Efficacy and safety of cefepime-nacubactam and aztreonam-nacubactam compared with imipenem-cilastatin for complicated urinary tract infection or acute uncomplicated pyelonephritis (Integral-1): a double-blind, randomised phase 3 trial.

We assessed the efficacy and safety of cefepime-nacubactam and aztreonam-nacubactam versus imipenem-cilastatin in complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis.

我们评估了头孢吡肟-纳库巴克坦和氨曲南-纳库巴克坦与亚胺培南-西司他丁在复杂性尿路感染(cUTI)或急性无并发症性肾盂肾炎中的疗效和安全性。

Methods

The Integral-1 global, phase 3, multicentre, randomised, double-blindstudy recruited adults (aged ≥18 years) with cUTI or acute uncomplicated pyelonephritis at 79 sites in Bulgaria, China, Czech Republic, Estonia, Georgia, Japan, Latvia, Lithuania, and Slovakia.

Integral-1 全球性 III 期多中心随机双盲研究招募了年龄≥18岁的成人患者，这些患者患有复杂性尿路感染（cUTI）或急性单纯性肾盂肾炎，在保加利亚、中国、捷克共和国、爱沙尼亚、格鲁吉亚、日本、拉脱维亚、立陶宛和斯洛伐克的79个研究地点进行。

Patients were randomly assigned (2:1:1) to receive intravenous cefepime (2 g) plus nacubactam (1 g), aztreonam (2 g) plus nacubactam (1 g), or imipenem (1 g) plus cilastatin (1 g) every 8 h for 5-14 days.

患者被随机分配（2:1:1）接受每8小时一次，为期5-14天的静脉注射头孢吡肟（2克）加纳库巴坦（1克）、氨曲南（2克）加纳库巴坦（1克）或亚胺培南（1克）加西拉司丁（1克）。

Randomisation was stratified by diagnosis and geographical region.

随机化是根据诊断和地理区域进行分层的。

The primary endpoint was the proportion of patients achieving composite clinical and microbiological success at test of cure in the microbiological modified intention-to-treatpopulation-all patients who were randomly assigned, received any amount of the study drug, and had a baseline qualifying pathogen that was susceptible to imipenem and meropenem.

主要终点是微生物学修改意向治疗人群中，在治愈测试时达到临床和微生物学成功比例的患者比例——所有被随机分配的患者，接受任何数量的研究药物，并且有对亚胺培南和美罗培南敏感的基线合格病原体。

The prespecified non-inferiority margin was more than 15 percentage points difference; the superiority margin was more than zero percentage points difference, for the lower bound of the two-sided 95% CI for imipenem-cilastatin.

预先设定的非劣效性边界是超过15个百分点的差异；优势边界是超过零个百分点的差异，对于两面95%置信区间（CI）的亚胺培南-西司他丁的下限。

Safety was assessed in all patients who received at least one dose of study drug.

安全性评估是在所有至少接受一剂研究药物的患者中进行的。

This study is registered with ClinicalTrials.gov, NCT05887908.

该研究已在ClinicalTrials.gov注册，注册号为NCT05887908。

Results

Between May 22, 2023, and Nov 26, 2024, 614 patients were randomly assigned and 431 were included in the primary efficacy analysis (cefepime-nacubactam [n=214], aztreonam-nacubactam [n=112], or imipenem-cilastatin [n=105]); 228 patients (53%) were male and 203 (47%) were female.

在2023年5月22日至2024年11月26日期间，共有614名患者被随机分配，其中431名患者纳入主要疗效分析（头孢吡肟-纳库巴坦[n=214]，氨曲南-纳库巴坦[n=112]或亚胺培南-西司他丁[n=105]）；228名患者（53%）为男性，203名患者（47%）为女性。

The primary endpoint was achieved by 176 (82%) of 214, 81 (72%) of 112, and 64 (61%) of 105 patients in the cefepime-nacubactam, aztreonam-nacubactam, and imipenem-cilastatin groups, respectively.

主要终点在头孢吡肟-纳曲巴坦组、阿奇霉素-纳曲巴坦组和亚胺培南-西司他丁组中分别由214名患者中的176名（82%）、112名患者中的81名（72%）和105名患者中的64名（61%）实现。

The percentage difference in the success rate versus imipenem-cilastatin was 21·3% (95% CI 10·9 to 32·0) for cefepime-nacubactam (non-inferior and superior), and 11·4% (-1·2 to 23·7) for aztreonam-nacubactam (non-inferior).

与亚胺培南-西司他丁相比，头孢吡肟-纳曲巴坦的成功率百分比差异为21.3%（95% 置信区间10.9至32.0），显示出非劣效且优越；而阿奇霉素-纳曲巴坦的成功率百分比差异为11.4%（95% 置信区间-1.2至23.7），显示出非劣效。

Treatment-emergent adverse events were reported in 100 (33%) of 306, 45 (30%) of 152, and 65 (43%) of 150 patients in the cefepime-nacubactam, aztreonam-nacubactam, and imipenem-cilastatin groups, respectively.

在接受头孢吡肟-纳库巴坦治疗的306名患者中，有100名（33%）报告了治疗相关不良事件；在152名接受阿兹特罗南-纳库巴坦治疗的患者中，有45名（30%）报告了不良事件；而在150名接受亚胺培南-西司他丁治疗的患者中，有65名（43%）报告了不良事件。

No treatment-related deaths occurred.

未发生与治疗相关的死亡事件。

interpretation

Cefepime-nacubactam and aztreonam-nacubactam are potential treatment options for Gram-negative cUTI and acute uncomplicated pyelonephritis, including infections caused by antimicrobial-resistant strains.

头孢吡肟-纳库巴坦和氨曲南-纳库巴坦是治疗革兰氏阴性复杂性尿路感染和急性无并发症肾盂肾炎的潜在治疗选择，包括由抗菌药物耐药菌株引起的感染。

funding

Meiji Seika Pharma and Japan Agency for Medical Research and Development.

明治制药和日本医药品医疗器械综合机构。