175 Clinical sub-phenotypes of Staphylococcus aureus bacteraemia 8 Introduction Staphylococcus aureus bacteraemia (SAB) has long been recognised as a difficultto-treat bacterial disease requiring prolonged antimicrobial treatment1,2. Major complications include the development of metastatic foci of infection (up to 37%3), recurrence of bacteraemia despite appropriate treatment (up to 10%4), and death (15-30% in-hospital5,6). Globally, S. aureus accounts for the most overall deaths due to a bacterial pathogen, and specifically the most deaths associated with bacteraemia7. A defining clinical feature of SAB is heterogeneity. This encompasses patient characteristics (e.g. age and co-morbidity), pathogen characteristics, place of acquisition (community or hospital), source of bacteraemia, and extent of infection. Currently, there is no consensus on rationalising this clinical heterogeneity to achieve patient stratification, and clinical trials mainly consider SAB to be a single syndrome. Strategy trials in SAB, frequently investigating combination antimicrobial therapy, have so far not succeeded in identifying approaches that improve outcomes compared to standards of care8-10. However, because of the clinical heterogeneity intrinsic to SAB, it is possible we fail to identify sub-groups of patients who may differentially benefit (or suffer harm) from specific therapies11. In contrast, clinically-relevant sub-phenotypes have been identified in similarly heterogenous diseases including the acute respiratory distress syndrome12, asthma13, chronic obstructive pulmonary disease14, and bronchiectasis15. In this context a sub-phenotype is considered to be a sub-group of patients with a specific disease who exhibit similar traits, such as clinical features, outcomes, or responses to treatment16. We aimed to test the hypothesis that clinically-relevant sub-phenotypes can be reproducibly identified amongst patients with SAB. Methods Patient cohorts Patients were included from three cohorts: a retrospective observational cohort study (Edinburgh cohort, n=458)17, the ARREST multicentre, randomised, doubleblind, placebo-controlled trial (n=758)10, and the SAFO randomised clinical trial (n=214)8. The Edinburgh cohort included consecutive adults (≥18 years) with monomicrobial SAB diagnosed between 20/12/2019 and 23/08/2022 in three UK hospitals (Supplementary Figure 1). The ARREST trial recruited adults (≥18 years) with monomicrobial SAB in 29 UK hospitals between 10/12/2012 and 25/10/2016, and randomised participants to receive adjunctive rifampicin (600mg or 900mg/day) or placebo for up to 14 days, in addition to standard antibiotic treatment. Exclusion criteria included evidence of rifampicin non-susceptible S. aureus, contraindications to rifampicin, or if adjunctive rifampicin was considered mandatory. The SAFO trial
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