{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T23:58:06Z","timestamp":1781567886378,"version":"3.54.5"},"reference-count":45,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T00:00:00Z","timestamp":1702944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T00:00:00Z","timestamp":1702944000000},"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":["mBio"],"published-print":{"date-parts":[[2023,12,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Multi-drug resistant (MDR)\n            <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n            harbor a complex array of \u03b2-lactamases and non-enzymatic resistance mechanisms. In this study, the activity of a \u03b2-lactam\/\u03b2-lactam-enhancer, cefepime\/zidebactam, and novel \u03b2-lactam\/\u03b2-lactamase inhibitor combinations was determined against an MDR phenotype-enriched, challenge panel of\n            <jats:italic>P. aeruginosa<\/jats:italic>\n            (\n            <jats:italic>n<\/jats:italic>\n            = 108). Isolates were multi-clonal as they belonged to at least 29 distinct sequence types (STs) and harbored metallo-\u03b2-lactamases, serine \u03b2-lactamases, penicillin binding protein (PBP) mutations, and other non-enzymatic resistance mechanisms. Ceftazidime\/avibactam, ceftolozane\/tazobactam, imipenem\/relebactam, and cefepime\/taniborbactam demonstrated MIC\n            <jats:sub>90<\/jats:sub>\n            s of &gt;128 mg\/L, while cefepime\/zidebactam MIC\n            <jats:sub>90<\/jats:sub>\n            was 16 mg\/L. In a neutropenic-murine lung infection model, a cefepime\/zidebactam human epithelial-lining fluid-simulated regimen achieved or exceeded a translational end point of 1\u2212log\n            <jats:sub>10<\/jats:sub>\n            kill for the isolates with elevated cefepime\/zidebactam MICs (16\u201332 mg\/L), harboring VIM-2 or KPC-2 and alterations in PBP2 and PBP3. In the same model, to assess the impact of zidebactam on the pharmacodynamic (PD) requirement of cefepime, dose-fractionation studies were undertaken employing cefepime-susceptible\n            <jats:italic>P. aeruginosa<\/jats:italic>\n            isolates. Administered alone, cefepime required 47%\u201368%\n            <jats:italic>f<\/jats:italic>\n            T &gt;MIC for stasis to ~1 log\n            <jats:sub>10<\/jats:sub>\n            kill effect, while cefepime in the presence of zidebactam required just 8%\u201316% for &gt;2 log\n            <jats:sub>10<\/jats:sub>\n            kill effect, thus, providing the pharmacokinetic\/PD basis for in vivo efficacy of cefepime\/zidebactam against isolates with MICs up to 32 mg\/L. Unlike \u03b2-lactam\/\u03b2-lactamase inhibitors, \u03b2-lactam enhancer mechanism-based cefepime\/zidebactam shows a potential to transcend the challenge of ever-evolving resistance mechanisms by targeting multiple PBPs and overcoming diverse \u03b2-lactamases including carbapenemases in\n            <jats:italic>P. aeruginosa<\/jats:italic>\n            .\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>\n              <jats:bold>IMPORTANCE<\/jats:bold>\n            <\/jats:title>\n            <jats:p>\n              Compared to other genera of Gram-negative pathogens,\n              <jats:italic>Pseudomonas<\/jats:italic>\n              is adept in acquiring complex non-enzymatic and enzymatic resistance mechanisms thus remaining a challenge to even novel antibiotics including recently developed \u03b2-lactam and \u03b2-lactamase inhibitor combinations. This study shows that the novel \u03b2-lactam enhancer approach enables cefepime\/zidebactam to overcome both non-enzymatic and enzymatic resistance mechanisms associated with a challenging panel of\n              <jats:italic>P. aeruginosa<\/jats:italic>\n              . This study highlights that the \u03b2-lactam enhancer mechanism is a promising alternative to the conventional \u03b2-lactam\/\u03b2-lactamase inhibitor approach in combating ever-evolving MDR\n              <jats:italic>P. aeruginosa<\/jats:italic>\n              .\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.01118-23","type":"journal-article","created":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T13:00:12Z","timestamp":1698411612000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":21,"title":["Transcending the challenge of evolving resistance mechanisms in\n            <i>Pseudomonas aeruginosa<\/i>\n            through \u03b2-lactam-enhancer-mechanism-based cefepime\/zidebactam"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3543-1826","authenticated-orcid":false,"given":"Andrea 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