Identification and validation of clinical phenotypes in Staphylococcus aureus bloodstream infection and their association with mortality (FEN-AUREUS study)

Abstract

Background: Staphylococcus aureus bacteraemia (SAB) is heterogeneous in patients and infection-related features. The aim of the study was to identify clinical phenotypes among patients with SAB, to evaluate their association with mortality, and to derive and validate a simplified probabilistic model for phenotypes assignment.

Methods: Phenotypes were derived using two-stage cluster analysis of 2128 patients from the ISAC cohort (recruited between 2013 and 2015), analysing 62 variables. Cox regression assessed phenotype-mortality associations. Logistic regression was employed to develop a simplified probabilistic model for sub-phenotype allocation, validated in two external international cohorts: INSTINCT (1217 patients, recruited between 2006 and 2011) and FEN-AUREUS (1185 patients, recruited between January 2021 and October 2024). The association between sub-phenotypes and 30-day mortality in the validation cohorts was also assessed.

Findings: Cluster analysis identified three clinical phenotypes based on the probable portal of entry: A (skin and soft tissues), 458 cases; B (vascular device-associated), 573 cases; and C (other portals of entry or unknown), 1097 cases. Their 30-day mortality was significantly different (13·1%, 18·2% and 25·3%, respectively, p < 0·001). Each phenotype contained two sub-phenotypes with differing characteristics and mortality risks. Also, three phenotypes were found in the INSTINCT cohort, which clustered on the same portals of entry, with two sub-phenotypes in each. When the simplified probabilistic model was applied, the sub-phenotypes showed significant associations with 30-day mortality in both validation cohorts. In INSTINCT, the aHRs were 1·93 (A2 vs A1), 3·40 (B2 vs B1), and 3·04 (C2 vs C1). In FEN-AUREUS, the aHRs were 2·02 (A2 vs A1), 2·11 (B2 vs B1), and 2·44 (C2 vs C1).

Interpretation: Patients with SAB can be classified into phenotypes and sub-phenotypes, each exhibiting considerable variations in mortality rates. To facilitate clinical application, a validated open-access algorithm and calculator for phenotype and sub-phenotype assignment have been developed, enabling their use at the time of SAB confirmation. This tool aims to support timely and personalised patient care.

Funding: Instituto de Salud Carlos III, Spanish Ministry of Science, Innovation and Universities (PI21/01801).

Keywords: Bacteraemia; Clinical profiles; Mortality; Phenotypes; Staphylococcus aureus.

Fig. 1

Databases used and procedures performed.

Fig. 2

Kaplan–Meier survival analysis: 30-day mortality by phenotype and sub-phenotype in the derivation cohort. A) Kaplan–Meier survival analysis: 30-day mortality by phenotype based on the likely portal of entry in the derivation cohort. B) Kaplan–Meier Survival Analysis: 30-Day mortality by sub-phenotype in patients belonging to the A phenotype in the derivation cohort. C) Kaplan–Meier Survival Analysis: 30-Day mortality by sub-phenotype in patients belonging to the B phenotype in the derivation cohort. D) Kaplan–Meier Survival Analysis: 30-Day mortality by sub-phenotype in patients belonging to the C phenotype in the derivation cohort.

Fig. 3

Proposed clinical management algorithm fortheclassification of patients with S. aureus bacteraemia based on identifiedphenotypes and sub-phenotypes. ∗See definitions to consider a probable portal of entry in Supplementary material. ∗∗Visit webpage: https://fen-aureus.com/ for phenotypes and subphenotypes assignment.