Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study
Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study
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DOI：
10.1016/s1473-3099(16)30004-4
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发表时间：
2016-06-01
影响因子：
56.3
通讯作者：
Gasink, Leanne B.
中科院分区：
文献类型：
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作者：
Carmeli, Yehuda;Armstrong, Jon;Gasink, Leanne B.
碳青霉烯类抗生素通常是多重耐药革兰氏阴性菌引起的严重感染的最后一道防线，但其使用受到产碳青霉烯酶病原体日益流行的威胁。头孢他啶-阿维巴坦是用于此类感染的潜在新药。我们的目的是评估头孢他啶-阿维巴坦的疗效，安全性和耐受性与最佳治疗方法相比，复杂的尿路感染或复杂的腹腔内感染患者由于头孢他啶耐药革兰氏阴性pathogene.Methods REPRISE是一种病原体导向，国际，随机，开放标签，3期临床试验，招募患者来自全球16个国家的医院。符合条件的患者年龄为18-90岁，患有由头孢他啶耐药肠杆菌科或铜绿假单胞菌引起的复杂性尿路感染或复杂性腹腔内感染。患者随机（1：1）接受头孢他啶-阿维巴坦（2000 mg头孢他啶+500 mg阿维巴坦联合给药，每8小时通过2小时静脉输注给药）或现有最佳治疗5-21天。主要终点是治愈验证访视时的临床应答，即研究治疗末次输注后7-10天，在至少有一种头孢他啶耐药革兰氏阴性病原体（经中心实验室确认）且至少接受过一剂研究药物的所有患者中进行分析。在接受至少一剂研究药物的所有患者中评估安全性终点。该研究注册于ClinicalTrials.gov，编号NCT 01644643。结果2013年1月7日至2014年8月29日，随机分配333例患者，165例接受头孢他啶-阿维巴坦治疗，168例接受最佳治疗。其中，154例分配至头孢他啶-阿维巴坦组（144例并发尿路感染，10例并发腹腔内感染），148例分配至最佳治疗组（137例并发尿路感染，11例并发腹腔内感染），对主要结局进行了分析。在现有最佳治疗组的168例患者中，163例（97%）接受了碳青霉烯类，161例（96%）接受了单药治疗。头孢他啶-阿维巴坦组（154例患者中的140例[91%; 95% CI 85.6-94.7]）和现有最佳治疗组（148例患者中的135例[91%; 85.9-95.0]）在治愈验证访视时临床治愈的患者总体比例相似。头孢他啶-阿维巴坦组51/164例患者（31%）和现有最佳治疗组66/168例患者（39%）发生不良事件，其中大多数为轻度或中度。胃肠道疾病是头孢他啶-阿维巴坦组（21/164例患者[13%]）和现有最佳治疗组（30/168例患者[18%]）最常报告的治疗后出现的不良事件。头孢他啶-阿维巴坦没有发现新的安全性问题。解释这些结果提供了头孢他啶-阿维巴坦作为碳青霉烯类的潜在替代药物在头孢他啶耐药肠杆菌科和铜绿假单胞菌患者中的疗效的证据。
Background Carbapenems are frequently the last line of defence in serious infections due to multidrug-resistant Gram-negative bacteria, but their use is threatened by the growing prevalence of carbapenemase-producing pathogens. Ceftazidime-avibactam is a potential new agent for use in such infections. We aimed to assess the efficacy, safety, and tolerability of ceftazidime-avibactam compared with best available therapy in patients with complicated urinary tract infection or complicated intra-abdominal infection due to ceftazidime-resistant Gram-negative pathogens.Methods REPRISE was a pathogen-directed, international, randomised, open-label, phase 3 trial that recruited patients from hospitals across 16 countries worldwide. Eligible patients were aged 18-90 years with complicated urinary tract infection or complicated intra-abdominal infection caused by ceftazidime-resistant Enterobacteriaceae or Pseudomonas aeruginosa. Patients were randomised (1:1) to 5-21 days of treatment with either ceftazidime-avibactam (a combination of 2000 mg ceftazidime plus 500 mg avibactam, administered via a 2-h intravenous infusion every 8 h) or best available therapy. The primary endpoint was clinical response at the test-of-cure visit, 7-10 days after last infusion of study therapy, analysed in all patients who had at least one ceftazidime-resistant Gram-negative pathogen, as confirmed by the central laboratory, and who received at least one dose of study drug. Safety endpoints were assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01644643.Findings Between Jan 7,2013, and Aug 29,2014,333 patients were randomly assigned, 165 to ceftazidime-avibactam and 168 to best available therapy. Of these, 154 assigned to ceftazidime-avibactam (144 with complicated urinary tract infection and ten with complicated intra-abdominal infection) and 148 assigned to best available therapy (137 with complicated urinary tract infection and 11 with complicated intra-abdominal infection) were analysed for the primary outcome. 163 (97%) of 168 patients in the best available therapy group received a carbapenem, 161 (96%) as monotherapy. The overall proportions of patients with a clinical cure at the test-of-cure visit were similar with ceftazidime-avibactam (140 [91%; 95% CI 85.6-94.7] of 154 patients) and best available therapy (135 [91%; 85.9-95.0] of 148 patients). 51 (31%) of 164 patients in the ceftazidime-avibactam group and 66 (39%) of 168 in the best available therapy group had an adverse event, most of which were mild or moderate in intensity. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events with both ceftazidime-avibactam (21 [13%] of 164 patients) and best available therapy (30 [18%] of 168 patients). No new safety concerns were identified for ceftazidime-avibactam.Interpretation These results provide evidence of the efficacy of ceftazidime-avibactam as a potential alternative to carbapenems in patients with ceftazidime-resistant Enterobacteriaceae and P aeruginosa.