{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T22:59:59Z","timestamp":1788303599822,"version":"build-2803163510"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T00:00:00Z","timestamp":1735171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["16GW0249K"],"award-info":[{"award-number":["16GW0249K"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100016394","name":"ANR","doi-asserted-by":"publisher","award":["R19094GG"],"award-info":[{"award-number":["R19094GG"]}],"id":[{"id":"10.13039\/501100016394","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,3,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>MDR Gram-negative bacteria, such as ESBL-producing and carbapenemase-producing Klebsiella pneumoniae, represent major global health threats. Treatment options are limited due to increasing resistance and slowed development of novel antimicrobials, making it necessary to apply effective combination therapies based on approved antibiotics.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To quantitatively evaluate the synergistic potential of meropenem and fosfomycin against carbapenem-resistant K. pneumoniae strains isolated from clinics.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We evaluated four MDR K. pneumoniae strains, each expressing KPC-2 or KPC-3, using static time\u2013kill assays that accounted for measured meropenem degradation. This was followed by pharmacokinetic\/pharmacodynamic (PK\/PD) interaction modelling, which estimated meropenem degradation rate constants and identified perpetrator\u2013victim relationships in PD interactions. Dynamic hollow-fibre infection model (HFIM) experiments were used to confirm synergy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Static time\u2013kill assays demonstrated high killing effects and suppressed regrowth for the combination of meropenem and fosfomycin, compared with the failure of monotherapy. Meropenem degradation was significantly higher in the presence of bacteria, attributable to carbapenemase activity. Pharmacometric models indicated a synergistic interaction primarily driven by meropenem as the perpetrator, enhancing the potency of fosfomycin. HFIM experiments confirmed in vitro synergy, demonstrating continuous bacterial suppression of the combination therapy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Meropenem and fosfomycin exhibited additive or synergistic potential against carbapenemase-expressing single- or double-resistant K. pneumoniae at clinically achievable concentrations. This combination therapy may offer a strategy against MDR infections, possibly improving clinical treatment outcomes. Further in vivo research is needed to translate these findings into clinical practice, emphasizing the importance of PK\/PD modelling in rationalizing antibiotic use.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkae459","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T11:23:21Z","timestamp":1735212201000},"page":"701-712","source":"Crossref","is-referenced-by-count":9,"title":["Pharmacokinetic\/pharmacodynamic analysis of meropenem and fosfomycin combinations in <i>in vitro<\/i> time\u2013kill and hollow-fibre infection models against multidrug-resistant and carbapenemase-producing <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1093","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9452-9865","authenticated-orcid":false,"given":"Aneeq","family":"Farooq","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg , Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miklas","family":"Martens","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg , Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Kroemer","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg , Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Pfaffendorf","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg , Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Winoc","family":"Decousser","sequence":"additional","affiliation":[{"name":"Dynamic Team\u2014EA 7380, Facult\u00e9 De Sant\u00e9, Universit\u00e9 Paris-Est-Cr\u00e9teil Val-De-Marne , Cr\u00e9teil ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrice","family":"Nordmann","sequence":"additional","affiliation":[{"name":"Medical and Molecular Microbiology, University of Fribourg , Fribourg ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian G","family":"Wicha","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg , Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,12,26]]},"reference":[{"key":"2025030423053004500_dkae459-B1","author":"WHO"},{"key":"2025030423053004500_dkae459-B2","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/s41579-018-0141-x","article-title":"Drug combinations: a strategy to extend the life of antibiotics in the 21st century","volume":"17","author":"Tyers","year":"2019","journal-title":"Nat Rev Microbiol"},{"key":"2025030423053004500_dkae459-B3","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1128\/CMR.05041-11","article-title":"Combination therapy for treatment of infections with Gram-negative bacteria","volume":"25","author":"Tamma","year":"2012","journal-title":"Clin Microbiol Rev"},{"key":"2025030423053004500_dkae459-B4","doi-asserted-by":"publisher","first-page":"ciad428","DOI":"10.1093\/cid\/ciad428","article-title":"Infectious Diseases Society of America 2023 guidance on the treatment of antimicrobial resistant Gram-negative infections","author":"Tamma","year":"2023","journal-title":"Clin Infect Dis"},{"key":"2025030423053004500_dkae459-B5","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1080\/14787210.2019.1673731","article-title":"Use of meropenem in treating carbapenem-resistant Enterobacteriaceae infections","volume":"17","author":"Pascale","year":"2019","journal-title":"Expert Rev Anti Infect Ther"},{"key":"2025030423053004500_dkae459-B6","doi-asserted-by":"publisher","first-page":"971","DOI":"10.3390\/antibiotics12060971","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"},{"key":"2025030423053004500_dkae459-B7","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1097\/QCO.0000000000000597","article-title":"The role of fosfomycin for multidrug-resistant gram-negative infections","volume":"32","author":"Bassetti","year":"2019","journal-title":"Curr Opin Infect Dis"},{"key":"2025030423053004500_dkae459-B8","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"},{"key":"2025030423053004500_dkae459-B9","doi-asserted-by":"publisher","first-page":"FSO461","DOI":"10.2144\/fsoa-2019-0074","article-title":"Synergistic activity of fosfomycin\u2013meropenem and fosfomycin\u2013colistin against carbapenem resistant Klebsiella pneumoniae: an in vitro evidence","volume":"6","author":"Bakthavatchalam","year":"2020","journal-title":"Future Sci OA"},{"key":"2025030423053004500_dkae459-B10","author":"EUCAST"},{"key":"2025030423053004500_dkae459-B11","first-page":"330","volume-title":"Antibiotics in Laboratory Medicine","author":"Eliopoulos","year":"1996"},{"key":"2025030423053004500_dkae459-B12","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1038\/s41467-017-01929-y","article-title":"A general pharmacodynamic interaction model identifies perpetrators and victims in drug interactions","volume":"8","author":"Wicha","year":"2017","journal-title":"Nat Commun"},{"key":"2025030423053004500_dkae459-B13","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1109\/TAC.1974.1100705","article-title":"A new look at the statistical model identification","volume":"19","author":"Akaike","year":"1974","journal-title":"IEEE Trans Autom Control"},{"key":"2025030423053004500_dkae459-B14","doi-asserted-by":"publisher","first-page":"e0260620","DOI":"10.1128\/AAC.02606-20","article-title":"Population pharmacokinetics of meropenem and vaborbactam based on data from noninfected subjects and infected patients","volume":"65","author":"Trang","year":"2021","journal-title":"Antimicrob Agents Chemother"},{"key":"2025030423053004500_dkae459-B15","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":"2025030423053004500_dkae459-B16","author":"EMA"},{"key":"2025030423053004500_dkae459-B17","doi-asserted-by":"publisher","first-page":"e00749-17","DOI":"10.1128\/mbio.00749-17","article-title":"Widespread fosfomycin resistance in Gram-negative bacteria attributable to the chromosomal fosA gene","volume":"8","author":"Ito","year":"2017","journal-title":"mBio"},{"key":"2025030423053004500_dkae459-B18","doi-asserted-by":"publisher","first-page":"816806","DOI":"10.3389\/fmicb.2022.816806","article-title":"Transporter genes and fosA associated with fosfomycin resistance in carbapenem-resistant Klebsiella pneumoniae","volume":"13","author":"Wang","year":"2022","journal-title":"Front Microbiol"},{"key":"2025030423053004500_dkae459-B19","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1016\/j.jchromb.2016.06.033","article-title":"Simultaneous determination and stability studies of linezolid, meropenem and vancomycin in bacterial growth medium by high-performance liquid chromatography","volume":"1028","author":"Wicha","year":"2016","journal-title":"J Chromatogr B"},{"key":"2025030423053004500_dkae459-B20","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1128\/AAC.41.2.223","article-title":"Carbapenem-hydrolyzing beta-lactamases","volume":"41","author":"Rasmussen","year":"1997","journal-title":"Antimicrob Agents Chemother"},{"key":"2025030423053004500_dkae459-B21","doi-asserted-by":"publisher","first-page":"e0174908","DOI":"10.1371\/journal.pone.0174908","article-title":"Evaluation of a modified meropenem hydrolysis assay on a large cohort of KPC and VIM carbapenemase-producing Enterobacteriaceae","volume":"12","author":"Calderaro","year":"2017","journal-title":"PLoS One"},{"key":"2025030423053004500_dkae459-B22","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1007\/s10096-011-1360-5","article-title":"Synergy of fosfomycin with carbapenems, colistin, netilmicin, and tigecycline against multidrug-resistant Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa clinical isolates","volume":"31","author":"Samonis","year":"2012","journal-title":"Eur J Clin Microbiol Infect Dis"},{"key":"2025030423053004500_dkae459-B23","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":"2025030423053004500_dkae459-B24","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":"2025030423053004500_dkae459-B25","doi-asserted-by":"publisher","first-page":"616","DOI":"10.3390\/antibiotics13070616","article-title":"Efficacy and safety of ceftazidime\u2013avibactam alone versus ceftazidime\u2013avibactam plus fosfomycin for the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia: a multicentric retrospective study from the SUSANA cohort","volume":"13","author":"Fois","year":"2024","journal-title":"Antibiotics"},{"key":"2025030423053004500_dkae459-B26","doi-asserted-by":"publisher","first-page":"e00775-17","DOI":"10.1128\/aac.00775-17","article-title":"Pharmacokinetics, safety, and tolerability of single-dose intravenous (ZTI-01) and oral fosfomycin in healthy volunteers","volume":"61","author":"Wenzler","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"2025030423053004500_dkae459-B27","doi-asserted-by":"publisher","first-page":"1620","DOI":"10.1016\/j.jiph.2021.09.025","article-title":"Efficacy and safety of intravenous fosfomycin for the treatment of difficult-to-treat Gram-negative bacterial infections","volume":"14","author":"Abdallah","year":"2021","journal-title":"J Infect Public Health"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/80\/3\/701\/61276798\/dkae459.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/80\/3\/701\/61276798\/dkae459.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T23:05:39Z","timestamp":1741129539000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/80\/3\/701\/7932791"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,26]]},"references-count":27,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,12,26]]},"published-print":{"date-parts":[[2025,3,3]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkae459","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,3]]},"published":{"date-parts":[[2024,12,26]]}}}