Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial
Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial
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DOI：
10.1016/s1473-3099(20)30796-9
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发表时间：
2021-01-27
影响因子：
56.3
通讯作者：
Nagata, Tsutae D.
中科院分区：
文献类型：
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作者：
Bassetti, Matteo;Echols, Roger;Nagata, Tsutae D.
背景新的抗生素需要用于治疗对碳青霉烯类耐药的革兰氏阴性感染患者的生命。我们评估了头孢地洛与现有最佳治疗方法在成人严重碳青霉烯耐药革兰氏阴性感染中的有效性和安全性。方法我们在北美、南美、欧洲和亚洲16个国家的95家医院进行了一项随机、开放、多中心、平行分组、以病原体为重点的描述性3期研究。我们招募了18岁或18岁以上的住院患者，他们患有院内肺炎、血流感染或败血症，或并发尿路感染(UTI)，并有碳青霉烯类耐药革兰氏阴性病原体的证据。参与者被随机分配(通过交互式网络或语音响应系统以2：1的比例)，接受每8小时静脉注射头孢地洛2克的3h或最佳可用疗法(由研究人员在随机化前预先指定，最多包括三种药物)，持续7-14天。对于肺炎或血流感染或脓毒症患者，头孢地洛可与一种辅助抗生素(不包括多粘菌素、头孢菌素和碳青霉烯类)联合治疗。院内肺炎、血流感染或败血症患者的主要终点是在碳青霉烯耐药微生物治疗意向人群(ITT；即，确诊的碳青霉烯耐药革兰氏阴性病原体接受至少一剂研究药物治疗)的治愈测试(治疗结束后7天[正负2])时的临床治愈。对于复杂性尿路感染患者，主要终点是在对碳青霉烯类抗生素耐药的微生物ITT人群中进行治愈测试时的微生物根除。安全性是在安全人群中进行评估的，包括所有接受至少一剂研究药物的患者。报告死亡率直到研究访问结束(治疗结束后28天[正负3])。收集了主要和安全终端的汇总统计数据，包括使用Clopper-Pearson方法计算的ARM内95%的CI。这项试验在ClinicalTrials.gov(NCT02714595)和EudraCT(2015-004703-23)注册。结果在2016年9月7日至2019年4月22日期间，我们随机分配152名患者接受治疗，101名接受头孢地洛，51名接受最佳可用治疗。150例患者接受治疗：101例头孢地洛(85例(85%)接受单一治疗)和49例最佳治疗(30例(61%)接受联合治疗)。在对碳青霉烯类抗生素耐药的118例患者中，最常见的碳青霉烯类耐药病原菌是鲍曼不动杆菌(54例，占46%)、肺炎克雷伯菌(39例，占33%)和铜绿假单胞菌(22例，占19%)。在同一人群中，对于院内肺炎患者，头孢羟乙醇组40例患者中临床治愈20例(50%，95%CI 33.8~66.2)，最佳治疗组19例患者中临床治愈10例(53%，28.9~75.6)；对于血液感染或败血症患者，头孢羟乙醇组23例中临床治愈10例(43%，23.2~65.5)，最佳治疗组14例中临床治愈6例(43%，17.7~71.1)。对于合并尿路感染的患者，头孢羟乙醇组17例患者中有9例(53%，27.8~77.0)实现了微生物根除，最佳可用治疗组5例患者中有1例(20%，0.5~71.6)实现了微生物根除。在安全人群中，头孢羟乙醇组91%(101名患者中的92名患者)和最佳可用治疗组的96%(49名患者中的47名患者)发生了紧急治疗不良事件。接受头孢地洛治疗的101名患者中有34名(34%)和接受最佳可用治疗的49名患者中有9名(18%)在研究结束时死亡；其中一名死亡(在最佳可用治疗组中)被认为与研究药物有关。在这种由碳青霉烯耐药革兰氏阴性菌引起的感染的异质患者群体中，解释头孢德罗具有类似于最佳可用治疗的临床和微生物学疗效。在数字上，头孢羟乙醇组发生了更多的死亡，主要发生在感染不动杆菌的患者亚组中。总而言之，这项研究的结果支持头孢地洛作为治疗碳青霉烯耐药感染的一种选择，这些患者的治疗选择有限。版权所有(C)2020爱思唯尔有限公司。保留所有权利。
Background New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections.Methods We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7-14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23).Findings Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33.8-66.2) of 40 patients in the cefiderocol group and ten (53%, 28.9-75.6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23.2-65.5) of 23 patients in the cefiderocol group and six (43%, 17.7-71.1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27.8-77.0) of 17 patients in the cefiderocol group and one (20%, 0.5-71.6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug.Interpretation Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options. Copyright (C) 2020 Elsevier Ltd. All rights reserved.