Weiss Emmanuel, Zahar Jean-Ralph, Alder Jeff, Asehnoune Karim, Bassetti Matteo, Bonten Marc J M, Chastre Jean, De Waele Jan, Dimopoulos George, Eggimann Philippe, Engelhardt Marc, Ewig Santiago, Kollef Marin, Lipman Jeffrey, Luna Carlos, Martin-Loeches Ignacio, Pagani Leonardo, Palmer Lucy B, Papazian Laurent, Poulakou Garyphallia, Prokocimer Philippe, Rello Jordi, Rex John H, Shorr Andrew F, Talbot George H, Thamlikitkul Visanu, Torres Antoni, Wunderink Richard G, Timsit Jean-François
Department of Anesthesiology and Critical Care, Assistance Publique-Hôpitaux de Paris (AP-HP), Beaujon Hospital, Clichy.
Unité Mixte de Recherche (UMR) 1149, Centre for Research on Inflammation, Institut national de la santé et de la recherche médicale (INSERM)/Université Paris Diderot, Paris.
Clin Infect Dis. 2019 Nov 13;69(11):1912-1918. doi: 10.1093/cid/ciz093.
Randomized clinical trials (RCTs) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively) are important for the evaluation of new antimicrobials. However, the heterogeneity in endpoints used in RCTs evaluating treatment of HABP/VABP may puzzle clinicians. The aim of this work was to reach a consensus on clinical endpoints to consider in future clinical trials evaluating antimicrobial treatment efficacy for HABP/VABP.
Twenty-six international experts from intensive care, infectious diseases, and the pharmaceutical industry were polled using the Delphi method.
The panel recommended a hierarchical composite endpoint including, by priority order, (1) survival at day 28, (2) mechanical ventilation-free days through day 28, and (3) clinical cure between study days 7 and 10 for VABP; and (1) survival (day 28) and (2) clinical cure (days 7-10) for HABP. Clinical cure was defined as the combination of resolution of signs and symptoms present at enrollment and improvement or lack of progression of radiological signs. More than 70% of the experts agreed to assess survival and mechanical ventilation-free days though day 28, and clinical cure between day 7 and day 10 after treatment initiation. Finally, the hierarchical order of endpoint components was reached after 3 Delphi rounds (72% agreement).
We provide a multinational expert consensus on separate hierarchical composite endpoints for VABP and HABP, and on a definition of clinical cure that could be considered for use in future HABP/VABP clinical trials.
医院获得性细菌性肺炎（HABP）和呼吸机相关性细菌性肺炎（VABP）的随机临床试验（RCT）对于评估新型抗菌药物很重要。然而，评估HABP/VABP治疗的RCT中使用的终点指标存在异质性，这可能会让临床医生感到困惑。这项工作的目的是就未来评估HABP/VABP抗菌治疗疗效的临床试验中应考虑的临床终点达成共识。
采用德尔菲法对来自重症监护、传染病和制药行业的26名国际专家进行了调查。
专家组推荐了一个分层综合终点指标，按优先顺序包括：（1）第28天的生存率；（2）至第28天无机械通气天数；（3）VABP在研究第7天至第10天的临床治愈情况；以及（1）HABP的生存率（第28天）和（2）临床治愈情况（第7 - 10天）。临床治愈定义为入组时存在的体征和症状消失，以及影像学表现改善或无进展。超过70%的专家同意评估至第28天的生存率和无机械通气天数，以及治疗开始后第7天至第10天的临床治愈情况。最后，经过三轮德尔菲法（达成72%的共识）确定了终点指标各组成部分的分层顺序。
我们就VABP和HABP各自的分层综合终点指标以及临床治愈的定义达成了多国专家共识，这些可用于未来的HABP/VABP临床试验。
