{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T18:41:09Z","timestamp":1788892869732,"version":"build-2803163510"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012264","name":"NIH","doi-asserted-by":"publisher","award":["R01AI146241"],"award-info":[{"award-number":["R01AI146241"]}],"id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012264","name":"NIH","doi-asserted-by":"publisher","award":["R01AI170889"],"award-info":[{"award-number":["R01AI170889"]}],"id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012264","name":"NIH","doi-asserted-by":"publisher","award":["SC3GM125556"],"award-info":[{"award-number":["SC3GM125556"]}],"id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Carbapenem-resistant Acinetobacter baumannii (CRAB) infections, driven by metallo- and class-D serine \u03b2-lactamases, pose significant therapeutic challenges. \u03b2-Lactam-based combinations offer a promising alternative to agents like colistin and tigecycline, which are associated with toxicity, and to cefiderocol, which is facing emerging resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The pharmacodynamic activity of ampicillin\/sulbactam and ceftazidime\/avibactam was evaluated against three CRAB strains: AMA3, AMA133, and AMA205. Genotypic and phenotypic resistance profiles were characterized, and antibacterial activity was assessed using static concentration time-kill (SCTK) assays. A mechanism-based pharmacodynamic model (MBM) was developed using SCTK data, incorporating the bacterial resistome. This model informed the design of in vitro dynamic infection model studies, which were subsequently used to validate MBM predictions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>These strains harboring resistance genes including blaOXA-23 (AMA133), blaNDM-1 (AMA3), or both (AMA205) were resistant to ampicillin\/sulbactam and ceftazidime\/avibactam. However, combination therapy significantly reduced bacterial burden, achieving approximately 90% reduction in the area under the log10-CFU-versus-time curve for AMA133, and approximately 50\u201370% for AMA3 and AMA205.<\/jats:p>\n                    <jats:p>The MBM incorporated sulbactam hydrolysis by NDM-1 and OXA23 enzymes, along with drug acylation kinetics to penicillin-binding proteins. Potency (EC50) estimates revealed a resistance hierarchy: AMA3 &amp;gt; AMA205 &amp;gt; AMA133. Avibactam notably enhanced sulbactam's activity. Simulations and experimental validation demonstrated that high-dose ampicillin\/sulbactam combinations were required to achieve 4\u20136 log10-CFU reductions in blaNDM-1 strains, while lower doses sufficed for AMA133.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study highlights the potential of integrating genomic insights into MBM to optimize antibiotic regimens. The ampicillin\/sulbactam and ceftazidime\/avibactam combinations demonstrated promising activity against highly resistant CRAB strains, supporting their potential for clinical application in managing difficult-to-treat infections.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/infdis\/jiaf567","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:15:32Z","timestamp":1762866932000},"page":"e521-e533","source":"Crossref","is-referenced-by-count":5,"title":["Ampicillin\/Sulbactam in Combination with Ceftazidime\/Avibactam Against Metallo-\u03b2-Lactamase-Producing Carbapenem-Resistant\n                    <i>Acinetobacter baumannii<\/i>\n                    : A Genomics-Informed Mechanism-based model"],"prefix":"10.1093","volume":"233","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7784-0241","authenticated-orcid":false,"given":"Bhavatharini","family":"Arun","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California , Los Angeles, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eloise","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California , Los Angeles, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quentin","family":"Vall\u00e9","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California , Los Angeles, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0891-7548","authenticated-orcid":false,"given":"Rajnikant","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California , Los Angeles, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5780-0864","authenticated-orcid":false,"given":"Ngoc Minh","family":"Bui","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California , Los Angeles, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1896-8450","authenticated-orcid":false,"given":"Vyanka","family":"Mezcord","sequence":"additional","affiliation":[{"name":"Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton , Fullerton, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6890-3619","authenticated-orcid":false,"given":"Irene","family":"Luu","sequence":"additional","affiliation":[{"name":"Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton , Fullerton, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4780-5311","authenticated-orcid":false,"given":"German Matias","family":"Traglia","sequence":"additional","affiliation":[{"name":"Unidad de Genomica y Bioinformatica, Departamento de Ciencias Biol\u00f3gicas, CENUR Litoral Norte, Universidad de la Rep\u00fablica , Salto ,","place":["Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5840-5869","authenticated-orcid":false,"given":"Fernando","family":"Pasteran","sequence":"additional","affiliation":[{"name":"National Regional Reference Laboratory for Antimicrobial Resistance (NRL), Servicio Antimicrobianos, Instituto Nacional de Enfermedades Infecciosas, ANLIS Dr. Carlos G. Malbr\u00e1n , Buenos Aires ,","place":["Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Paterson","sequence":"additional","affiliation":[{"name":"Saw Swee Hock School of Public Health, National University of Singapore , Singapore ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A","family":"Bonomo","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Case Western Reserve University School of Medicine , Cleveland, Ohio ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Soledad","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton , Fullerton, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gauri G","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California , Los Angeles, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"2026031304550927600_jiaf567-B1","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1128\/CMR.00058-16","article-title":"Clinical and pathophysiological overview of Acinetobacter infections: a century of challenges","volume":"30","author":"Wong","year":"2016","journal-title":"Clin Microbiol Rev"},{"key":"2026031304550927600_jiaf567-B2","author":"CDC"},{"key":"2026031304550927600_jiaf567-B3","doi-asserted-by":"crossref","first-page":"373","DOI":"10.3390\/pathogens10030373","article-title":"Acinetobacter baumannii antibiotic resistance 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