Linezolid Plus Standard of Care

The hierarchical composite endpoint DOOR will be calculated based on the following 4 criteria:

• Alive at 90 days
• Return to usual level of function by day 90
• None of the following complications: Microbiological or clinical failure leading to treatment change; Serious adverse reaction; Adverse event leading to study drug discontinuation
• 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.

Proportion of patients who died from any cause during the duration of the study.

Proportion of participants back to their usual level of function prior to the infection.

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.

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.

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.

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.

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.

For participants who die during the hospitalisation, 90 days will be recorded.

Number of days a participant is alive and not hospitalised in the Intensive Care Unit.

Number of days a participant is alive and not on any antibiotics.

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.

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.

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.

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)

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.

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.

Any adverse event (irrespective of grade) leading to study drug discontinuation as documented by the treating physician.

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.

Assessed using the Hunter Serotonin Toxicity Criteria.

Laboratory confirmation of thrombocytopenia, anaemia, or leukopenia.

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.

Assessed on day 5 and, if participant remains hospitalised, on day 14, using the Kidney Disease Improving Global Outcomes (KDIGO) definition.

This means a stool submitted to a clinical laboratory has tested positive for C. difficile toxin or toxin gene.

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).

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.