{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T15:36:23Z","timestamp":1791905783181,"version":"4.3.4"},"reference-count":107,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T00:00:00Z","timestamp":1770422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The global spread of multidrug-resistant (MDR) Gram-negative bacteria, particularly extended-spectrum \u03b2-lactamase (ESBL)- and carbapenemase-producing Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii, presents a significant public health challenge by limiting effective antimicrobial treatment options. Cefepime, a fourth-generation cephalosporin with broad-spectrum activity, is increasingly compromised by \u03b2-lactamase production, efflux pumps, and porin loss. In response, novel cefepime-based \u03b2-lactam\/\u03b2-lactamase inhibitor (BL\/BLI) combinations have been developed to overcome these resistance mechanisms. This review examines preclinical and clinical studies on cefepime-based BL\/BLI combinations, specifically cefepime\/enmetazobactam, cefepime\/taniborbactam, cefepime\/zidebactam, and cefepime\/nacubactam, as found in the PubMed database. Key findings include the restoration of activity against class A ESBLs with cefepime\/enmetazobactam, while cefepime\/taniborbactam and cefepime\/zidebactam show broader inhibition of serine \u03b2-lactamases and selected metallo-\u03b2-lactamases. Additionally, zidebactam and nacubactam target penicillin-binding protein 2, enhancing bactericidal potency. Preclinical and early-phase clinical trial data indicate potent in vitro activity and favorable pharmacokinetic\/pharmacodynamic (PK\/PD) profiles. Specifically, the combination of cefepime with enmetazobactam has demonstrated an optimal Cmax\/MIC ratio of 8\u201310, supporting its efficacy in treating MDR Gram-negative infections. Phase III studies are ongoing to confirm efficacy in complicated infections. Cefepime-based BL\/BLI combinations are emerging as promising carbapenem-sparing agents, offering broad-spectrum activity, dual mechanisms of action, and encouraging clinical outcomes. These findings support their inclusion in antimicrobial stewardship strategies aimed at mitigating resistance.<\/jats:p>","DOI":"10.3390\/ph19020283","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T09:41:02Z","timestamp":1770630062000},"page":"283","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Cefepime and New Cefepime\/Beta-Lactamase Inhibitor Combination for the Treatment of Gram-Negative Bacteria: Chemical Structure and Mechanism of Action, Microbiological Target, Clinical Use and PK\/PD Characteristics"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4411-0407","authenticated-orcid":false,"given":"Davide","family":"Carcione","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Microbiology and Virology, ASST Valle Olona, 21013 Gallarate, VA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gioconda","family":"Brigante","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Microbiology and Virology, ASST Valle Olona, 21013 Gallarate, VA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Carducci","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Microbiology and Virology, ASST Valle Olona, 21013 Gallarate, VA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0978-9573","authenticated-orcid":false,"given":"Jari","family":"Intra","sequence":"additional","affiliation":[{"name":"Clinical Chemistry Laboratory, Fondazione IRCCS San Gerardo Dei Tintori, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8358-339X","authenticated-orcid":false,"given":"Simone","family":"Ambretti","sequence":"additional","affiliation":[{"name":"Microbiology Unit, IRCCS Azienda Ospedaliero-Universitaria of Bologna, 40138 Bologna, Italy"},{"name":"Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8405-5425","authenticated-orcid":false,"given":"Floriana","family":"Campanile","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Section of Microbiology, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Arcari","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Microbiology and Virology, Department of Medicine and Technological Innovation, University of Insubria, 21100 Varese, Italy"},{"name":"Laboratory of Medical Microbiology and Virology, Fondazione Macchi University Hospital, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicasio","family":"Mancini","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Microbiology and Virology, Department of Medicine and Technological Innovation, University of Insubria, 21100 Varese, Italy"},{"name":"Laboratory of Medical Microbiology and Virology, Fondazione Macchi University Hospital, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1512-6530","authenticated-orcid":false,"given":"Dario","family":"Cattaneo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 MI, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2680-5176","authenticated-orcid":false,"given":"Floriana","family":"Gona","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences (BIOMETEC), University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7370-1455","authenticated-orcid":false,"given":"Mariagrazia","family":"Perilli","sequence":"additional","affiliation":[{"name":"Department of Biotechnological and Applied Clinical Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Piccirilli","sequence":"additional","affiliation":[{"name":"Department of Biotechnological and Applied Clinical Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7988-5419","authenticated-orcid":false,"given":"Nicholas","family":"Geremia","sequence":"additional","affiliation":[{"name":"Unit of Infectious Diseases, Department of Clinical Medicine, Ospedale \u201cdell\u2019Angelo\u201d, 30174 Venice, Italy"},{"name":"Unit of Infectious Diseases, Department of Clinical Medicine, Ospedale Civile \u201cS.S. Giovanni e Paolo\u201d, 30122 Venice, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9204-032X","authenticated-orcid":false,"given":"Verena","family":"Zerbato","sequence":"additional","affiliation":[{"name":"Infectious Disease Unit, Trieste University Hospital (ASUGI), 34125 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6121-7009","authenticated-orcid":false,"given":"Stefano","family":"Di Bella","sequence":"additional","affiliation":[{"name":"Infectious Disease Unit, Trieste University Hospital (ASUGI), 34125 Trieste, Italy"},{"name":"Clinical Department of Medical, Surgical, and Health Sciences, Trieste University, 34129 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8817-2123","authenticated-orcid":false,"given":"Giovanna Maria","family":"Nicol\u00f2","sequence":"additional","affiliation":[{"name":"Microbiology and Virology Unit, Great Metropolitan Hospital \u201cBianchi-Melacrino-Morelli\u201d, 89100 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2000-5322","authenticated-orcid":false,"given":"Luigi","family":"Principe","sequence":"additional","affiliation":[{"name":"Microbiology and Virology Unit, Great Metropolitan Hospital \u201cBianchi-Melacrino-Morelli\u201d, 89100 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1586\/14787210.6.6.805","article-title":"Cefepime: A reappraisal in an era of increasing antimicrobial resistance","volume":"6","author":"Endimiani","year":"2008","journal-title":"Expert Rev. 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