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来源：危重症医学系CMU
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
Harris, P. N. A., et al.
Jama, 320(10), 984–994.
http://doi.org/10.1001/jama.2018.12163
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Original Research
IMPORTANCE
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.
重要性
超广谱β-内酰胺酶介导了大肠杆菌和肺炎克雷伯杆菌对三代头孢菌素（如头孢曲松）的耐药。这些菌株所致显著的感染通常用碳氢酶烯类抗生素治疗，但可能会选择产生新的碳氢酶烯类耐药菌株。哌拉西林他唑巴坦可能是有效且能“节省碳氢酶烯类抗生素”的一种治疗产超广谱β-内酰胺酶菌感染的选择。
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OBJECTIVES
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.
目的
为了明确哌拉西林他唑巴坦治疗头孢曲松非敏感大肠杆菌或肺炎克雷伯杆菌血行感染患者的疗效是否不劣于美罗培南（一种碳氢酶烯类抗生素）。
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DESIGN, SETTING, AND PARTICIPANTS
Non inferiority, 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.
设计，场景及研究人群
非劣效性，平行组，随机临床试验，纳入9个国家26个中心自2014年2月至2017年7月间的住院患者。符合条件的成人患者为：至少1次血培养结果为大肠杆菌或克雷伯氏菌属阳性，且药敏证实对头孢曲松耐药而对哌拉西林他唑巴坦敏感。共筛查了1646例患者，391例患者纳入此项研究。
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INTERVENTIONS
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 aminimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician.
干预方法
患者1:1随机分为2组，其中188例患者接受静脉滴注哌拉西林他唑巴坦（4.5g, q6h）治疗，而191例患者接受静脉滴注美罗培南（1g，q8h）治疗。治疗周期为4-14天，具体时间由临床医生决定。
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MAIN OUTCOMES AND MEASURES
The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used.
主要结局和测量
主要结局为随机化后患者30天全因死亡率，采用5%非劣效性界值。
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RESULTS
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.
结果
在379例（平均年龄66.5岁；女性占47.8%）接受了随机化、至少接受1次用药及纳入主要分析人群的患者中，有378例（99.7%）完成了该项研究并最终接受主要结局评估。接受哌拉西林他唑巴坦治疗的187例患者中有23例（12.3%）满足主要研究结局标准（即30天内死亡），而191例接受美罗培南治疗的患者中有仅有7例（3.7%）满足主要结局指标 (风险差：8.6% [单侧 97.5%置信区间, ∞ ~ 14.5%]；非劣效性检验 P = .90)。符合方案人群分析结果一致。188例哌拉西林他唑巴坦治疗组有5例（2.7%）发生了非致命性严重不良反应，而191例美罗培南治疗组仅有3例（1.6%）。
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CONCLUSIONS AND RELEVANCE
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.
结论和意义
和美罗培南治疗组相比，哌拉西林他唑巴坦治疗耐头孢曲松的大肠杆菌或肺炎克雷伯杆菌血行感染患者并不能满足非劣效30天死亡率假设。这些研究结果不支持该类患者使用哌拉西林他唑巴坦抗感染治疗。
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首都医科大学附属北京安贞医院 SICU聽 徐雪峰译
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