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.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
606
linezolid 600 mg tablets (twice a day for 5 days)
Placebo tablets (twice a day for 5 days)
Kantonsspital Aarau (KSA)
Aarau, Canton of Aargau, Switzerland
NOT_YET_RECRUITINGSt. Claraspital
Basel, Canton of Basel-City, Switzerland
NOT_YET_RECRUITINGDesirability of Outcome Ranking (DOOR)
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.
Time frame: From randomisation (day 1) until day 90
All-cause mortality
Proportion of patients who died from any cause during the duration of the study.
Time frame: From randomisation (day 1) until day 90
Time to death
Time frame: From randomisation (day 1) until day 90
Level of function
Proportion of participants back to their usual level of function prior to the infection.
Time frame: From randomisation (day 1) until day 90
Number of participants with microbiological failure leading to treatment change
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.
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Hôpitaux universitaires de Genève (HUG)
Geneva, Canton of Geneva, Switzerland
NOT_YET_RECRUITINGHôpital du Jura
Delémont, Canton of Jura, Switzerland
NOT_YET_RECRUITINGCentre hospitalier universitaire vaudois (CHUV)
Lausanne, Canton of Vaud, Switzerland
NOT_YET_RECRUITINGKantonsspital Winterthur (KSW)
Winterthur, Canton of Zurich, Switzerland
NOT_YET_RECRUITINGEnte Ospedaliero Cantonale (EOC)
Lugano, Canton Ticino, Switzerland
NOT_YET_RECRUITINGUniversity Hospital Basel (USB)
Basel, Switzerland
RECRUITINGInselspital Bern
Bern, Switzerland
NOT_YET_RECRUITINGHOCH Health Ostschweiz, Kantonsspital St.Gallen
Sankt Gallen, Switzerland
NOT_YET_RECRUITING...and 2 more locations
Time frame: From day 14 to day 90 (randomisation = day 1)
Number of participants with early microbiological failure leading to treatment change
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.
Time frame: From day 5 to day 13 (randomisation = day 1)
Number of participants with clinical failure leading to treatment change
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.
Time frame: From day 14 to day 90 (randomisation = day 1)
Number of participants with early clinical failure leading to treatment change
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.
Time frame: From day 5 to day 13 (randomisation = day 1)
Hospital length of stay
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 frame: From randomisation (day 1) until day 90
Time to being discharged alive
For participants who die during the hospitalisation, 90 days will be recorded.
Time frame: From randomisation (day 1) until day 90
Days alive without being on the Intensive Care Unit (ICU)
Number of days a participant is alive and not hospitalised in the Intensive Care Unit.
Time frame: From randomisation (day 1) until day 90
Days alive without antibiotics
Number of days a participant is alive and not on any antibiotics.
Time frame: From randomisation (day 1) until day 90
Mental health
Mental health assessed by patient-reported outcome using Short Form-36 (SF-36) questionnaire. The SF-36 questionnaire score ranges from 0 to 100, with higher scores indicating better health.
Time frame: At day 90 (randomisation = day 1)
Physical health
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.
Time frame: At day 90 (randomisation = day 1)
Number of participants with persistent bacteraemia
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.
Time frame: At day 5 (randomisation = day 1)
Two or more systemic inflammatory response syndrome (SIRS) criteria fulfilled
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)
Time frame: At day 5 (randomisation = day 1)
Change in C-reactive protein (CRP)
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.
Time frame: From randomisation (day 1) until day 5
Development of new antibiotic drug resistance in Staphylococcus aureus
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.
Time frame: From randomisation (day 1) until day 90
Adverse events leading to study drug discontinuation
Any adverse event (irrespective of grade) leading to study drug discontinuation as documented by the treating physician.
Time frame: From randomisation (day 1) until day 5
Serious adverse reactions 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.
Time frame: From randomisation (day 1) until day 90
Clinical signs of serotonin toxicity
Assessed using the Hunter Serotonin Toxicity Criteria.
Time frame: From randomisation (day 1) until day 7
Laboratory signs of myelosuppression
Laboratory confirmation of thrombocytopenia, anaemia, or leukopenia.
Time frame: From randomisation (day 1) until day 7
Evidence of hyperlactatemia
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.
Time frame: From randomisation (day 1) until day 7
Acute kidney injury
Assessed on day 5 and, if participant remains hospitalised, on day 14, using the Kidney Disease Improving Global Outcomes (KDIGO) definition.
Time frame: From randomisation until day 14
Number of participants with Clostridioides difficile (C. difficile)-associated diarrhoea
This means a stool submitted to a clinical laboratory has tested positive for C. difficile toxin or toxin gene.
Time frame: From randomisation (day 1) until day 90