":"2025040208384727900_dkaf020-B11","doi-asserted-by":"publisher","first-page":"105985","DOI":"10.1016\/j.ijantimicag.2020.105985","article-title":"The pharmacodynamics of fosfomycin against Staphylococcus aureus studied in an in vitro model of infection","volume":"56","author":"Noel","year":"2020","journal-title":"Int J Antimicrob Agents"},{"key":"2025040208384727900_dkaf020-B12","doi-asserted-by":"publisher","first-page":"5602","DOI":"10.1128\/aac.00752-15","article-title":"Pharmacodynamics of fosfomycin: insights into clinical use for antimicrobial resistance","volume":"59","author":"Docobo-P\u00e9rez","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"2025040208384727900_dkaf020-B13","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.1093\/jac\/dkac038","article-title":"Flomoxef and fosfomycin in combination for the treatment of neonatal sepsis in the setting of highly prevalent antimicrobial resistance","volume":"77","author":"Darlow","year":"2022","journal-title":"J Antimicrob Chemother"},{"key":"2025040208384727900_dkaf020-B14","doi-asserted-by":"publisher","first-page":"e0331823","DOI":"10.1128\/spectrum.03318-23","article-title":"Pharmacokinetic\/pharmacodynamic analysis of ceftazidime\/avibactam and fosfomycin combinations in an in vitro hollow fiber infection model against multidrug-resistant Escherichia coli","volume":"12","author":"Kroemer","year":"2024","journal-title":"Microbiol Spectr"},{"key":"2025040208384727900_dkaf020-B15","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1128\/AAC.47.3.1088-1095.2003","article-title":"Activities of moxifloxacin against, and emergence of resistance in, Streptococcus pneumoniae and Pseudomonas aeruginosa in an in vitro pharmacokinetic model","volume":"47","author":"MacGowan","year":"2003","journal-title":"Antimicrob Agents Chemother"},{"key":"2025040208384727900_dkaf020-B16","doi-asserted-by":"publisher","first-page":"2411","DOI":"10.1093\/jac\/dky225","article-title":"Antibacterial effect of ceftolozane\/tazobactam in combination with amikacin against aerobic gram-negative bacilli studied in an in vitro pharmacokinetic model of infection","volume":"73","author":"Noel","year":"2018","journal-title":"J Antimicrob Chemother"},{"key":"2025040208384727900_dkaf020-B17","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: a flexible trimmer for illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"2025040208384727900_dkaf020-B18","doi-asserted-by":"publisher","first-page":"2068","DOI":"10.1093\/bioinformatics\/btu153","article-title":"Prokka: rapid prokaryotic genome annotation","volume":"30","author":"Seemann","year":"2014","journal-title":"Bioinformatics"},{"key":"2025040208384727900_dkaf020-B19","doi-asserted-by":"publisher","first-page":"2640","DOI":"10.1093\/jac\/dks261","article-title":"Identification of acquired antimicrobial resistance genes","volume":"67","author":"Zankari","year":"2012","journal-title":"J Antimicrob Chemother"},{"key":"2025040208384727900_dkaf020-B20"},{"key":"2025040208384727900_dkaf020-B21","first-page":"35","volume-title":"Clinical Antimicrobial Assays","author":"Andrews","year":"1999"},{"key":"2025040208384727900_dkaf020-B22","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1128\/am.14.2.170-177.1966","article-title":"Simplified accurate method for antibiotic assay of clinical specimens","volume":"14","author":"Bennett","year":"1966","journal-title":"Applied Microbiology"},{"issue":"Suppl 1","key":"2025040208384727900_dkaf020-B23","first-page":"45","article-title":"Fosfomycin in infections caused by multidrug-resistant Gram-negative pathogens","volume":"32","author":"Ruiz Ramos","year":"2019","journal-title":"Rev Esp Quimioter"},{"key":"2025040208384727900_dkaf020-B24","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1093\/jac\/dkz519","article-title":"Impact of bacterial species and baseline resistance on fosfomycin efficacy in urinary tract infections","volume":"75","author":"Abbott","year":"2020","journal-title":"J Antimicrob Chemother"},{"key":"2025040208384727900_dkaf020-B25","doi-asserted-by":"publisher","first-page":"e02307-18","DOI":"10.1128\/aac.02307-18","article-title":"Generating robust and informative nonclinical in vitro and in vivo bacterial infection model efficacy data to support translation to humans","volume":"63","author":"Bulitta","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"key":"2025040208384727900_dkaf020-B26","doi-asserted-by":"publisher","first-page":"E37","DOI":"10.1111\/j.1469-0691.2011.03752.x","article-title":"The role of pharmacokinetics\/pharmacodynamics in setting clinical MIC breakpoints: the EUCAST approach","volume":"18","author":"Mouton","year":"2012","journal-title":"Clin Microbiol Infect"},{"key":"2025040208384727900_dkaf020-B27","doi-asserted-by":"publisher","first-page":"e01816-19","DOI":"10.1128\/AAC.01816-19","article-title":"Ceftazidime-avibactam resistance associated with increased blaKPC-3 gene copy number mediated by pKpQIL plasmid derivatives in sequence type 258 Klebsiella pneumoniae","volume":"64","author":"Coppi","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"key":"2025040208384727900_dkaf020-B28","doi-asserted-by":"publisher","first-page":"24","DOI":"10.3390\/antibiotics6040024","article-title":"Fosfomycin: pharmacological, clinical and future perspectives","volume":"6","author":"Dijkmans","year":"2017","journal-title":"Antibiotics (Basel)"},{"key":"2025040208384727900_dkaf020-B29","doi-asserted-by":"publisher","first-page":"2524","DOI":"10.1093\/jac\/dkad264","article-title":"Evaluation of in vitro pharmacodynamic drug interactions of ceftazidime\/avibactam and fosfomycin in Escherichia coli","volume":"78","author":"Kroemer","year":"2023","journal-title":"J Antimicrob Chemother"},{"key":"2025040208384727900_dkaf020-B30","doi-asserted-by":"publisher","first-page":"153","DOI":"10.3390\/antibiotics11020153","article-title":"Assessment of in-vitro synergy of fosfomycin with meropenem, amikacin and tigecycline in whole genome sequenced extended and pan drug resistant Klebsiella pneumoniae: exploring a colistin sparing protocol","volume":"11","author":"Al-Quraini","year":"2022","journal-title":"Antibiotics (Basel)"},{"key":"2025040208384727900_dkaf020-B31","doi-asserted-by":"publisher","first-page":"1840","DOI":"10.1093\/jac\/dkab112","article-title":"The pharmacodynamics of minocycline alone and in combination with rifampicin against Staphylococcus aureus studied in an in vitro pharmacokinetic model of infection","volume":"76","author":"Noel","year":"2021","journal-title":"J Antimicrob Chemother"},{"key":"2025040208384727900_dkaf020-B32","doi-asserted-by":"publisher","first-page":"3303","DOI":"10.1093\/jac\/dkae363","article-title":"Population pharmacokinetics\/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus (MRSA)","volume":"79","author":"Pardos","year":"2024","journal-title":"J Antimicrob Chemother"},{"key":"2025040208384727900_dkaf020-B33","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1128\/AAC.35.6.1235","article-title":"In vitro testing procedures for fosfomycin tromethamine","volume":"35","author":"Barry","year":"1991","journal-title":"Antimicrob Agents Chemother"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/80\/4\/967\/61716671\/dkaf020.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/80\/4\/967\/61716671\/dkaf020.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T05:26:53Z","timestamp":1743571613000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/80\/4\/967\/7993865"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,31]]},"references-count":33,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,1,31]]},"published-print":{"date-parts":[[2025,4,2]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkaf020","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,4]]},"published":{"date-parts":[[2025,1,31]]}}}