Washington University School of Medicine, St Louis, MO, USA.
General Hospital of Kolin, Kolin, Czech Republic.
Lancet Infect Dis. 2019 Dec;19(12):1299-1311. doi: 10.1016/S1473-3099(19)30403-7. Epub 2019 Sep 25.
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.
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.gov, NCT02070757.
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.
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.
Merck & Co.
由耐药病原体引起的医院获得性肺炎与高死亡率相关。我们评估了复方抗菌药物头孢洛扎他唑巴坦与美罗培南治疗革兰氏阴性医院获得性肺炎的疗效和安全性。
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，患有医院获得性肺炎（呼吸机相关性肺炎或有创性医院获得性肺炎）。患者以 1:1 的比例随机分配（分组大小为 4），按医院获得性肺炎的类型和年龄（<65 岁与≥65 岁）分层，接受头孢洛扎他唑巴坦 3 g 或美罗培南 1 g 每 8 小时静脉输注，疗程 8-14 天。主要终点为 28 天全因死亡率（以 10%非劣效性边界）。关键次要终点为治疗后评估时的临床反应（治疗结束后 7-14 天；以 12.5%非劣效性边界）。两个终点均在意向治疗人群中进行评估。研究者、研究人员、患者和患者代表对治疗分配进行了盲法。所有接受研究治疗的随机分配患者均进行了安全性评估。该试验在 ClinicalTrials.gov 注册，NCT02070757。
2015 年 1 月 16 日至 2018 年 4 月 27 日期间，共纳入并随机分配了 726 名患者，362 名患者接受头孢洛扎他唑巴坦治疗，364 名患者接受美罗培南治疗。总体而言，519 名（71%）患者患有呼吸机相关性肺炎，239 名（33%）患者急性生理学和慢性健康评估 II 评分至少为 20，668 名（92%）患者在重症监护病房。在 28 天时，头孢洛扎他唑巴坦组有 87 名（24.0%）患者和美罗培南组有 92 名（25.3%）患者死亡（加权治疗差异 1.1%[95%CI-5.1 至 7.4]）。在治疗后评估时，头孢洛扎他唑巴坦组有 197 名（54%）患者和美罗培南组有 194 名（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 天全因死亡率和治疗后评估的临床治愈率方面不劣于美罗培南。头孢洛扎他唑巴坦组 361 名患者中有 38 名（11%）和美罗培南组 359 名患者中有 27 名（8%）发生与治疗相关的不良事件。头孢洛扎他唑巴坦组有 8 名（2%）患者和美罗培南组有 2 名（1%）患者发生严重与治疗相关的不良事件。没有与治疗相关的死亡。
高剂量头孢洛扎他唑巴坦是一种有效且耐受良好的治疗机械通气患者革兰氏阴性医院获得性肺炎的药物，这些患者是高危、危重人群。
默克公司。
