哌拉西林-他唑巴坦与美罗培南治疗对第三代头孢菌素耐药的肠杆菌科细菌引起的血流感染：一项非劣效性开放标签随机对照试验（PeterPen）的研究方案
Piperacillin-tazobactam versus meropenem for treatment of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacteriaceae: a study protocol for a non-inferiority open-label randomised controlled trial (PeterPen).
作者信息
Bitterman Roni, Koppel Fidi, Mussini Cristina, Geffen Yuval, Chowers Michal, Rahav Galia, Nesher Lior, Ben-Ami Ronen, Turjeman Adi, Huberman Samuel Maayan, Cheng Matthew P, Lee Todd C, Leibovici Leonard, Yahav Dafna, Paul Mical
机构信息
Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel.
Technion Israel Institute of Technology Ruth and Bruce Rappaport Faculty of Medicine, Haifa, Haifa, Israel.
出版信息
BMJ Open. 2021 Feb 8;11(2):e040210. doi: 10.1136/bmjopen-2020-040210.
INTRODUCTION
The optimal treatment for extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae bloodstream infections has yet to be defined. Retrospective studies have shown conflicting results, with most data suggesting the non-inferiority of beta-lactam-beta-lactamase inhibitor combinations compared with carbapenems. However, the recently published MERINO trial failed to demonstrate the non-inferiority of piperacillin-tazobactam to meropenem. The potential implications of the MERINO trial are profound, as widespread adoption of carbapenem treatment will have detrimental effects on antimicrobial stewardship in areas endemic for ESBL and carbapenem-resistant bacteria. Therefore, we believe that it is justified to re-examine the comparison in a second randomised controlled trial prior to changing clinical practice.
METHODS AND ANALYSIS
PeterPen is a multicentre, investigator-initiated, open-label, randomised controlled non-inferiority trial, comparing piperacillin-tazobactam with meropenem for third-generation cephalosporin-resistant and bloodstream infections. The study is currently being conducted in six centres in Israel and one in Canada with other centres from Israel, Italy and Canada expected to join. The two primary outcomes are all-cause mortality at day 30 from enrolment and treatment failure at day seven (death, fever above 38°C in the last 48 hours, continuous symptoms, increasing Sequential Organ Failure Assessment Score or persistent blood cultures with the index pathogen). A sample size of 1084 patients was calculated for the mortality endpoint assuming a 12.5% mortality rate in the control group with a 5% non-inferiority margin and assuming 100% follow-up for this outcome.
ETHICS AND DISSEMINATION
The study is approved by local and national ethics committees as required. Results will be published, and trial data will be made available.
TRIAL REGISTRATION NUMBERS
ClinicalTrials.gov Registry (NCT03671967); Israeli Ministry of Health Trials Registry (MOH_2018-12-25_004857).
引言
产超广谱β-内酰胺酶（ESBL）的肠杆菌科细菌血流感染的最佳治疗方案尚未明确。回顾性研究结果相互矛盾，大多数数据表明β-内酰胺-β-内酰胺酶抑制剂联合用药与碳青霉烯类药物相比疗效不差。然而，最近发表的MERINO试验未能证明哌拉西林-他唑巴坦不劣于美罗培南。MERINO试验的潜在影响意义深远，因为广泛采用碳青霉烯类药物治疗将对ESBL和耐碳青霉烯类细菌流行地区的抗菌药物管理产生不利影响。因此，我们认为在改变临床实践之前，有必要在第二项随机对照试验中重新审视这种比较。
方法与分析
PeterPen是一项多中心、由研究者发起的开放标签随机对照非劣效性试验，比较哌拉西林-他唑巴坦与美罗培南治疗对第三代头孢菌素耐药的血流感染的疗效。该研究目前正在以色列的六个中心和加拿大的一个中心进行，预计以色列、意大利和加拿大的其他中心也将加入。两个主要结局是入组后30天的全因死亡率和第7天的治疗失败（死亡、过去48小时内体温高于38°C、持续症状、序贯器官衰竭评估评分增加或血培养持续检出指数病原体）。假设对照组死亡率为12.5%，非劣效界值为5%，并假设该结局的随访率为100%，计算得出死亡率终点的样本量为1084例患者。
伦理与传播
该研究已按要求获得当地和国家伦理委员会的批准。研究结果将予以发表，并提供试验数据。
试验注册号
ClinicalTrials.gov注册库（NCT03671967）；以色列卫生部试验注册库（MOH_2018 - 12 - 25_004857）。
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