WCK 5222 (cefepime-zidebactam, 2 g + 1g, every 8 h [q8h]) is in clinical development for the treatment of infections caused by carbapenem-resistant and multidrug-resistant (MDR) Gram-negative bacilli. We determined the in vitro susceptibility of 1,385 clinical isolates of non-carbapenem-susceptible Enterobacterales, MDR Pseudomonas aeruginosa (also non-carbapenem susceptible), Stenotrophomonas maltophilia, and Burkholderia spp. collected worldwide (49 countries) from 2014 to 2016 to cefepime-zidebactam (1:1 ratio), ceftazidime-avibactam, imipenem-relebactam, ceftolozane-tazobactam, and colistin using the CLSI broth microdilution method. Cefepime-zidebactam inhibited 98.5% of non-carbapenem-susceptible Enterobacterales (n = 1,018) at ≤8 μg/ml (provisional cefepime-zidebactam-susceptible MIC breakpoint). Against the subset of metallo-β-lactamase (MBL)-positive Enterobacterales (n = 214), cefepime-zidebactam inhibited 94.9% of isolates at ≤8 μg/ml. Further, it inhibited 99.6% of MDR P. aeruginosa (n = 262) isolates at ≤32 μg/ml (proposed cefepime-zidebactam-susceptible pharmacokinetic/pharmacodynamic MIC breakpoint), including all MBL-positive isolates (n = 94). Moreover, cefepime-zidebactam was active against the majority of isolates of Enterobacterales (≥95%) and P. aeruginosa (99%) that were not susceptible to ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, and colistin. Most isolates (99%) of S. maltophilia (n = 101; MIC₅₀, 8 μg/ml; MIC₉₀, 32 μg/ml) and Burkholderia spp. (n = 4; MIC range, 16 to 32 μg/ml) were also inhibited by cefepime-zidebactam at ≤32 μg/ml. The activity of cefepime-zidebactam against carbapenem-resistant Gram-negative bacteria is ascribed to its β-lactam enhancer mechanism of action (i.e., zidebactam binding to penicillin binding protein 2 [PBP2] and its universal stability to both serine β-lactamases and MBLs). The results from this study support the continued development of cefepime-zidebactam as a potential therapy for infections caused by Enterobacterales, P. aeruginosa, and other nonfermentative Gram-negative bacilli where resistance to marketed antimicrobial agents is a limiting factor.

中文翻译：

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WCK 5222（头孢吡肟-齐德巴坦）对全球范围内碳青霉烯不敏感的革兰氏阴性杆菌的体外活性。

WCK 5222（头孢吡肟-齐德巴坦，每8小时[q8h] 2 g + 1g）正在临床开发中，用于治疗由耐碳青霉烯和多药（MDR）革兰氏阴性杆菌引起的感染。我们确定了1385株非卡巴培南敏感肠杆菌，MDR铜绿假单胞菌（也对卡巴培南不敏感），嗜麦芽窄食单胞菌和伯克霍尔德氏菌的临床分离株的体外敏感性。使用CLSI肉汤微稀释法从2014年至2016年在全球（49个国家）收集了头孢吡肟-齐德巴坦（1：1比率），头孢他啶-avibactam，亚胺培南-雷巴坦，头孢洛赞-他唑巴坦和粘菌素。头孢吡肟-齐达巴坦抑制了98.5％的非卡巴培南敏感性肠杆菌（n = 1,018）≤8μg/ ml（临时的头孢吡肟-齐德巴坦易感MIC断点）。针对金属-β-内酰胺酶（MBL）阳性肠杆菌的亚群（n = 214），头孢吡肟-齐德巴坦在≤8μg/ ml的情况下抑制了94.9％的分离株。此外，它以≤32μg/ ml（建议的头孢吡肟-齐德巴坦易感药代动力学/药效学MIC断裂点）抑制了99.6％的MDR铜绿假单胞菌（n = 262）分离株，包括所有MBL阳性分离株（n = 94）。此外，头孢吡肟-齐德巴坦对大多数分离的肠杆菌（≥95％）和铜绿假单胞菌具有活性。（99％）对头孢他啶-avibactam，头孢唑烷-他唑巴坦，亚胺培南-雷巴坦和粘菌素不敏感。的大多数菌株（99％）S.麦芽（Ñ ; MIC = 101 ₅₀ ;，8微克/毫升的MIC ₉₀和32微克/毫升）洋葱伯克霍尔德菌 （n= 4; 头孢吡肟-齐达巴坦的MIC范围为16至32μg/ ml（≤32μg/ ml）。头孢吡肟-齐德巴坦对耐碳青霉烯类革兰氏阴性细菌的活性归因于其β-内酰胺增强剂的作用机制（即齐德巴坦与青霉素结合蛋白2 [PBP2]结合以及对丝氨酸β-内酰胺酶和MBL的普遍稳定性） ）。这项研究的结果支持继续开发头孢吡肟-齐德巴坦，作为对肠杆菌，铜绿假单胞菌和其他非发酵革兰氏阴性杆菌引起的感染的潜在疗法，其中对市售抗菌剂的耐药性是一个限制因素。