{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:10:06Z","timestamp":1790644206131,"version":"4.1.0"},"reference-count":56,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2015,4,1]],"date-time":"2015-04-01T00:00:00Z","timestamp":1427846400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Acinetobacter baumannii<\/jats:named-content>\n            is among the most dangerous pathogens and emergence of resistance is highly problematic. Our objective was to identify and rationally optimize \u03b2-lactam-plus-aminoglycoside combinations via novel mechanism-based modeling that synergistically kill and prevent resistance of carbapenem-resistant\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">A. baumannii<\/jats:named-content>\n            . We studied combinations of 10 \u03b2-lactams and three aminoglycosides against four\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">A. baumannii<\/jats:named-content>\n            strains, including two imipenem-intermediate (MIC, 4 mg\/liter) and one imipenem-resistant (MIC, 32 mg\/liter) clinical isolate, using high-inoculum static-concentration time-kill studies. We present the first application of mechanism-based modeling for killing and resistance of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">A. baumannii<\/jats:named-content>\n            using Monte Carlo simulations of human pharmacokinetics to rationally optimize combination dosage regimens for immunocompromised, critically ill patients. All monotherapies achieved limited killing (\u22642.3 log\n            <jats:sub>10<\/jats:sub>\n            ) of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">A. baumannii<\/jats:named-content>\n            ATCC 19606 followed by extensive regrowth for aminoglycosides. Against this strain, imipenem-plus-aminoglycoside combinations yielded more rapid and extensive killing than other \u03b2-lactam-plus-aminoglycoside combinations. Imipenem at 8 mg\/liter combined with an aminoglycoside yielded synergistic killing (&gt;5 log\n            <jats:sub>10<\/jats:sub>\n            ) and prevented regrowth of all four strains. Modeling demonstrated that imipenem likely killed the aminoglycoside-resistant population and vice versa and that aminoglycosides enhanced the target site penetration of imipenem. Against carbapenem-resistant\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">A. baumannii<\/jats:named-content>\n            (MIC, 32 mg\/liter), optimized combination regimens (imipenem at 4 g\/day as a continuous infusion plus tobramycin at 7 mg\/kg of body weight every 24 h) were predicted to achieve &gt;5 log\n            <jats:sub>10<\/jats:sub>\n            killing without regrowth in 98.2% of patients. Bacterial killing and suppression of regrowth were best achieved for combination regimens with unbound imipenem steady-state concentrations of at least 8 mg\/liter. Imipenem-plus-aminoglycoside combination regimens are highly promising and warrant further evaluation.\n          <\/jats:p>","DOI":"10.1128\/aac.04379-14","type":"journal-article","created":{"date-parts":[[2015,2,3]],"date-time":"2015-02-03T06:04:54Z","timestamp":1422943494000},"page":"2286-2298","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":58,"title":["Novel Approach To Optimize Synergistic Carbapenem-Aminoglycoside Combinations against Carbapenem-Resistant Acinetobacter baumannii"],"prefix":"10.1128","volume":"59","author":[{"given":"Rajbharan","family":"Yadav","sequence":"first","affiliation":[{"name":"Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia B.","family":"Landersdorfer","sequence":"additional","affiliation":[{"name":"Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia"},{"name":"School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger L.","family":"Nation","sequence":"additional","affiliation":[{"name":"Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Boyce","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen B.","family":"Bulitta","sequence":"additional","affiliation":[{"name":"Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia"},{"name":"School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/595011"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir153"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1175325"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2009.1754"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1053\/srin.2000.20944"},{"key":"e_1_3_2_7_2","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1164\/ajrccm\/139.4.877","article-title":"Nosocomial pneumonia in patients receiving continuous mechanical ventilation. 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