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[Lancet Infect Dis在线发表]:头孢洛扎/阿维巴坦对比美罗培南治疗医院获得性肺炎
2019年11月15日 时讯速递, 进展交流 暂无评论

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Ceftolozane–tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial

Marin H Kollef, Martin Nováček, Ülo Kivistik, et al

Lancet Infect Dis September 25, 2019 DOI:https://doi.org/10.1016/S1473-3099(19)30403-7

Summary

Background 背景

Nosocomial pneumonia due to antimicrobial-resistant pathogens is associated with high mortality. We assessed the efficacy and safety of the combination antibacterial drug ceftolozane–tazobactam versus meropenem for treatment of Gram-negative nosocomial pneumonia.

耐药菌引起的医院获得性肺炎病死率很高。我们比较了头孢洛扎/阿维巴坦与美罗培南治疗革兰阴性菌引起的医院获得性肺炎的疗效及安全性。

Methods 方法

We conducted a randomised, controlled, double-blind, non-inferiority trial at 263 hospitals in 34 countries. Eligible patients were aged 18 years or older, were undergoing mechanical ventilation, and had nosocomial pneumonia (either ventilator-associated pneumonia or ventilated hospital-acquired pneumonia). Patients were randomly assigned (1:1) with block randomisation (block size four), stratified by type of nosocomial pneumonia and age (<65 years vs ≥65 years), to receive either 3 g ceftolozane–tazobactam or 1 g meropenem intravenously every 8 h for 8–14 days. The primary endpoint was 28-day all-cause mortality (at a 10% non-inferiority margin). The key secondary endpoint was clinical response at the test-of-cure visit (7–14 days after the end of therapy; 12·5% non-inferiority margin). Both endpoints were assessed in the intention-to-treat population. Investigators, study staff, patients, and patients' representatives were masked to treatment assignment. Safety was assessed in all randomly assigned patients who received study treatment. This trial was registered with ClinicalTrials.govNCT02070757.

我们在34个国家的263所医院进行了一项随机、对照、双盲、非劣效临床试验。入选患者为18岁以上,接受机械通气,且罹患医院获得性肺炎(包括呼吸机相关肺炎及接受机械通气的医院获得性肺炎)。患者按照1:1的比例接受区组随机(区组大小为4),并根据医院获得性肺炎的种类及年龄(<65 岁 vs ≥ 65 岁)分层,分别接受头孢洛扎/阿维巴坦 3 g 或美罗培南 1 g iv q8h,疗程8-14天。主要预后终点为28天全因病死率(非劣效界值10%)。关键的次要终点为治愈测试访视(治疗结束后7-14天;非劣效界值12.5%)时的临床反应。上述2个预后终点均在意向治疗人群进行评估。治疗分组对研究者、研究人员、患者及代理人隐藏。对于随机分组后接受试验治疗的所有患者评估安全性。试验在ClinicalTrials.gov注册,注册号 NCT02070757

Findings 结果

Between Jan 16, 2015, and April 27, 2018, 726 patients were enrolled and randomly assigned, 362 to the ceftolozane–tazobactam group and 364 to the meropenem group. Overall, 519 (71%) patients had ventilator-associated pneumonia, 239 (33%) had Acute Physiology and Chronic Health Evaluation II scores of at least 20, and 668 (92%) were in the intensive care unit. At 28 days, 87 (24·0%) patients in the ceftolozane–tazobactam group and 92 (25·3%) in the meropenem group had died (weighted treatment difference 1·1% [95% CI −5·1 to 7·4]). At the test-of-cure visit 197 (54%) patients in the ceftolozane–tazobactam group and 194 (53%) in the meropenem group were clinically cured (weighted treatment difference 1·1% [95% CI −6·2 to 8·3]). Ceftolozane–tazobactam was thus non-inferior to meropenem in terms of both 28-day all-cause mortality and clinical cure at test of cure. Treatment-related adverse events occurred in 38 (11%) of 361 patients in the ceftolozane–tazobactam group and 27 (8%) of 359 in the meropenem group. Eight (2%) patients in the ceftolozane–tazobactam group and two (1%) in the meropenem group had serious treatment-related adverse events. There were no treatment-related deaths.

2015年1月16日至2018年4月27日间,共有726名患者接受随机分组,362名患者分至头孢洛扎/阿维巴坦组,364名患者分至美罗培南组。共有519名患者(71%)为呼吸机相关肺炎,239名患者(33%)的APACHE II评分至少为20分,668名患者(92%)住在ICU。在第28天时,头孢洛扎/阿维巴坦组87名患者(24.0%)和美罗培南组92名患者(25.3%)死亡(加权后治疗差异1.1% [95% CI −5·1 to 7·4])。治愈测试访视时,头孢洛扎组197名患者 (54%) 及美罗培南组194名患者 (53%) 临床治愈(加权后治疗差异1·1% [95% CI −6·2 to 8·3])。头孢洛扎/阿维巴坦治疗患者28天病死率及治愈测试时临床治愈率不劣于美罗培南。头孢洛扎/阿维巴坦组361名患者中38名 (11%) 及美罗培南组359名患者中27名 (8%) 发生治疗相关不良事件。头孢洛扎组8名患者(2%)及美罗培南组2名患者(1%)发生治疗相关严重不良事件。无治疗相关死亡病例。

Interpretation 结论

High-dose ceftolozane–tazobactam is an efficacious and well tolerated treatment for Gram-negative nosocomial pneumonia in mechanically ventilated patients, a high-risk, critically ill population.

对于罹患革兰阴性杆菌引起医院获得性肺炎的机械通气患者,大剂量头孢洛扎/阿维巴坦治疗有效且耐受性良好。

Funding 资助

Merck & Co.

评论[仅代表个人观点]

  • 多数研究显示,中国大陆医院获得性肺炎最常见的致病菌为不动杆菌。因此,这一结果需要谨慎解读
  • Merck赞助的临床试验,相信头孢洛扎/阿维巴坦是Merck自己的产品。但是,对照组为何不选择Merck自己的亚胺培南?是因为Merck自己相信,医院获得性肺炎的标准抗生素选择应该是美罗培南吗?

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