Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Lancet. 2018 Feb 17;391(10121):668-678. doi: 10.1016/S0140-6736(17)32456-X. Epub 2017 Dec 14.
Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.
In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.
Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).
Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.
UK National Institute for Health Research Health Technology Assessment.
金黄色葡萄球菌菌血症是全球范围内严重社区获得性和医院获得性感染的常见原因。我们检验了这样一种假设，即辅助利福平可以通过早期增强金黄色葡萄球菌的杀菌作用、更快地使受感染的病灶和血液无菌化、降低传播和转移性感染的风险，从而减少细菌学确认的治疗失败、疾病复发或死亡。
在这项多中心、随机、双盲、安慰剂对照试验中，我们招募了来自英国 29 家医院的金黄色葡萄球菌菌血症患者，这些患者在接受≤96 小时的有效抗生素治疗后接受了治疗。患者通过计算机生成的序贯随机分组列表以 1:1 的比例随机分配接受 2 周的辅助利福平（根据体重每天口服或静脉给予 600 毫克或 900 毫克）或相同的安慰剂，同时接受标准抗生素治疗。随机分组按中心分层。患者、研究者和照顾患者的人员对分组情况均不知情。主要结局是从随机分组到 12 周时，经独立审查委员会裁决的细菌学确认的治疗失败或疾病复发或死亡（全因）。分析采用意向治疗。该试验已注册，编号为 ISRCTN37666216，目前已不再招募新的参与者。
2012 年 12 月 10 日至 2016 年 10 月 25 日期间，共有 758 名符合条件的参与者被随机分配：370 名接受利福平，388 名接受安慰剂。485 名（64%）参与者患有社区获得性金黄色葡萄球菌感染，132 名（17%）患有医院获得性金黄色葡萄球菌感染。132 名（17%）患者存在耐甲氧西林感染。47 名（6%）患者存在初始深部感染病灶。标准抗生素治疗 29 天（IQR 18-45）；619 名（82%）参与者接受了氟氯西林治疗。在第 12 周时，接受利福平治疗的 62 名（17%）参与者与接受安慰剂治疗的 71 名（18%）参与者经历了治疗失败或疾病复发或死亡（绝对风险差异-1.4%，95%CI-7.0 至 4.3；风险比 0.96，0.68-1.35，p=0.81）。从随机分组到 12 周，未观察到严重不良事件（p=0.17）或 3-4 级不良事件（p=0.36）差异的证据；然而，利福平组 63 名（17%）参与者与安慰剂组 39 名（10%）参与者出现抗生素或试验药物改变的不良事件（p=0.004），24 名（6%）参与者与 6 名（2%）参与者出现药物相互作用（p=0.0005）。
在金黄色葡萄球菌菌血症患者中，辅助利福平与标准抗生素治疗相比，并未带来总体获益。
英国国家卫生研究院卫生技术评估。
