Clinical trial NCT06958835: Linezolid Plus Standard of Care
Official title: Combination Antibiotic Treatment With Linezolid for Staphylococcus Aureus Bacteraemia: a Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Staphylococcus Aureus Bloodstream Infections (BSI; Bacteremia)
Keywords: Virulence factors
Linezolid
Bloodstream Infection
Hierarchical composite endpoint
Staphylococcus aureus
Bacteremia
Bacteraemia
MRSA
PSSA
MSSA
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
Collaborators: name: Swiss National Science Foundation
First posted: 2025-05-06
Enrollment: 606
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion criteria:

* Staphyloccus aureus (S. aureus) grown from at least one blood culture
* Hospitalised at a participating centre
* ≥18 years old
* Written informed consent

Exclusion criteria:

* 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
* Previous type 1 hypersensitivity reaction to linezolid
* Current severe thrombocytopenia (i.e. \<30 x 10\^9/L)
* Application of study drug not possible (per mouth or per gastric tube)
* 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

Primary outcomes:
measure: Desirability of Outcome Ranking (DOOR)
timeFrame: From randomisation (day 1) until day 90
Secondary outcomes:
measure: All-cause mortality
timeFrame: From randomisation (day 1) until day 90
measure: Time to death
timeFrame: From randomisation (day 1) until day 90
measure: Level of function
timeFrame: From randomisation (day 1) until day 90
measure: Number of participants with microbiological failure leading to treatment change
timeFrame: From day 14 to day 90 (randomisation = day 1)
measure: Number of participants with early microbiological failure leading to treatment change
timeFrame: From day 5 to day 13 (randomisation = day 1)
measure: Number of participants with clinical failure leading to treatment change
timeFrame: From day 14 to day 90 (randomisation = day 1)
measure: Number of participants with early clinical failure leading to treatment change
timeFrame: From day 5 to day 13 (randomisation = day 1)
measure: Hospital length of stay
timeFrame: From randomisation (day 1) until day 90
measure: Time to being discharged alive
timeFrame: From randomisation (day 1) until day 90
measure: Days alive without being on the Intensive Care Unit (ICU)
timeFrame: From randomisation (day 1) until day 90
measure: Days alive without antibiotics
timeFrame: From randomisation (day 1) until day 90
measure: Mental health
timeFrame: At day 90 (randomisation = day 1)
measure: Physical health
timeFrame: At day 90 (randomisation = day 1)
measure: Number of participants with persistent bacteraemia
timeFrame: At day 5 (randomisation = day 1)
measure: Two or more systemic inflammatory response syndrome (SIRS) criteria fulfilled
timeFrame: At day 5 (randomisation = day 1)
measure: Change in C-reactive protein (CRP)
timeFrame: From randomisation (day 1) until day 5
measure: Development of new antibiotic drug resistance in Staphylococcus aureus
timeFrame: From randomisation (day 1) until day 90
measure: Adverse events leading to study drug discontinuation
timeFrame: From randomisation (day 1) until day 5
measure: Serious adverse reactions until day 90
timeFrame: From randomisation (day 1) until day 90
measure: Clinical signs of serotonin toxicity
timeFrame: From randomisation (day 1) until day 7
measure: Laboratory signs of myelosuppression
timeFrame: From randomisation (day 1) until day 7
measure: Evidence of hyperlactatemia
timeFrame: From randomisation (day 1) until day 7
measure: Acute kidney injury
timeFrame: From randomisation until day 14
measure: Number of participants with Clostridioides difficile (C. difficile)-associated diarrhoea
timeFrame: From randomisation (day 1) until day 90
Other outcomes:
measure: Linezolid trough plasma concentrations at day 4 or 5
timeFrame: At day 5 (day of randomisation = day 1)
measure: Molecular mechanisms of S. aureus bacteraemia
timeFrame: From randomisation (day 1) until day 90 or until the date of the participant's first blood culture negative for S. aureus, whichever came first.
Locations:
city: Basel
country: Switzerland
facility: University Hospital Basel
Study officials:
affiliation: University Hospital, Basel, Switzerland
name: Richard Kühl, PD Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Basel, Switzerland
name: Benjamin Speich, PD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Basel, Switzerland
name: Nina Khanna, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: