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| Name | Class |
|---|---|
| Swiss National Science Foundation | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Linezolid | Experimental | 600mg twice a day for 5 days (in addition to the standard antibiotic treatment) |
|
| Placebo | Placebo Comparator | oral placebo tablets twice a day for 5 days (in addition to the standard antibiotic treatment) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Linezolid 600 mg | Drug | linezolid 600 mg tablets (twice a day for 5 days) |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Desirability of Outcome Ranking (DOOR) | The hierarchical composite endpoint DOOR will be calculated based on the following 4 criteria:
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. | From randomisation (day 1) until day 90 |
| Measure | Description | Time Frame |
|---|---|---|
| All-cause mortality | Proportion of patients who died from any cause during the duration of the study. | From randomisation (day 1) until day 90 |
| Time to death | From randomisation (day 1) until day 90 |
| Measure | Description | Time Frame |
|---|---|---|
| Linezolid trough plasma concentrations at day 4 or 5 | Additional exploratory laboratory outcome for a subset of participants only in participating centres (results may be reported in a publication separate from the publication of the main study results). | At day 5 (day of randomisation = day 1) |
| Molecular mechanisms of S. aureus bacteraemia |
Inclusion criteria:
Exclusion criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Richard Kühl, PD Dr. med. | Contact | +41 61 328 66 61 | richardalexander.kuehl@usb.ch | |
| Natalie Rose, PhD | Contact | +41 61 328 35 54 | natalie.rose@usb.ch |
| Name | Affiliation | Role |
|---|---|---|
| Richard Kühl, PD Dr. med. | University Hospital, Basel, Switzerland | Principal Investigator |
| Benjamin Speich, PD, PhD | University Hospital, Basel, Switzerland | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Kantonsspital Aarau (KSA) | Recruiting | Aarau | Canton of Aargau | Switzerland |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 42009378 | Derived | Rose N, Bernasconi NS, Schumacher M, Werlen L, Buchel D, Weisser M, Vogt SB, Wehrle-Wieland E, Conen A, Thurnheer MC, Martin Y, Birrer M, Bongiovanni M, Albrich WC, Karrer U, Schibli A, Harbarth S, Papadimitriou-Olivgeris M, Briel M, Hasse B, Khanna N, Kuehl R, Speich B. Linezolid in addition to standard antibiotic treatment for Staphylococcus aureus bacteraemia: study protocol for a randomised, placebo-controlled trial. BMJ Open. 2026 Apr 20;16(4):e118509. doi: 10.1136/bmjopen-2026-118509. |
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After publication of the main results, the full dataset will be submitted to the Data Access Committee of the Faculty of Medicine (MF-DAC) at the University of Basel. Other researchers interested in using the study data may contact the independent MF-DAC of the University of Basel to request access.
A detailed statistical analysis plan will be finalised before database lock. The statistical analysis plan will be made publicly available on clinicaltrials.gov.
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jul 30, 2025 | Sep 30, 2025 | Prot_001.pdf |
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| ID | Term |
|---|---|
| D016470 | Bacteremia |
| D018805 | Sepsis |
| D013203 | Staphylococcal Infections |
| D014115 | Toxemia |
| ID | Term |
|---|---|
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
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| ID | Term |
|---|---|
| D000069349 | Linezolid |
| ID | Term |
|---|---|
| D000081 | Acetamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000085 | Acetates |
| D000144 |
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| Placebo |
| Drug |
Placebo tablets (twice a day for 5 days) |
|
| Level of function | Proportion of participants back to their usual level of function prior to the infection. | 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. | 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. | 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. | 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. | 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. | From randomisation (day 1) until day 90 |
| Time to being discharged alive | For participants who die during the hospitalisation, 90 days will be recorded. | 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. | From randomisation (day 1) until day 90 |
| Days alive without antibiotics | Number of days a participant is alive and not on any antibiotics. | 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. | 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. | 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. | At day 5 (randomisation = day 1) |
| Two or more systemic inflammatory response syndrome (SIRS) criteria fulfilled | SIRS criteria:
| 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. | 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. | 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. | 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. | From randomisation (day 1) until day 90 |
| Clinical signs of serotonin toxicity | Assessed using the Hunter Serotonin Toxicity Criteria. | From randomisation (day 1) until day 7 |
| Laboratory signs of myelosuppression | Laboratory confirmation of thrombocytopenia, anaemia, or leukopenia. | 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. | 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. | 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. | From randomisation (day 1) until day 90 |
Basic research on the location of S. aureus in human blood (extracellular or intracellular). This will be conducted in a sub-sample of participants consenting to additional blood sampling and published separately from the publication of the main study results. |
| 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. |
| Nina Khanna, Prof. Dr. med. |
| University Hospital, Basel, Switzerland |
| Principal Investigator |
| St. Claraspital | Recruiting | Basel | Canton of Basel-City | Switzerland |
|
| Hôpitaux universitaires de Genève (HUG) | Not yet recruiting | Geneva | Canton of Geneva | Switzerland |
|
| Hôpital du Jura | Not yet recruiting | Delémont | Canton of Jura | Switzerland |
|
| Centre hospitalier universitaire vaudois (CHUV) | Not yet recruiting | Lausanne | Canton of Vaud | Switzerland |
|
| Kantonsspital Winterthur (KSW) | Not yet recruiting | Winterthur | Canton of Zurich | Switzerland |
|
| Ente Ospedaliero Cantonale (EOC) | Recruiting | Lugano | Canton Ticino | Switzerland |
|
| University Hospital Basel (USB) | Recruiting | Basel | 4031 | Switzerland |
|
| Inselspital Bern | Not yet recruiting | Bern | Switzerland |
|
| HOCH Health Ostschweiz, Kantonsspital St.Gallen | Not yet recruiting | Sankt Gallen | Switzerland |
|
| Stadtspital Zürich Triemli | Recruiting | Zurich | Switzerland |
|
| Universitätsspital Zürich (USZ) | Recruiting | Zurich | Switzerland |
|
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D016908 | Gram-Positive Bacterial Infections |
| Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D023303 | Oxazolidinones |
| D010080 | Oxazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |