Background Novel treatments are needed for Staphylococcus aureus bacteremia, particularly for methicillin-resistant S. aureus (MRSA). Exebacase is a first-in-class antistaphylococcal lysin that is rapidly bactericidal and synergizes with antibiotics. Methods In DISRUPT, a superiority-design phase 3 study, patients with S. aureus bacteremia/endocarditis were randomly assigned to receive a single dose of IV exebacase or placebo in addition to standard-of-care antibiotics. The primary efficacy outcome was clinical response at Day 14 in the MRSA population. Results A total of 259 patients were randomized before the study was stopped for futility based on the recommendation of the unblinded Data Safety Monitoring Board. Clinical response rates at Day 14 in the MRSA population (n = 97) were 50.0% (exebacase + antibiotics; 32/64) vs. 60.6% (antibiotics alone; 20/33) (P = 0.392). Overall, rates of adverse events were similar across groups. No adverse events of hypersensitivity related to exebacase were reported. Conclusions Exebacase + antibiotics failed to improve clinical response at Day 14 in patients with MRSA bacteremia/endocarditis. This result was unexpected based on phase 2 data that established proof-of-concept for exebacase + antibiotics in patients with MRSA bacteremia/endocarditis. In the antibiotics alone group, the clinical response rate was higher than that seen in phase 2. Heterogeneity within the study population and a relatively small sample size in either the phase 2 or phase 3 studies may have increased the probability of imbalances in the multiple components of Day 14 clinical outcome. This study provides lessons for future superiority studies in S. aureus bacteremia/endocarditis.

中文翻译：

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Exebacase 联合标准护理抗生素治疗金黄色葡萄球菌血流感染和右侧感染性心内膜炎：3 期、优越性设计、安慰剂对照、随机临床试验 (DISRUPT)

背景 金黄色葡萄球菌菌血症，特别是耐甲氧西林金黄色葡萄球菌 (MRSA)，需要新的治疗方法。 Exebacase 是一种一流的抗葡萄球菌溶素，具有快速杀菌作用并与抗生素具有协同作用。方法 在 DISRUPT（一项优效性设计 3 期研究）中，金黄色葡萄球菌菌血症/心内膜炎患者被随机分配接受单剂静脉注射 exebacase 或安慰剂以及标准护理抗生素。主要疗效结果是 MRSA 人群在第 14 天的临床反应。结果 根据非盲数据安全监测委员会的建议，共有 259 名患者被随机分配，然后研究因无效而停止。 MRSA 群体 (n = 97) 第 14 天的临床缓解率为 50.0%（exebacase + 抗生素；32/64）vs. 60.6%（单独抗生素；20/33）（P = 0.392）。总体而言，各组的不良事件发生率相似。没有报告与 exebacase 相关的超敏反应不良事件。结论 Exebacase + 抗生素未能改善 MRSA 菌血症/心内膜炎患者第 14 天的临床反应。基于 2 期数据得出的这一结果是出乎意料的，该数据为 MRSA 菌血症/心内膜炎患者建立了 exebacase + 抗生素的概念验证。在单独使用抗生素组中，临床反应率高于第 2 阶段的临床反应率。研究人群内的异质性以及第 2 阶段或第 3 阶段研究中相对较小的样本量可能增加了多个组成部分不平衡的可能性。第 14 天的临床结果。这项研究为未来金黄色葡萄球菌菌血症/心内膜炎的优越性研究提供了经验教训。