Mortality Risk Profiling of Staphylococcus aureus Bacteremia by Multi-omic Serum Analysis Reveals Early Predictive and Pathogenic Signatures

Staphylococcus aureus bacteremia (SaB) causes significant disease in humans, carrying mortality rates of ∼25%. The ability to rapidly predict SaB patient responses and guide personalized treatment regimens could reduce mortality. Here, we present a resource of SaB prognostic biomarkers. Integrating proteomic and metabolomic techniques enabled the identification of >10,000 features from >200 serum samples collected upon clinical presentation. We interrogated the complexity of serum using multiple computational strategies, which provided a comprehensive view of the early host response to infection. Our biomarkers exceed the predictive capabilities of those previously reported, particularly when used in combination. Last, we validated the biological contribution of mortality-associated pathways using a murine model of SaB. Our findings represent a starting point for the development of a prognostic test for identifying high-risk patients at a time early enough to trigger intensive monitoring and interventions. [Display omitted] •Multi-omic analysis of S. aureus bacteremia serum reveals early mortality signatures•Modified peptides demonstrate enhanced predictive capabilities•Cytokine inference predicts major underlying signaling networks•Host metabolic responses represent actionable therapeutic targets Multi-omic analysis of the serum of patients with Staphylococcus aureus bacteremia identified features with predictive value to determine disease mortality and guide treatment decisions.