Background: Current guidelines recommend at least 2 weeks duration of antibiotic therapy (DOT) for patients with uncomplicated Staphylococcus aureus bacteraemia (SAB) but the evidence for this recommendation is unclear.

Objectives: To perform a systematic literature review assessing current evidence for recommended DOT for patients with SAB.

Methods: The following are the methods used for this study.

Data sources: We searched MEDLINE, ISI Web of Science, the Cochrane Database and clinicaltrials.gov from inception to March 30, 2024. References of eligible studies were screened and experts in the field contacted for additional articles.

Study eligibility criteria: All clinical studies, regardless of design, publication status and language.

Participants: Adult patients with uncomplicated SAB.

Interventions: Long (>14 days; >18 days; 11-16 days) vs. short (≤14 days; 10-18 days; 6-10 days, respectively) DOT with the DOT being defined as the first until the last day of antibiotic therapy.

Assessment of risk of bias: Risk of bias was assessed using the ROBINS-I-tool.

Methods of data synthesis: The primary outcome was 90-day all-cause mortality. Only studies presenting results of adjusted analyses for mortality were included. Data synthesis could not be performed.

Results: Eleven nonrandomized studies were identified that fulfilled the pre-defined inclusion criteria, of which three studies reported adjusted effect ratios. Only these were included in the final analysis. We did not find any RCT. Two studies with 1230 patients reported the primary endpoint 90-day all-cause mortality. Neither found a statistically significant superiority for longer (>14 days; 11-16 days) or shorter DOT (≤14 days; 6-10 days, respectively) for patients with uncomplicated SAB. Two studies investigated the secondary endpoint 30-day all-cause mortality (>18 days; 11-16 days vs. 10-18 days; 6-10 days, respectively) and did not find a statistically significant difference. All included studies had a moderate risk of bias.

Conclusions: Sound evidence that supports any duration of antibiotic treatment for patients with uncomplicated SAB is lacking.