{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T13:39:04Z","timestamp":1787578744766,"version":"build-2736575974"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T00:00:00Z","timestamp":1658102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Objective:<\/jats:bold> Cefoperazone\/sulbactam is a commonly used antibiotic combination against the extended-spectrum beta-lactamases (ESBLs)-producing bacteria. The objective of this study was to evaluate the efficacy of a new cefoperazone\/sulbactam combination (3:1) for Enterobacteriaceae infection via model-informed drug development (MIDD) approaches.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Sulperazon [cefoperazone\/sulbactam (2:1)] was used as a control. Pharmacokinetic (PK) data was collected from a clinical phase I trial. Minimum inhibitory concentrations (MICs) were determined using two-fold broth microdilution method. The percent time that the free drug concentration exceeded the minimum inhibitory concentration (%<jats:italic>f<\/jats:italic>T<jats:sub>&amp;gt;MIC<\/jats:sub>) was used as the pharmacokinetic\/pharmacodynamic indicator correlated with efficacy. Models were developed to characterize the PK profile of cefoperazone and sulbactam. Monte Carlo simulations were employed to determine the investigational regimens of cefoperazone\/sulbactam (3:1) for the treatment of infections caused by Enterobacteriaceae based on the probability of target attainment (PTA) against the tested bacteria.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Two 2-compartment models were developed to describe the PK profiles of cefoperazone and sulbactam. Simulation results following the single-dose showed that the regimens of cefoperazone\/sulbactam combinations in the ratios of 3:1 and 2:1 achieved similar PTA against the tested bacteria. Simulation results from the multiple-dose showed that the dosing regimen of cefoperazone\/sulbactam (4\u00a0g, TID, 3\u00a0g:1\u00a0g) showed slightly better antibacterial effect than cefoperazone\/sulbactam (6\u00a0g, BID, 4\u00a0g:2\u00a0g) against the <jats:italic>Escherichia coli<\/jats:italic> (ESBL<jats:sup>\u2212<\/jats:sup>) and <jats:italic>Klebsiella pneumoniae<\/jats:italic> (ESBL<jats:sup>\u2212<\/jats:sup>). For the other tested bacteria, the above regimens achieved a similar PTA.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> Cefoperazone\/sulbactam (3:1) showed similar bactericidal activity to sulperazon [cefoperazone\/sulbactam (2:1)] against the tested bacteria. For the ESBL-producing and cefoperazone-resistant <jats:italic>E. coli<\/jats:italic> and <jats:italic>K. pneumoniae<\/jats:italic>, Cefoperazone\/sulbactam (3:1) did not exhibit advantage as anticipated. Our study indicated that further clinical trials should be carried out cautiously to avoid the potential risks of not achieving the expected target.<\/jats:p>","DOI":"10.3389\/fphar.2022.856792","type":"journal-article","created":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T07:32:52Z","timestamp":1658129572000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Model-Informed Drug Development of New Cefoperazone Sodium and Sulbactam Sodium Combination (3:1): Pharmacokinetic\/Pharmacodynamic Analysis and Antibacterial Efficacy Against Enterobacteriaceae"],"prefix":"10.3389","volume":"13","author":[{"given":"Xi-Wei","family":"Ji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle Hui San","family":"Kuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-Feng","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Rui","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Qiang","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Min","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1055\/s-0034-1398490","article-title":"Applying Pharmacokinetic\/Pharmacodynamic Principles in Critically Ill Patients: Optimizing Efficacy and Reducing Resistance Development","volume":"36","author":"Abdul-Aziz","year":"2015","journal-title":"Semin. 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