Combination Antibiotic Treatment With Linezolid for Staphylococcus Aureus Bacteraemia: a Randomised Controlled Trial
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 606
- 试验地点
- 12
- 主要终点
- Desirability of Outcome Ranking (DOOR)
研究概览
简要总结
The aim of the study is to assess whether targeting virulence factors by administering linezolid in addition to standard antibiotic treatment improves outcomes in patients with Staphylococcus aureus bacteraemia.
详细描述
Staphylococcus aureus (S. aureus) is one of the deadliest bacterial pathogens, especially in high-income countries, and causes bloodstream infections (bacteraemia) in 20-30 per 100,000 people annually. Despite widely available antibiotic treatments, the 90-day mortality rate remains high at 20-30%, and complications such as organ damage, relapses, and long-term impairment affect many survivors. Existing treatments have failed to improve survival rates highlighting the urgent need for novel therapeutic strategies.
Virulence factors produced by S. aureus facilitate bacterial persistence and spread, and tissue damage. Preclinical research suggests that inhibiting the production of virulence factors may improve patient outcomes. While some clinical guidelines recommend this approach for toxin-mediated infections, randomized controlled trials (RCTs) evaluating this approach in S. aureus bacteraemia have not yet been conducted.
Linezolid, an antibiotic commonly used for pneumonia and complicated skin and soft-tissue infections, has shown strong inhibition of the expression of S. aureus virulence factors in preclinical studies. Studies in animal models demonstrated that linezolid, when combined with other antibiotics, enhances treatment efficacy and reduces bacterial toxin production. Observational studies suggest that early initiation of linezolid may lead to better patient outcomes, but no RCT has tested this approach in S. aureus bacteraemia.
This placebo-controlled trial will evaluate whether adding a 5-day course of linezolid to standard antibiotic therapy improves clinical outcomes in patients with S. aureus bacteraemia.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Staphylococcus aureus (S. aureus) grown from at least one blood culture
- •Hospitalised at a participating centre
- •≥18 years old
- •Written informed consent or fulfilling criteria for an emergency exception from informed consent requirements
排除标准
- •Administration of the initial drug treatment not feasible within 72 hours since the collection of the first positive blood culture with S. aureus
- •Documented history of positive blood cultures for S. aureus occurring between 72 hours and 180 days prior to the eligibility assessment
- •Necrotising fasciitis
- •Currently receiving linezolid or clindamycin
- •Use of any monoamine oxidase A or B inhibitor within the last two weeks
- •Known hypersensitivity to linezolid or any other ingredients of the study drugs
- •Current severe thrombocytopenia (i.e. <30 x 10^9/L)
- •Application of study drug not possible (per mouth or per gastric tube)
- •Currently breastfeeding
- •Local treating team believes that death is imminent and inevitable
- •Patient is receiving end of life care and antibiotic treatment is not considered appropriate
- •Local treating team believes that participation in the study is not in the best interest of the patient
- •Any indication that the patient is unwilling to participate in the study including an advance directive stating such unwillingness
研究组 & 干预措施
Placebo
oral placebo tablets twice a day for 5 days (in addition to the standard antibiotic treatment)
干预措施: Placebo (Drug)
Linezolid
600mg twice a day for 5 days (in addition to the standard antibiotic treatment)
干预措施: Linezolid 600 mg (Drug)
结局指标
主要结局
Desirability of Outcome Ranking (DOOR)
时间窗: From randomisation (day 1) until day 90
The hierarchical composite endpoint DOOR will be calculated based on the following 4 criteria: 1. Alive at 90 days 2. Return to usual level of function by day 90 3. None of the following complications: Microbiological or clinical failure leading to treatment change; Serious adverse reaction; Adverse event leading to study drug discontinuation 4. Hospital length of stay The primary outcome will be expressed as the win ratio, i.e., the ratio of the number of times that participants in the intervention group have a lower DOOR compared to those in the control group. In this study, a pairwise comparison is used, i.e., every participant in the linezolid group is compared with every participant in the control group. When comparing two participants, the winner will be determined by the first component of the DOOR in which the two participants differ, the only exceptions being ties when both participants die or if they do not die but have the same length of hospitalisation.
次要结局
- Time to being discharged alive(From randomisation (day 1) until day 90)
- Level of function(From randomisation (day 1) until day 90)
- All-cause mortality(From randomisation (day 1) until day 90)
- Time to death(From randomisation (day 1) until day 90)
- Number of participants with early microbiological failure leading to treatment change(From day 5 to day 13 (randomisation = day 1))
- Mental health(At day 90 (randomisation = day 1))
- Physical health(At day 90 (randomisation = day 1))
- Change in C-reactive protein (CRP)(From randomisation (day 1) until day 5)
- All-cause mortality(From randomisation (day 1) until day 90)
- Time to death(From randomisation (day 1) until day 90)
- Number of participants with microbiological failure leading to treatment change(From day 14 to day 90 (randomisation = day 1))
- Two or more systemic inflammatory response syndrome (SIRS) criteria fulfilled(At day 5 (randomisation = day 1))
- Change in C-reactive protein (CRP)(From randomisation (day 1) until day 5)
- Development of new antibiotic drug resistance in Staphylococcus aureus(From randomisation (day 1) until day 90)
- Number of participants with clinical failure leading to treatment change(From day 14 to day 90 (randomisation = day 1))
- Number of participants with early clinical failure leading to treatment change(From day 5 to day 13 (randomisation = day 1))
- Serious adverse reactions until day 90(From randomisation (day 1) until day 90)
- Clinical signs of serotonin toxicity(From randomisation (day 1) until day 7)
- Laboratory signs of myelosuppression(From randomisation (day 1) until day 7)
- Number of participants with microbiological failure leading to treatment change(From day 14 to day 90 (randomisation = day 1))
- Hospital length of stay(From randomisation (day 1) until day 90)
- Days alive without being on the Intensive Care Unit (ICU)(From randomisation (day 1) until day 90)
- Days alive without antibiotics(From randomisation (day 1) until day 90)
- Number of participants with persistent bacteraemia(At day 5 (randomisation = day 1))
- Two or more systemic inflammatory response syndrome (SIRS) criteria fulfilled(At day 5 (randomisation = day 1))
- Development of new antibiotic drug resistance in Staphylococcus aureus(From randomisation (day 1) until day 90)
- Adverse events leading to study drug discontinuation(From randomisation (day 1) until day 5)
- Evidence of hyperlactatemia(From randomisation (day 1) until day 7)
- Acute kidney injury(From randomisation until day 14)
- Number of participants with Clostridioides difficile (C. difficile)-associated diarrhoea(From randomisation (day 1) until day 90)