Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial
Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial
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DOI：
10.1016/s1473-3099(19)30403-7
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发表时间：
2019-12-01
影响因子：
56.3
通讯作者：
Rhee, Elizabeth G.
中科院分区：
文献类型：
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作者：
Kollef, Marin H.;Novacek, Martin;Rhee, Elizabeth G.
背景耐药病原体引起的医院内肺炎死亡率高。我们评估了联合抗菌药物头孢洛扎-他唑巴坦与美罗培南治疗革兰阴性菌医院获得性肺炎的疗效和安全性。方法我们在34个国家的263家医院进行了一项随机、对照、双盲、非劣效性试验。符合条件的患者年龄在18岁或以上，正在接受机械通气，并患有医院获得性肺炎（呼吸机相关性肺炎或机械通气医院获得性肺炎）。患者随机分配（1：1）区组随机化（区组大小为4），按医院获得性肺炎类型和年龄（≥ 65岁）分层，接受3 g头孢洛扎-他唑巴坦或1 g美罗培南静脉注射，每8小时1次，持续8-14天。主要终点为28天全因死亡率（非劣效性界值为10%）。关键次要终点是治愈检验访视时的临床应答（治疗结束后7-14天;非劣效性界值为12.5%）。在意向治疗人群中评估两个终点。研究者、研究工作人员、患者和患者代表对治疗分配设盲。在所有随机分配的接受研究治疗的患者中评估安全性。该试验注册于ClinicalTrials.gov，NCT 02070757。结果在2015年1月16日至2018年4月27日期间，726名患者入组并随机分配，362名患者入组头孢洛扎-他唑巴坦组，364名患者入组美罗培南组。总体而言，519例（71%）患者患有呼吸机相关性肺炎，239例（33%）患者的急性生理学和慢性健康评估II评分至少为20，668例（92%）患者在重症监护室。第28天时，头孢洛扎-他唑巴坦组87例（24.0%）患者和美罗培南组92例（25.3%）患者死亡（加权治疗差异1.1% [95% CI -5.1至7.4]）。在治愈验证访视时，头孢洛扎-他唑巴坦组197例（54%）患者和美罗培南组194例（53%）患者临床治愈（加权治疗差异1.1% [95% CI -6.2至8.3]）。因此，头孢洛扎-他唑巴坦在28天全因死亡率和临床治愈率方面均不劣于美罗培南。头孢洛扎-他唑巴坦组361例患者中有38例（11%）发生治疗相关不良事件，美罗培南组359例患者中有27例（8%）发生治疗相关不良事件。头孢洛扎-他唑巴坦组8例（2%）患者和美罗培南组2例（1%）患者发生严重治疗相关不良事件。无治疗相关死亡。解释高剂量头孢洛扎-他唑巴坦是一种有效且耐受性良好的治疗机械通气患者（高危重症人群）的革兰氏阴性医院获得性肺炎的药物。资金默克公司版权所有（c）2019爱思唯尔有限公司保留所有权利。
Background 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.Methods 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), 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.gov, NCT02070757.Findings 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.Interpretation 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.Funding Merck & Co. Copyright (c) 2019 Elsevier Ltd. All rights reserved.