{"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":1791905783269,"version":"4.3.4"},"reference-count":25,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T00:00:00Z","timestamp":1571788800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Wockhardt Bio AG","award":["1265\u201332"],"award-info":[{"award-number":["1265\u201332"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>WCK 5222 combines cefepime with zidebactam, a \u03b2-lactam enhancer that binds PBP2 and inhibits class A and C \u03b2-lactamases. The efficacy of human-simulated bronchopulmonary exposures of WCK 5222 against MDR Pseudomonas aeruginosa was investigated in a neutropenic murine pneumonia model.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Nineteen MDR isolates of P. aeruginosa (cefepime MICs \u226564\u2009mg\/L) were studied. MICs of zidebactam and WCK 5222 ranged from 4 to 512\u2009mg\/L and from 4 to 32\u2009mg\/L, respectively. Dosing regimens of cefepime and zidebactam alone and in combination that achieved epithelial lining fluid (ELF) exposures in mice approximating human ELF exposures after doses of 2\u2009g of cefepime\/1 g of zidebactam every 8\u2009h (1\u2009h infusion) were utilized; controls were vehicle-dosed. Lungs were intranasally inoculated with 107\u2013108\u2009cfu\/mL bacterial suspensions. Mice were dosed subcutaneously 2\u2009h after inoculation for 24\u2009h, then lungs were harvested.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In vitro MIC was predictive of in vivo response to WCK 5222 treatment. Mean\u202f\u00b1\u202fSD changes in bacterial density at 24\u2009h compared with 0\u2009h controls (6.72\u202f\u00b1\u202f0.50\u2009log10\u2009cfu\/lungs) for 13 isolates with WCK 5222 MICs \u226416\u2009mg\/L were 1.17\u202f\u00b1\u202f1.00, \u22120.99\u202f\u00b1\u202f1.45 and \u22122.21\u202f\u00b1\u202f0.79\u2009log10\u2009cfu\/lungs for cefepime, zidebactam and WCK 5222, respectively. Against these isolates, zidebactam yielded &gt;1\u2009log10\u2009cfu\/lungs reductions in 8\/13, while activity was enhanced with WCK 5222, producing &gt;2\u2009log10\u2009cfu\/lungs reductions in 10\/13 and &gt;1\u2009log10\u2009cfu\/lungs reductions in 12\/13. Among isolates with WCK 5222 MICs of 32\u2009mg\/L, five out of six showed a bacteriostatic response.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Human-simulated bronchopulmonary exposure of WCK 5222 is effective against MDR P. aeruginosa at MIC \u226416\u2009mg\/L in a murine pneumonia model. These data support the clinical development of WCK 5222 for pseudomonal lung infections.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkz414","type":"journal-article","created":{"date-parts":[[2019,9,6]],"date-time":"2019-09-06T19:30:09Z","timestamp":1567798209000},"source":"Crossref","is-referenced-by-count":14,"title":["Efficacy of human-simulated bronchopulmonary exposures of cefepime, zidebactam and the combination (WCK 5222) against MDR Pseudomonas aeruginosa in a neutropenic murine pneumonia model"],"prefix":"10.1093","author":[{"given":"James M","family":"Kidd","sequence":"first","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital, Harford, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamilia","family":"Abdelraouf","sequence":"additional","affiliation":[{"name":"Center for Anti-Infective Research and Development, Hartford Hospital, Harford, CT, 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