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Here, we present an extensive study that profiles molecular differences in plasma from EcB patients using an unbiased multi-omics approach. We performed shotgun proteomics and metabolomics on 105 plasma samples, including those from EcB patients and healthy volunteers. Comparison between healthy volunteer and EcB-infected patient samples revealed significant disparities in proteins and metabolites involved in the acute phase response, inflammatory processes, and cholestasis. Several features distinguish these two groups with remarkable accuracy. Cross-referencing EcB signatures with those of\n                      <jats:italic>Staphylococcus aureus<\/jats:italic>\n                      bacteremia revealed shared reductions in cholesterol metabolism proteins and differing responses in platelet alpha granule and neutrophil-associated proteins. Characterization of\n                      <jats:italic>Enterococcus<\/jats:italic>\n                      isolates derived from patients facilitated a nuanced comparison between EcB caused by\n                      <jats:italic>Enterococcus faecalis<\/jats:italic>\n                      and\n                      <jats:italic>Enterococcus faecium,<\/jats:italic>\n                      uncovering reduced immunoglobulin abundances in\n                      <jats:italic>E. faecium<\/jats:italic>\n                      cases and features capable of distinguishing the underlying microbe. Leveraging extensive patient metadata, we now have identified features associated with mortality or survival, revealing significant multi-omic differences and pinpointing histidine-rich glycoprotein and fetuin-B as features capable of distinguishing survival status with excellent accuracy. Altogether, this study aims to culminate in the creation of objective risk stratification algorithms\u2014a pivotal step toward enhancing patient management and care. To facilitate the exploration of this rich data source, we provide a user-friendly interface at\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/gonzalezlab.shinyapps.io\/EcB_multiomics\/\" xlink:type=\"simple\">https:\/\/gonzalezlab.shinyapps.io\/EcB_multiomics\/<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Enterococcus<\/jats:italic>\n                      infections have emerged as the second most common nosocomial infection, with enterococcal bacteremia (EcB) contributing to thousands of patient deaths annually. To address a lack of detailed understanding regarding the specific systemic response to EcB, we conducted a comprehensive multi-omic evaluation of the systemic host response observed in patient plasma. Our findings reveal significant features in the metabolome and proteome associated with the presence of infection, species differences, and survival outcome. We identified features capable of discriminating EcB infection from healthy states and survival from mortality with excellent accuracy, suggesting potential practical clinical utility. However, our study also established that systemic features to distinguish\n                      <jats:italic>Enterococcus faecalis<\/jats:italic>\n                      from\n                      <jats:italic>Enterococcus faecium<\/jats:italic>\n                      EcB show only a moderate degree of discriminatory accuracy, unlikely to significantly improve upon current diagnostic methods. Comparisons of differences in the plasma proteome relative to healthy samples between bacteremia caused by\n                      <jats:italic>Enterococcus<\/jats:italic>\n                      and\n                      <jats:italic>Staphylococcus aureus<\/jats:italic>\n                      suggest the presence of bacteria-specific responses alongside conserved inflammatory reactions.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/msystems.01471-24","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T09:00:25Z","timestamp":1737450025000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Multi-omic signatures of host response associated with presence, type, and outcome of enterococcal 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