Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial
Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial
复制标题
DOI：
10.1186/s13054-019-2627-y
复制
发表时间：
2019-11-28
期刊：
影响因子：
15.1
通讯作者：
Vidal, P.
中科院分区：
文献类型：
--
作者：
Cisneros, Jose M.;Maria Rosso-Fernandez, Clara;Vidal, P.
粘菌素被推荐用于碳青霉烯耐药革兰氏阴性杆菌（CR-GNB）高发的呼吸机相关性肺炎（VAP）的经验治疗。然而，粘菌素的疗效和安全性尚不明确。方法在32个欧洲中心进行的一项多中心前瞻性随机试验比较了粘菌素（450万单位负荷剂量，随后维持剂量为300万单位每8小时）与美罗南（2 g每8小时）联合左氧氟沙星（500 mg每12小时）治疗晚期VAP患者7-14天的疗效和安全性。2012年5月至2015年10月，232例患者随机分为2个治疗组。主要终点是随机分组后28天微生物修饰意向治疗（mMITT）人群的死亡率。次要结局包括临床和微生物治愈、治疗结束时的肾功能和严重不良事件。由于粘菌素组肾毒性过大，中期分析后中断研究；因此，没有达到样本量。结果mMITT患者共157例（67.7%），其中36例（22.9%）为CR-GNB所致VAP。在mMITT人群中，粘菌素组（19/82,23.2%）与美罗培南组（19/75,25.3%）的死亡率差异无统计学意义，风险差异为- 2.16 (- 15.59 ~ 11.26,p = 0.377)；粘菌素的非劣效性未被证实，因为早期终止和感染碳青霉烯耐药病原体的患者数量有限。粘菌素联合左氧氟沙星增加了肾功能衰竭的发生率（40/120,33.3%，比21/112,18.8%,p = 0.012）和肾脏替代治疗（11/120,9.1%，比2/112,1.8%,p = 0.015）。结论本研究并未证明粘菌素与美罗培南联合左氧氟沙星经验治疗晚期VAP的疗效无劣效性，但证明粘菌素具有更大的肾毒性。这些发现不支持使用粘菌素治疗早期终止的晚期VAP。
Background Colistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). However, the efficacy and safety of colistin are not well defined. Methods A multicenter prospective randomized trial conducted in 32 European centers compared the efficacy and safety of colistin (4.5 million unit loading dose followed by a maintenance dose of 3 million units every 8 h) versus meropenem (2 g every 8 h), both in combination with levofloxacin (500 mg every 12 h) for 7-14 days in patients with late VAP. Between May 2012 and October 2015, 232 patients were randomly assigned to the 2 treatment groups. The primary endpoint was mortality at 28 days after randomization in the microbiologically modified intention-to-treat (mMITT) population. Secondary outcomes included clinical and microbiological cure, renal function at the end of the treatment, and serious adverse events. The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group; therefore, the sample size was not achieved. Results A total of 157 (67.7%) patients were included in the mMITT population, 36 of whom (22.9%) had VAP caused by CR-GNB. In the mMITT population, no significant difference in mortality between the colistin group (19/82, 23.2%) and the meropenem group (19/75, 25.3%) was observed, with a risk difference of - 2.16 (- 15.59 to 11.26, p = 0.377); the noninferiority of colistin was not demonstrated due to early termination and limited number of patients infected by carbapenem-resistant pathogens. Colistin plus levofloxacin increased the incidence of renal failure (40/120, 33.3%, versus 21/112, 18.8%; p = 0.012) and renal replacement therapy (11/120, 9.1%, versus 2/112, 1.8%; p = 0.015). Conclusions This study did not demonstrate the noninferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but demonstrated the greater nephrotoxicity of colistin. These findings do not support the empirical use of colistin for the treatment of late VAP due to early termination.