Use of ribaxamase (SYN-004), a β-lactamase, to prevent Clostridium difficile infection in β-lactam-treated patients: a double-blind, phase 2b, randomised placebo-controlled trial
Use of ribaxamase (SYN-004), a β-lactamase, to prevent Clostridium difficile infection in β-lactam-treated patients: a double-blind, phase 2b, randomised placebo-controlled trial
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DOI：
10.1016/s1473-3099(18)30731-x
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发表时间：
2019-05-01
影响因子：
56.3
通讯作者：
Sliman, Joseph
中科院分区：
文献类型：
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作者：
Kokai-Kun, John F.;Roberts, Tracey;Sliman, Joseph
艰难梭菌感染是一种健康威胁，但目前尚无产品获批用于预防原发性艰难梭菌感染。静脉注射β -内酰胺类抗生素被认为具有艰难梭菌感染的高风险，因为它们的胆汁排泄进入胃肠道并破坏肠道微生物群。ribaxamase （SYN-004）是一种口服给药的β -内酰胺酶，设计用于静脉注射β -内酰胺抗生素，以降解上胃肠道中过量的抗生素，防止它们破坏肠道微生物群并导致艰难梭菌感染。因此，我们的目的是确定利巴沙酶是否可以预防静脉注射头孢曲松治疗下呼吸道感染的患者的艰难梭菌感染，从而支持持续的临床研究。方法：在这项平行组、双盲、多中心、2b期随机安慰剂对照试验中，我们招募了肺炎指数评分为90-130的下呼吸道感染住院患者，这些患者预计接受头孢曲松治疗至少5天。患者从美国、加拿大、保加利亚、匈牙利、波兰、罗马尼亚和塞尔维亚的54个临床地点招募。我们使用交互式门户网站将50岁以上的患者随机分为四组（1:1）；这些组在头孢曲松治疗期间和治疗后72小时内每天接受4次150毫克利巴沙酶或安慰剂。所有患者、临床研究者、研究人员和申办者都对研究药物分配不知情。主要终点是接受至少一次治疗剂量的患者的当地实验室诊断的艰难梭菌感染发生率，并在治疗期间和治疗后4周评估这一结果。本研究已在ClinicalTrials.gov注册，注册号NCT02563106。在2015年11月16日至2016年11月10日期间，我们筛选了433名患者纳入研究。在这些患者中，20例（5%）患者被排除在研究之外（16例[4%]患者不符合纳入标准；4例[1%]患者由于剂量限制）。我们招募并随机分配了413名患者，其中207名患者被分配到接受头孢曲松加利巴沙酶治疗的组，206名患者被分配到接受头孢曲松加安慰剂治疗的组。然而，有一个(
Background Infections with Clostridium difficile are a health threat, yet no products are currently licensed for prevention of primary C difficile infections. Intravenous beta-lactam antibiotics are considered to confer a high risk of C difficile infection because of their biliary excretion into the gastrointestinal tract and disruption of the gut microbiome. ribaxamase (SYN-004) is an orally administered beta-lactamase that was designed to be given with intravenous beta-lactam antibiotics to degrade excess antibiotics in the upper gastrointestinal tract before they disrupt the gut microbiome and lead to C difficile infection. We therefore aimed to determine whether administration of ribaxamase could prevent C difficile infection in patients being treated with intravenous ceftriaxone for a lower respiratory tract infection, thereby supporting continued clinical development.Methods In this parallel-group, double-blind, multicentre, phase 2b, randomised placebo-controlled trial, we recruited patients who had been admitted to a hospital with a lower respiratory tract infection with a pneumonia index score of 90-130 and who were expected to be treated with ceftriaxone for at least 5 days. Patients were recruited from 54 clinical sites in the USA, Canada, Bulgaria, Hungary, Poland, Romania, and Serbia. We randomly assigned patients older than 50 years to groups (1: 1) in blocks of four by use of an interactive web portal; these groups were assigned to receive either 150 mg ribaxamase or placebo four times per day during, and for 72 h after, treatment with ceftriaxone. All patients, clinical investigators, study staff, and sponsor personnel were masked to the study drug assignments. The primary endpoint was the incidence of C difficile infection, as diagnosed by the local laboratory, in patients who received at least one treatment dose, and this outcome was assessed during treatment and for 4 weeks after treatment. This study is registered with ClinicalTrials.gov, number NCT02563106.Findings Between Nov 16, 2015, and Nov 10, 2016, we screened 433 patients for inclusion in the study. Of these patients, 20 (5%) patients were excluded from the study (16 [ 4%] patients did not meet inclusion criteria; four [ 1%] patients because of dosing restrictions). We enrolled and randomly assigned 413 patients to groups, of whom 207 patients were assigned to receive ceftriaxone plus ribaxamase and 206 patients were assigned to receive ceftriaxone plus placebo. However, one (