Linezolid Plus Standard of Care

Not Applicable

Not yet recruiting

• Conditions: Staphylococcus Aureus Bloodstream Infections (BSI; Bacteremia)
• Interventions: Drug: Linezolid 600 mg; Drug: Placebo

• Registration Number: NCT06958835
• Lead Sponsor: University Hospital, Basel, Switzerland

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Status Verified: 2025-04
• Study First Submitted: 2025-04-01
• Study First Submitted QC: 2025-04-25
• Last Update Submitted: 2025-04-25
• Study First Posted: 2025-05-06
• Last Update Posted: 2025-05-06
• Study Start: 2025-09
• Primary Completion: 2028-10
• Study Completion: 2028-10

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 606

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Linezolid	Linezolid 600 mg	600mg twice a day for 5 days (in addition to the standard antibiotic treatment)
Placebo	Placebo	oral placebo tablets twice a day for 5 days (in addition to the standard antibiotic treatment)

Primary Outcome Measures

Name	Time	Method
Desirability of Outcome Ranking (DOOR)	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.

Secondary Outcome Measures

Name	Time	Method
All-cause mortality	From randomisation (day 1) until day 90	Proportion of patients who died from any cause during the duration of the study.
Time to death	From randomisation (day 1) until day 90
Level of function	From randomisation (day 1) until day 90	Proportion of participants back to their usual level of function prior to the infection.
Clinical signs of serotonin toxicity	From randomisation (day 1) until day 7	Assessed using the Hunter Serotonin Toxicity Criteria.
Laboratory signs of myelosuppression	From randomisation (day 1) until day 7	Laboratory confirmation of thrombocytopenia, anaemia, or leukopenia.
Hospital length of stay	From randomisation (day 1) until day 90	Duration of the index acute hospital stay from randomisation until the day of hospital discharge. Transfers to another acute care hospital for continuation of acute treatment will be included in the assessment of hospital length of stay. Days after transfer to rehabilitation centres or switch to outpatient parenteral ambulatory treatment will not be included in the acute hospital stay.
Time to being discharged alive	From randomisation (day 1) until day 90	For participants who die during the hospitalisation, 90 days will be recorded.
Days alive without being on the Intensive Care Unit (ICU)	From randomisation (day 1) until day 90	Number of days a participant is alive and not hospitalised in the Intensive Care Unit.
Mental health	At day 90 (randomisation = day 1)	Mental health assessed by patient-reported outcome using SF-36 questionnaire. The SF-36 questionnaire score ranges from 0 to 100, with higher scores indicating better health.
Physical health	At day 90 (randomisation = day 1)	Physical health assessed by patient-reported outcome using SF-36 questionnaire. The SF-36 questionnaire score ranges from 0 to 100, with higher scores indicating better health.
Number of participants with persistent bacteraemia	At day 5 (randomisation = day 1)	S. aureus-positive blood culture on day 5 (±1 day) after randomisation. If day 2 or day 3 blood cultures are negative and no subsequent blood cultures are performed, the day 5 blood culture is presumed to be negative.
Change in C-reactive protein (CRP)	From randomisation (day 1) until day 5	Day 1 CRP means any blood CRP measurement taken on randomisation day 1 or the calendar day prior to randomisation. If there is more than one measurement, the value recorded is the one taken closest before randomisation.
Evidence of hyperlactatemia	From randomisation (day 1) until day 7	In case of clinical suspicion of hyperlactatemia, lactate levels will be measured and compared to specific laboratory-defined reference ranges. For increased lactate levels, the causality with the study treatment will be assessed.
Acute kidney injury	From randomisation until day 14	Assessed on day 5 and, if participant remains hospitalised, on day 14, using the Kidney Disease Improving Global Outcomes (KDIGO) definition.
Number of participants with Clostridioides difficile (C. difficile)-associated diarrhoea	From randomisation (day 1) until day 90	This means a stool submitted to a clinical laboratory has tested positive for C. difficile toxin or toxin gene.
Number of participants with early clinical failure leading to treatment change	From day 5 to day 13 (randomisation = day 1)	Newly identified focus of S. aureus between 5 and 13 days after randomisation as determined by the site investigator (or delegated physician) that leads to a change in treatment. This can incorporate clinical, radiological, microbiological and pathological findings.
Days alive without antibiotics	From randomisation (day 1) until day 90	Number of days a participant is alive and not on any antibiotics.
Number of participants with microbiological failure leading to treatment change	From day 14 to day 90 (randomisation = day 1)	Any positive sterile site culture with Staphylococcus aureus (S. aureus) between 14 and 90 days after randomisation that leads to a change in treatment. A sterile site means any site of the body where microorganisms are usually absent, i.e. below the outer and inner colonised surfaces of the skin and mucous membranes. Positive sterile sites cultures include deep visceral and musculoskeletal abscesses obtained in a sterile manner.
Number of participants with early microbiological failure leading to treatment change	From day 5 to day 13 (randomisation = day 1)	Any positive sterile site culture with S. aureus between 5 and 13 days after randomisation that leads to a change in treatment. A sterile site means any site of the body where microorganisms are usually absent, i.e. below the outer and inner colonised surfaces of the skin and mucous membranes. Positive sterile sites cultures include deep visceral and musculoskeletal abscesses obtained in a sterile manner.
Number of participants with clinical failure leading to treatment change	From day 14 to day 90 (randomisation = day 1)	Newly identified focus of S. aureus between 14 and 90 days after randomisation as determined by the site investigator (or delegated physician) that leads to a change in treatment. This can incorporate clinical, radiological, microbiological and pathological findings.
Two or more systemic inflammatory response syndrome (SIRS) criteria fulfilled	At day 5 (randomisation = day 1)	SIRS criteria: * Abnormal body temperature (\<36°C or \>38°C); * tachypnoea or mechanical ventilation (RR\>20 breaths per minute); * tachycardia (HR \>90 beats per minute in an adult; * abnormal leukocyte count (from routine blood sampling on day 5 ±1 day, defined as \>12.0 x 10\^9/L or \<4.0 x 10\^9/L or \>10% of immature (band) forms)
Development of new antibiotic drug resistance in Staphylococcus aureus	From randomisation (day 1) until day 90	Any new resistance absent in the S. aureus from the initial blood culture and detected in any S. aureus cultured after the start of the intervention.
Adverse events leading to study drug discontinuation	From randomisation (day 1) until day 5	Any adverse event (irrespective of grade) leading to study drug discontinuation as documented by the treating physician.
Serious adverse reactions until day 90	From randomisation (day 1) until day 90	Any serious adverse event will be reported to the study-site principal investigator, who then assesses whether there is a reasonable causal relationship with the investigational medicinal product.

Trial Locations

Locations (1)

University Hospital Basel; 🇨🇭 Basel, Switzerland