{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T02:39:27Z","timestamp":1792809567744,"version":"4.5.0"},"reference-count":13,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:00:00Z","timestamp":1792713600000},"content-version":"vor","delay-in-days":17,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Basilea Pharmaceutica International Ltd"},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["HHSN272201600029C"],"award-info":[{"award-number":["HHSN272201600029C"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000016","name":"Department of Health and Human Services","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000016","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Basilea Pharmaceutica International Ltd"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Ceftibuten and ledaborbactam etzadroxil are being developed as an oral fixed-dose combination for the treatment of complicated urinary tract infections caused by multidrug-resistant Enterobacterales. This study evaluated their effects on cardiac repolarization using concentration-QTc analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>ECG and pharmacokinetic data from two randomized, single-centre, double-blind, placebo-controlled, phase I, dose-escalation studies in healthy adults (ClinicalTrials.gov: NCT04314206 and NCT04243863) were analysed using concentration-QTc modelling. Thirty-six participants were randomized to the ceftibuten study (27 active, nine placebo) and 48 to the ledaborbactam etzadroxil study (36 active, 12 placebo). Linear mixed-effects models characterized the relationship between plasma concentrations and placebo-corrected change from baseline in Fridericia-corrected QT interval (\u0394\u0394QTcF). Model-based predictions estimated QTc effects across observed and clinically relevant plasma concentrations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Neither agent produced clinically relevant changes in ECG parameters. Concentration-QTc analyses demonstrated no statistically or clinically meaningful relationship between plasma concentrations and \u0394\u0394QTcF. An effect on \u0394\u0394QTcF exceeding the regulatory threshold of 10\u2005ms could be excluded at plasma concentrations up to 44\u2005\u00b5g\/mL for cis-ceftibuten (the predominant and more potent isomer), 2.2\u2005\u00b5g\/mL for trans-ceftibuten, 30.3\u2005\u00b5g\/mL for ledaborbactam (active drug), and 2.6\u2005\u00b5g\/mL for ledaborbactam etzadroxil (prodrug). A small, transient, not clinically relevant increase in heart rate was observed with ceftibuten, whereas ledaborbactam etzadroxil had no clinically meaningful effect on heart rate.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Ceftibuten and ledaborbactam etzadroxil demonstrated no clinically relevant effects on cardiac repolarization or ECG parameters. Concentration-QTc analyses excluded clinically meaningful QTc effects at and above anticipated therapeutic plasma concentrations, supporting the cardiac safety profile of this oral fixed-dose combination.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jac\/dkag365","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T09:59:29Z","timestamp":1792749569000},"source":"Crossref","is-referenced-by-count":0,"title":["No clinically relevant QTc prolongation with ceftibuten or ledaborbactam etzadroxil: concentration-QTc analyses from two phase I studies"],"prefix":"10.1093","volume":"81","author":[{"given":"Borje","family":"Darpo","sequence":"first","affiliation":[{"name":"Clario, part of Thermo Fisher Scientific , Philadelphia, PA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3157-1874","authenticated-orcid":false,"given":"Hongqi","family":"Xue","sequence":"additional","affiliation":[{"name":"Clario, part of Thermo Fisher Scientific , Philadelphia, PA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1896-9736","authenticated-orcid":false,"given":"Kamal A","family":"Hamed","sequence":"additional","affiliation":[{"name":"Basilea Pharmaceutica International Ltd , Allschwil ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8243-0482","authenticated-orcid":false,"given":"Karine","family":"Litherland","sequence":"additional","affiliation":[{"name":"Basilea Pharmaceutica International Ltd , Allschwil ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2432-0212","authenticated-orcid":false,"given":"Marc","family":"Engelhardt","sequence":"additional","affiliation":[{"name":"Basilea Pharmaceutica International Ltd , Allschwil ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Lowe","sequence":"additional","affiliation":[{"name":"Venatorx Pharmaceuticals, Inc. , Malvern, PA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5906-2818","authenticated-orcid":false,"given":"Paul C","family":"McGovern","sequence":"additional","affiliation":[{"name":"McGovern ID Consulting LLC , Berwyn, PA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,10,23]]},"reference":[{"key":"2026102322225600200_dkag365-B1","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00087-25","article-title":"Pharmacokinetics and safety of single and repeat doses of ceftibuten in healthy participants: a phase 1 dose escalation study","volume":"69","author":"Dorr","year":"2025","journal-title":"Antimicrob Agents Chemother"},{"key":"2026102322225600200_dkag365-B2"},{"key":"2026102322225600200_dkag365-B3","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00552-21","article-title":"Microbiological characterization of VNRX-5236, a broad-spectrum \u03b2-lactamase inhibitor for rescue of the orally bioavailable cephalosporin ceftibuten as a carbapenem-sparing agent against strains of enterobacterales expressing extended-spectrum \u03b2-lactamases and serine carbapenemases","volume":"65","author":"Chatwin","year":"2021","journal-title":"Antimicrob Agents Chemother"},{"key":"2026102322225600200_dkag365-B4","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00210-25","article-title":"Safety and pharmacokinetics of single and multiple doses of ledaborbactam etzadroxil with or without ceftibuten in healthy volunteers","volume":"69","author":"de Oliveira","year":"2025","journal-title":"Antimicrob Agents Chemother"},{"key":"2026102322225600200_dkag365-B5","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01304-21","article-title":"In vitro activity of ceftibuten\/VNRX-5236 against urinary tract infection isolates of antimicrobial-resistant Enterobacterales","volume":"66","author":"Karlowsky","year":"2022","journal-title":"Antimicrob Agents Chemother"},{"key":"2026102322225600200_dkag365-B6","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00934-22","article-title":"Ceftibuten-ledaborbactam activity against multidrug-resistant and extended-spectrum-\u03b2-lactamase-positive clinical isolates of enterobacterales from a 2018-2020 global surveillance collection","volume":"66","author":"Karlowsky","year":"2022","journal-title":"Antimicrob Agents Chemother"},{"key":"2026102322225600200_dkag365-B7","author":"Woosley"},{"key":"2026102322225600200_dkag365-B8","author":"ICH E14\/S7B Implementation Working Group"},{"key":"2026102322225600200_dkag365-B9","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/s10928-025-09985-4","article-title":"FDA's insights: implementing new strategies for evaluating drug-induced QTc prolongation","volume":"52","author":"Ji","year":"2025","journal-title":"J Pharmacokinet Pharmacodyn"},{"key":"2026102322225600200_dkag365-B10","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1007\/s10928-017-9558-5","article-title":"Scientific white paper on concentration-QTc modeling","volume":"45","author":"Garnett","year":"2018","journal-title":"J Pharmacokinet Pharmacodyn"},{"key":"2026102322225600200_dkag365-B11","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1007\/s10928-025-09998-z","article-title":"Sample size determination for cardiodynamic ECG assessment using the concentration-QTc analysis method","volume":"52","author":"Xue","year":"2025","journal-title":"J Pharmacokinet Pharmacodyn"},{"key":"2026102322225600200_dkag365-B12","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1002\/cpt.60","article-title":"Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase","volume":"97","author":"Darpo","year":"2015","journal-title":"Clin Pharmacol Ther"},{"key":"2026102322225600200_dkag365-B13","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1111\/anec.12227","article-title":"Detection of QTc effects in small studies: implications for replacing the thorough QT study","volume":"20","author":"Ferber","year":"2015","journal-title":"Ann Noninvasive Electrocardiol"}],"container-title":["Journal of Antimicrobial 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