Reproducible identification of Staphylococcus aureus bacteremia clinical subphenotypes

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Background Clinical heterogeneity in Staphylococcus aureus bacteremia (SAB) complicates clinical management and research. We have previously identified five clinically distinct subphenotypes of SAB associated with differences in outcomes and response to adjunctive rifampicin. Here, we aimed to identify these subphenotypes in geographically diverse observational cohorts, including a higher prevalence of methicillin-resistant S. aureus (MRSA) bacteremia and the USA300 clone. Methods We studied three cohorts of adults with SAB from observational studies: a UK retrospective study (Edinburgh cohort 2, n=463); a Dutch prospective study (IDISA, n=490); and a USA prospective study (SABG-PCS, n=755). Subphenotypes were identified from routinely available clinical data using latent class analysis. Results Patients from the SABG-PCS cohort had greater multimorbidity and more MRSA bacteremia (40.2%, 303/755), including infection with the USA300 clone (14.7%, 111/755). Five distinct subphenotypes were identified in each cohort: (A) older age and cardio-metabolic multimorbidity; (B) nosocomial acquisition and intravenous catheter portal of entry; (C) community acquisition and metastatic infection; (D) chronic kidney disease; and (E) younger age, injection drug use, and metastatic infection. Bacterial genotypes varied substantially between the Edinburgh 2 and SABG-PCS cohorts but did not differ between subphenotypes within each cohort. 90-day mortality was highest in subphenotype A, and persistent bacteremia in subphenotypes C and E. Conclusions We have reproducibly identified five clinical subphenotypes of SAB in observational cohorts including diverse bacterial genetic lineages and a cohort with a high prevalence of MRSA and USA300 bacteremia. These robustly reproducible clinical subphenotypes provide a framework to rationalize the heterogeneity intrinsic to SAB.