本文由小咖机器人翻译整理

期刊来源：Lancet

原文链接：https://doi.org/10.1016/S0140-6736(23)02196-7

摘要内容如下：

背景

吉泊地辛是一种新型的、杀菌的、第一类三氮杂tri烯抗生素，其通过独特的作用机制和独特的结合位点抑制细菌DNA复制，提供对两种II型拓扑异构酶的良好平衡抑制。口服吉泊地辛治疗无并发症的尿路感染正在研究中。我们的目的是比较口服吉泊地辛与呋喃妥因治疗青少年和成年女性无并发症尿路感染的疗效和安全性。

方法

EAGLE-2和EAGLE-3是3期、随机、多中心、双盲、双模拟、非劣效性（10%界值）试验，患者在全球219个中心登记。符合入选条件的患者为出生时指定的女性，未怀孕，年龄12岁或以上，体重40 kg或以上，有两种或两种以上排尿困难、尿频、尿急或下腹痛症状，并有尿亚硝酸盐、脓尿或两者兼有的证据。通过交互反应技术将患者随机分配（1:1）接受口服吉泊地辛（1500 mg，每日两次，共5天）或口服呋喃妥因（100 mg，每日两次，共5天），根据年龄类别和无并发症的复发性尿路感染史进行随机分层。患者、研究者和主办方研究团队对治疗分配不知情。主要终点，即治愈试验（即第10-13天）时的治疗反应（成功或失败），在随机分配的患者中进行评估，这些患者患有呋喃妥因敏感的合格泌尿系病原体（≥105菌落形成单位[CFU]/mL），并且至少接受了一剂研究治疗。根据监管指南，治疗成功被定义为临床成功（即症状完全消失）和微生物学成功（即合格的泌尿系病原体减少至<103 CFU/mL），且无其他全身性抗菌药物使用。安全性分析包括随机分配并接受至少一剂研究治疗的患者。这些试验已在ClinicalTrials.gov、NCT04020341（EAGLE-2）和NCT04187144（EAGLE-3）上注册并完成。

调查结果

研究于2019年10月17日至2022年11月30日（EAGLE-2）和2020年4月23日至2022年12月1日（EAGLE-3）进行。对EAGLE-2中的1680名患者和EAGLE-3中的1731名患者进行了筛选，其中1531名患者和1605名患者分别被随机分配（EAGLE-2中的767名患者和764名患者被随机分配到吉泊替丁组，EAGLE-3中的805名患者被随机分配到吉泊替丁组，800名患者被随机分配到呋喃妥因组）。在中期分析（前瞻性同意作为方案修正案）后，两项研究均因疗效而终止。因此，主要分析人群仅包括在中期分析数据截止时有机会达到治愈试验访视或已知在治愈试验访视前未获得治疗成功的患者。在EAGLE-2中，吉泊替丁组320例患者中162例（50.6%）和呋喃妥因组287例患者中135例（47.0%）治疗成功（校正差异4.3%，95%CI-3.6~12.1）。在EAGLE-3中，使用吉泊替丁的277例患者中有162例（58.5%）获得治疗成功，使用呋喃妥因的264例患者中有115例（43.6%）获得治疗成功（校正差异14.6%，95%CI 6.4~22.8）。吉泊地辛在两项研究中均不劣于呋喃妥因，在EAGLE-3中优于呋喃妥因。吉泊地辛最常见的不良事件是腹泻（在EAGLE-2的766名患者中观察到111[14%]，在EAGLE-3的804名患者中观察到147[18%]），而呋喃妥因最常见的不良事件是恶心（在EAGLE-2的760名患者中观察到29[4%]，在EAGLE-3的798名患者中观察到35[4%]）。病例多为轻度或中度。未发生危及生命或致命的事件。

解释

吉泊地辛是一种有效的口服抗生素，具有可接受的安全性和耐受性。作为一种具有抗常见泌尿系病原体（包括临床上重要的耐药表型）活性的一流试验性口服抗生素，吉泊替丁有可能为患者带来实质性的益处。

英文原文如下：

Abstracts

BACKGROUND  Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and a unique binding site, providing well balanced inhibition of two type II topoisomerase enzymes. Oral gepotidacin is under investigation to treat uncomplicated urinary tract infections. We aimed to compare the efficacy and safety of oral gepotidacin with that of nitrofurantoin in adolescent and adult female individuals with uncomplicated urinary tract infections.

METHODS  EAGLE-2 and EAGLE-3 were phase 3, randomised, multicentre, double-blind, double-dummy, non-inferiority (10% margin) trials, in which patients were enrolled at 219 centres worldwide. Patients assigned female at birth, non-pregnant, aged 12 years or older, weighing 40 kg or more, with two or more symptoms of dysuria, frequency, urgency, or lower abdominal pain, and with evidence of urinary nitrite, pyuria, or both were eligible for inclusion. Patients were randomly assigned (1:1) centrally by interactive response technology to receive oral gepotidacin (1500 mg twice daily for 5 days) or oral nitrofurantoin (100 mg twice daily for 5 days), with randomisation stratified by age category and history of recurrent uncomplicated urinary tract infections. Patients, investigators, and the sponsor study team were masked to treatment assignment. The primary endpoint, therapeutic response (success or failure) at test-of-cure (ie, day 10-13), was evaluated in randomly assigned patients with nitrofurantoin-susceptible qualifying uropathogens (≥105 colony-forming units [CFU] per mL) and who received at least one dose of study treatment. Conforming to regulatory guidance, therapeutic success was defined as combined clinical success (ie, complete symptom resolution) and microbiological success (ie, reduction of qualifying uropathogens to <103 CFU/mL) without other systemic antimicrobial use. Safety analyses included patients who were randomly assigned and who received at least one dose of study treatment. The trials are registered with ClinicalTrials.gov, NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3), and are completed.

FINDINGS  Studies were undertaken from Oct 17, 2019, to Nov 30, 2022 (EAGLE-2), and from April 23, 2020, to Dec 1, 2022 (EAGLE-3). 1680 patients in EAGLE-2 and 1731 patients in EAGLE-3 were screened for eligibility, of whom 1531 and 1605 were randomly assigned, respectively (767 in the gepotidacin group and 764 in the nitrofurantoin group in EAGLE-2, and 805 in the gepotidacin group and 800 in the nitrofurantoin group in EAGLE-3). After an interim analysis, which was prospectively agreed as a protocol amendment, both studies were stopped for efficacy. Thus, the primary analysis population included only patients who, at the time of the interim analysis data cutoff, had the opportunity to reach the test-of-cure visit or were known to not have attained therapeutic success before the test-of-cure visit. In EAGLE-2, 162 (50·6%) of 320 patients assigned gepotidacin and 135 (47·0%) of 287 patients assigned nitrofurantoin had therapeutic success (adjusted difference 4·3%, 95% CI -3·6 to 12·1). In EAGLE-3, 162 (58·5%) of 277 patients assigned gepotidacin and 115 (43·6%) of 264 patients assigned nitrofurantoin had therapeutic success (adjusted difference 14·6%, 95% CI 6·4 to 22·8). Gepotidacin was non-inferior to nitrofurantoin in both studies and superior to nitrofurantoin in EAGLE-3. The most common adverse event with gepotidacin was diarrhoea (observed in 111 [14%] of 766 patients in EAGLE-2 and in 147 [18%] of 804 patients in EAGLE-3), whereas the most common adverse event with nitrofurantoin was nausea (in 29 [4%] of 760 patients in EAGLE-2 and in 35 [4%] of 798 patients in EAGLE-3). Cases were mostly mild or moderate. No life-threatening or fatal events occurred.

INTERPRETATION  Gepotidacin is an efficacious oral antibiotic with acceptable safety and tolerability profiles. As a first-in-class investigational oral antibiotic with activity against common uropathogens, including clinically important drug-resistant phenotypes, gepotidacin has the potential to offer substantial benefit to patients.

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