Importance Cefepime/enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination and a potential empirical therapy for resistant gram-negative infections. Objective To evaluate whether cefepime/enmetazobactam was noninferior to piperacillin/tazobactam for the primary outcome of treatment efficacy in patients with complicated urinary tract infections (UTIs) or acute pyelonephritis. Design, Setting, and Participants A phase 3, randomized, double-blind, active-controlled, multicenter, noninferiority clinical trial conducted at 90 sites in Europe, North and Central America, South America, and South Africa. Recruitment occurred between September 24, 2018, and November 2, 2019. Final follow-up occurred November 26, 2019. Participants were adult patients aged 18 years or older with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by gram-negative urinary pathogens. Interventions Eligible patients were randomized to receive either cefepime, 2 g/enmetazobactam, 0.5 g (n = 520), or piperacillin, 4 g/tazobactam, 0.5 g (n = 521), by 2-hour infusion every 8 hours for 7 days (up to 14 days in patients with a positive blood culture at baseline). Main Outcomes and Measures The primary outcome was the proportion of patients in the primary analysis set (patients who received any amount of study drug with a baseline gram-negative pathogen not resistant to either treatment and ≥105 colony-forming units [CFU]/mL in urine culture or the same pathogen present in concurrent blood and urine cultures) who achieved overall treatment success (defined as clinical cure combined with microbiological eradication [<103 CFU/mL in urine] of infection). Two-sided 95% CIs were computed using the stratified Newcombe method. The prespecified noninferiority margin was -10%. If noninferiority was established, a superiority comparison was also prespecified. Results Among 1041 patients randomized (mean age, 54.7 years; 573 women [55.0%]), 1034 (99.3%) received study drug and 995 (95.6%) completed the trial. Among the primary analysis set, the primary outcome occurred in 79.1% (273/345) of patients receiving cefepime/enmetazobactam compared with 58.9% (196/333) receiving piperacillin/tazobactam (between-group difference, 21.2% [95% CI, 14.3% to 27.9%]). Treatment-emergent adverse events occurred in 50.0% (258/516) of patients treated with cefepime/enmetazobactam and 44.0% (228/518) with piperacillin/tazobactam; most were mild to moderate in severity (89.9% vs 88.6%, respectively). A total of 1.7% (9/516) of participants who received cefepime/enmetazobactam and 0.8% (4/518) of those who received piperacillin/tazobactam did not complete the assigned therapy due to adverse events. Conclusions and Relevance Among patients with complicated UTI or acute pyelonephritis caused by gram-negative pathogens, cefepime/enmetazobactam, compared with piperacillin/tazobactam, met criteria for noninferiority as well as superiority with respect to the primary outcome of clinical cure and microbiological eradication. Further research is needed to determine the potential role for cefepime/enmetazobactam in the treatment of complicated UTI and pyelonephritis. Trial Registration ClinicalTrials.gov Identifier: NCT03687255.

中文翻译：

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头孢吡肟/恩美唑巴坦与哌拉西林/他唑巴坦对复杂性尿路感染或急性肾盂肾炎患者临床治愈和微生物根除的影响：一项随机临床试验。

重要性 头孢吡肟/恩美唑巴坦是一种新型 β-内酰胺/β-内酰胺酶抑制剂组合，是耐药革兰氏阴性菌感染的潜在经验疗法。目的 评估头孢吡肟/恩美唑巴坦是否不劣于哌拉西林/他唑巴坦治疗复杂性尿路感染 (UTI) 或急性肾盂肾炎患者疗效的主要结局。设计、设置和参与者 在欧洲、北美洲和中美洲、南美洲和南非的 90 个地点进行的 3 期、随机、双盲、主动对照、多中心、非劣效性临床试验。招募发生在 2018 年 9 月 24 日至 2019 年 11 月 2 日之间。最终随访发生在 2019 年 11 月 26 日。参与者是 18 岁或以上的成年患者，临床诊断为复杂性 UTI 或由革兰氏阴性泌尿系统病原体引起的急性肾盂肾炎。干预 符合条件的患者随机接受头孢吡肟 2 g/恩美唑巴坦 0.5 g (n = 520) 或哌拉西林 4 g/他唑巴坦 0.5 g (n = 521)，每 8 小时输注 2 小时，持续 7 天（基线时血培养呈阳性的患者最多 14 天）。主要结果和测量 主要结果是主要分析集中患者的比例（接受任何数量的研究药物且基线革兰氏阴性病原体对任何一种治疗均不耐药且≥105 菌落形成单位 [CFU]/mL 的患者）在尿液培养或同时出现的血液和尿液培养中存在相同的病原体）取得整体治疗成功（定义为临床治愈与微生物学根除[<103 CFU / mL感染]）。使用分层 Newcombe 方法计算双侧 95% CI。预设的非劣效性界值为 -10%。如果确定了非劣效性，则也预先指定了优效性比较。结果 在随机分组的 1041 名患者中（平均年龄 54.7 岁；573 名女性 [55.0%]），1034 名 (99.3%) 接受了研究药物治疗，995 名 (95.6%) 完成了试验。在主要分析集中，接受头孢吡肟/恩美唑巴坦的患者中有 79.1% (273/345) 发生了主要结果，而接受哌拉西林/他唑巴坦的患者为 58.9% (196/333)（组间差异，21.2% [95% CI， 14.3% 至 27.9%]）。50.0% (258/516) 接受头孢吡肟/恩美唑巴坦治疗的患者和 44.0% (228/518) 接受哌拉西林/他唑巴坦治疗的患者发生治疗中出现的不良事件；大多数严重程度为轻度至中度（分别为 89.9% 和 88.6%）。共有 1.7% (9/516) 接受头孢吡肟/恩美唑巴坦的参与者和 0.8% (4/518) 接受哌拉西林/他唑巴坦的参与者由于不良事件而未完成分配的治疗。结论和相关性在复杂性 UTI 或由革兰氏阴性病原体引起的急性肾盂肾炎患者中，头孢吡肟/恩美唑巴坦，与哌拉西林/他唑巴坦相比，在临床治愈和微生物根除的主要结果方面符合非劣效性和优效性标准。需要进一步的研究来确定头孢吡肟/恩美唑巴坦在治疗复杂性尿路感染和肾盂肾炎中的潜在作用。试验注册 ClinicalTrials.gov 标识符：NCT03687255。