{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T16:27:16Z","timestamp":1786724836835,"version":"build-2736575974"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"9","funder":[{"DOI":"10.13039\/100000038","name":"U.S. Food and Drug Administration","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000938","name":"Department of Veterans Affairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000938","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Meropenem is commonly used to treat serious bacterial infections, but its short half-life in mice impedes achieving human-like drug exposure profiles. This study aimed to create humanized meropenem dosage regimens in immunocompetent mice with bloodstream infections by Acinetobacter baumannii.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cilastatin was administered to prolong the meropenem half-life in mice and match the concentration\u2013time profiles of meropenem in patients. An integrated population pharmacokinetic model was developed to characterize the concentration-dependent inhibition of meropenem clearance by cilastatin. Murine dosage regimens were humanized based on a novel matching framework. Firstly, meropenem plasma concentrations in mice should remain within the 5th to 95th percentiles of plasma concentrations for meropenem monotherapy in critically ill patients. Secondly, the free-time-above-MIC versus MIC profiles of meropenem in mice should match those in patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The meropenem half-life in mice increased from 22.2\u2005min without cilastatin to 57.7\u2005min at high cilastatin concentrations. Cilastatin inhibited the meropenem clearance half-maximally at 0.230\u2005mg\/L. Subcutaneous doses of 53\/10\u2005mg\/kg meropenem\/cilastatin at 0\u2005h and 26\/10\u2005mg\/kg at 3\u2005h in mice, both repeated every 8\u2005h, resulted in well-matched pharmacokinetic profiles to those of 2\u2005g meropenem infusions over 30\u2005min at the same dosing interval in patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Co-administration of cilastatin substantially prolonged the meropenem half-life in mice and enabled humanized meropenem dosage regimens with six doses per day to stay within the 5th and 95th percentiles of plasma concentrations in patients. This novel framework to humanize murine dosage regimens is based on quantitative matching criteria and supports translational research by achieving clinically relevant exposure profiles in mice.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jac\/dkag274","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T11:13:02Z","timestamp":1785237182000},"source":"Crossref","is-referenced-by-count":0,"title":["Humanizing meropenem dosage regimens by co-administration of cilastatin in an immunocompetent mouse bloodstream infection model of\n                    <i>Acinetobacter baumannii<\/i>\n                    based on a novel quantitative matching framework"],"prefix":"10.1093","volume":"81","author":[{"given":"Yuanyuan","family":"Jiao","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida , Orlando, FL 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Pharmacy and Pharmaceutical Sciences, St. Jude Children\u2019s Research Hospital , 262 Danny Thomas Pl, Memphis, TN 38105 ,","place":["USA"]},{"name":"Department of Pharmaceutical Sciences, University of Tennessee Health Science Center , Memphis, TN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeferino","family":"Reyna","sequence":"additional","affiliation":[{"name":"Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3632-1709","authenticated-orcid":false,"given":"Brad","family":"Spellberg","sequence":"additional","affiliation":[{"name":"Department of Medicine, Los Angeles General Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert 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