Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial

Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective “carbapenem-sparing” option to treat extended-spectrum β-lactamase producers.

超广谱β-内酰胺酶能够介导大肠杆菌和肺炎克雷白杆菌对三代头孢菌素（如头孢曲松）的耐药性。通常使用碳青霉烯类抗生素治疗这些耐药菌株引起的感染，但可能选择碳青霉烯耐药。对于产生超广谱β-内酰胺酶的细菌感染而言，哌拉西林-他唑巴坦可能是碳青霉烯以外的有效抗生素。

Objectives 目的

To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae.

对于耐头孢曲松大肠杆菌或肺炎克雷白杆菌引起的血行性感染，采用哌拉西林-他唑巴坦进行针对性治疗不劣于美罗培南。

Design, Setting, and Participants 设计，场景及研究人群

Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study.

这是一项针对住院患者的非劣效、平行分组、随机临床试验。研究于2014年2月至2017年7月在9个国家的26个中心进行。成年患者入选标准包括，至少一次血培养为大肠杆菌或克雷白杆菌属，药敏结果对头孢曲松不敏感，但对哌拉西林-他唑巴坦敏感。在接受筛查的1646名患者中，391名患者纳入此项研究。

Interventions 干预措施

Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician.

患者按照1:1的比例随机分组，分别接受静脉哌拉西林-他唑巴坦4.5 g q6h (n = 188) 或美罗培南1 g q8h (n = 191)，疗程最少7天，最长不超过14天，由主治医生自行决定。

Main Outcomes and Measures 主要预后指标

The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used.

主要预后指标为随机分组后30天全因病死率。采用5%的非劣效界值。

Results 结果

Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, −∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group.

随机分组的379名患者（平均年龄66.5岁，47.8%为女性）接受了至少一剂研究药物，纳入主要分析人群，其中378名(99.7%)完成试验方案，可以对主要预后终点进行评估。哌拉西林-他唑巴坦组187名患者中23名(12.3%)满足主要预后终点，即在30天内死亡，美罗培南组191名患者中7名死亡（风险差异，8.6% [单尾 97.5% CI, −∞ to 14.5%]; 非劣效P = .90）。符合方案人群分析结果一致。哌拉西林-他唑巴坦组188名患者中5名(2.7%)以及美罗培南组191名患者中3名(1.6%)发生非致死性严重不良事件。

Conclusions and relevance 结果与意义

Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting.

对于耐头孢曲松的大肠杆菌或肺炎克雷白杆菌引起的血行性感染患者，与美罗培南相比，采用哌拉西林-他唑巴坦进行针对性治疗30天病死率并不满足非劣效假设。这一结果不支持在这种情况下使用哌拉西林-他唑巴坦。

Trial Registration 试验注册

anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122