Clinical sub-phenotypes of Staphylococcus aureus bacteraemia

Maaike C Swets; Zsuzsa Bakk; Annette C Westgeest; Karla Berry; George Cooper; Wynne Sim; Rui Shian Lee; Tze Yi Gan; William Donlon; Antonia Besu; Emily Heppenstall; Luke Tysall; Simon Dewar; Mark de Boer; Vance G. Fowler Jr.; David H Dockrell; Guy Thwaites; Miquel Pujol; Natalia Pallares; Cristian Tebe; Jordi Carratala; Alexander Szubert; Geert H. Groeneveld; Clark D Russell

doi:10.1093/cid/ciae338

Clinical sub-phenotypes of Staphylococcus aureus bacteraemia

Maaike C Swets, Zsuzsa Bakk, Annette C Westgeest, Karla Berry, George Cooper, Wynne Sim, Rui Shian Lee, Tze Yi Gan, William Donlon, Antonia Besu, Emily Heppenstall, Luke Tysall, Simon Dewar, Mark de Boer, Vance G. Fowler Jr., David H Dockrell, Guy Thwaites, Miquel Pujol, Natalia Pallares, Cristian TebeJordi Carratala, Alexander Szubert, Geert H. Groeneveld, Clark D Russell

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Staphylococcus aureus bacteremia (SAB) is a clinically heterogeneous disease. The ability to identify subgroups of patients with shared traits (subphenotypes) is an unmet need to allow patient stratification for clinical management and research. We aimed to test the hypothesis that clinically relevant subphenotypes can be reproducibly identified among patients with SAB.

METHODS: We studied 3 cohorts of adults with monomicrobial SAB: a UK retrospective observational study (Edinburgh cohort, n = 458), the UK ARREST trial (n = 758), and the Spanish SAFO trial (n = 214). Latent class analysis was used to identify subphenotypes using routinely collected clinical data without considering outcomes. Mortality and microbiologic outcomes were then compared between subphenotypes.

RESULTS: Included patients had predominantly methicillin-susceptible SAB (1366 of 1430, 95.5%). We identified 5 distinct, reproducible clinical subphenotypes: (A) SAB associated with older age and comorbidity, (B) nosocomial intravenous catheter-associated SAB in younger people without comorbidity, (C) community-acquired metastatic SAB, (D) SAB associated with chronic kidney disease, and (E) SAB associated with injection drug use. Survival and microbiologic outcomes differed between the subphenotypes. Mortality was highest in subphenotype A and lowest in subphenotypes B and E. Microbiologic outcomes were worse in subphenotype C. In a secondary analysis of the ARREST trial, adjunctive rifampicin was associated with increased mortality in subphenotype B and improved microbiologic outcomes in subphenotype C.

CONCLUSIONS: We have identified reproducible and clinically relevant subphenotypes within SAB and provide proof of principle of differential treatment effects. Through clinical trial enrichment and patient stratification, these subphenotypes could contribute to a personalized medicine approach to SAB.

Original language	English
Pages (from-to)	1153-1161
Journal	Clinical Infectious Diseases
Volume	79
Issue number	5
DOIs	https://doi.org/10.1093/cid/ciae338
Publication status	Published - 25 Jun 2024

Keywords / Materials (for Non-textual outputs)

Adult
Aged
Anti-Bacterial Agents/therapeutic use
Bacteremia/microbiology
Comorbidity
Female
Humans
Male
Middle Aged
Phenotype
Retrospective Studies
Staphylococcal Infections/microbiology
Staphylococcus aureus/classification
United Kingdom/epidemiology
bacteraemia
patient stratification
adjunctive treatment
subphenotypes
Staphylococcus aureus

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10.1093/cid/ciae338Licence: Creative Commons: Attribution (CC-BY)

ciae338Final published version, 813 KBLicence: Creative Commons: Attribution (CC-BY)

Optimising Innate Host Defence to Combat Antimicrobial Resistance
Dockrell, D. (Principal Investigator), Baillie, K. (Co-investigator), Bradley, M. (Co-investigator), Brown, H. (Co-investigator), Dhaliwal, K. (Co-investigator), Fitzgerald, R. (Co-investigator), Haslett, C. (Co-investigator), Hume, D. (Co-investigator), Rossi, A. (Co-investigator), Walmsley, S. (Co-investigator) & Whyte, M. (Co-investigator)
MRC
1/12/16 → 30/11/22
Project: Research

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Swets, M. C., Bakk, Z., Westgeest, A. C., Berry, K., Cooper, G., Sim, W., Lee, R. S., Gan, T. Y., Donlon, W., Besu, A., Heppenstall, E., Tysall, L., Dewar, S., de Boer, M., Fowler Jr., V. G., Dockrell, D. H., Thwaites, G., Pujol, M., Pallares, N., ... Russell, C. D. (2024). Clinical sub-phenotypes of Staphylococcus aureus bacteraemia. Clinical Infectious Diseases, 79(5), 1153-1161. https://doi.org/10.1093/cid/ciae338

@article{0a77c5c135054aa68cad76accbf2a2db,

title = "Clinical sub-phenotypes of Staphylococcus aureus bacteraemia",

abstract = "BACKGROUND: Staphylococcus aureus bacteremia (SAB) is a clinically heterogeneous disease. The ability to identify subgroups of patients with shared traits (subphenotypes) is an unmet need to allow patient stratification for clinical management and research. We aimed to test the hypothesis that clinically relevant subphenotypes can be reproducibly identified among patients with SAB.METHODS: We studied 3 cohorts of adults with monomicrobial SAB: a UK retrospective observational study (Edinburgh cohort, n = 458), the UK ARREST trial (n = 758), and the Spanish SAFO trial (n = 214). Latent class analysis was used to identify subphenotypes using routinely collected clinical data without considering outcomes. Mortality and microbiologic outcomes were then compared between subphenotypes.RESULTS: Included patients had predominantly methicillin-susceptible SAB (1366 of 1430, 95.5%). We identified 5 distinct, reproducible clinical subphenotypes: (A) SAB associated with older age and comorbidity, (B) nosocomial intravenous catheter-associated SAB in younger people without comorbidity, (C) community-acquired metastatic SAB, (D) SAB associated with chronic kidney disease, and (E) SAB associated with injection drug use. Survival and microbiologic outcomes differed between the subphenotypes. Mortality was highest in subphenotype A and lowest in subphenotypes B and E. Microbiologic outcomes were worse in subphenotype C. In a secondary analysis of the ARREST trial, adjunctive rifampicin was associated with increased mortality in subphenotype B and improved microbiologic outcomes in subphenotype C.CONCLUSIONS: We have identified reproducible and clinically relevant subphenotypes within SAB and provide proof of principle of differential treatment effects. Through clinical trial enrichment and patient stratification, these subphenotypes could contribute to a personalized medicine approach to SAB.",

keywords = "Adult, Aged, Anti-Bacterial Agents/therapeutic use, Bacteremia/microbiology, Comorbidity, Female, Humans, Male, Middle Aged, Phenotype, Retrospective Studies, Staphylococcal Infections/microbiology, Staphylococcus aureus/classification, United Kingdom/epidemiology, bacteraemia, patient stratification, adjunctive treatment, subphenotypes, Staphylococcus aureus",

author = "Swets, {Maaike C} and Zsuzsa Bakk and Westgeest, {Annette C} and Karla Berry and George Cooper and Wynne Sim and Lee, {Rui Shian} and Gan, {Tze Yi} and William Donlon and Antonia Besu and Emily Heppenstall and Luke Tysall and Simon Dewar and {de Boer}, Mark and {Fowler Jr.}, {Vance G.} and Dockrell, {David H} and Guy Thwaites and Miquel Pujol and Natalia Pallares and Cristian Tebe and Jordi Carratala and Alexander Szubert and Groeneveld, {Geert H.} and Russell, {Clark D}",

year = "2024",

month = jun,

day = "25",

doi = "10.1093/cid/ciae338",

language = "English",

volume = "79",

pages = "1153--1161",

journal = "Clinical Infectious Diseases",

issn = "1058-4838",

publisher = "Oxford University Press",

number = "5",

}

Swets, MC, Bakk, Z, Westgeest, AC, Berry, K, Cooper, G, Sim, W, Lee, RS, Gan, TY, Donlon, W, Besu, A, Heppenstall, E, Tysall, L, Dewar, S, de Boer, M, Fowler Jr., VG, Dockrell, DH, Thwaites, G, Pujol, M, Pallares, N, Tebe, C, Carratala, J, Szubert, A, Groeneveld, GH & Russell, CD 2024, 'Clinical sub-phenotypes of Staphylococcus aureus bacteraemia', Clinical Infectious Diseases, vol. 79, no. 5, pp. 1153-1161. https://doi.org/10.1093/cid/ciae338

TY - JOUR

T1 - Clinical sub-phenotypes of Staphylococcus aureus bacteraemia

AU - Swets, Maaike C

AU - Bakk, Zsuzsa

AU - Westgeest, Annette C

AU - Berry, Karla

AU - Cooper, George

AU - Sim, Wynne

AU - Lee, Rui Shian

AU - Gan, Tze Yi

AU - Donlon, William

AU - Besu, Antonia

AU - Heppenstall, Emily

AU - Tysall, Luke

AU - Dewar, Simon

AU - de Boer, Mark

AU - Fowler Jr., Vance G.

AU - Dockrell, David H

AU - Thwaites, Guy

AU - Pujol, Miquel

AU - Pallares, Natalia

AU - Tebe, Cristian

AU - Carratala, Jordi

AU - Szubert, Alexander

AU - Groeneveld, Geert H.

AU - Russell, Clark D

PY - 2024/6/25

Y1 - 2024/6/25

N2 - BACKGROUND: Staphylococcus aureus bacteremia (SAB) is a clinically heterogeneous disease. The ability to identify subgroups of patients with shared traits (subphenotypes) is an unmet need to allow patient stratification for clinical management and research. We aimed to test the hypothesis that clinically relevant subphenotypes can be reproducibly identified among patients with SAB.METHODS: We studied 3 cohorts of adults with monomicrobial SAB: a UK retrospective observational study (Edinburgh cohort, n = 458), the UK ARREST trial (n = 758), and the Spanish SAFO trial (n = 214). Latent class analysis was used to identify subphenotypes using routinely collected clinical data without considering outcomes. Mortality and microbiologic outcomes were then compared between subphenotypes.RESULTS: Included patients had predominantly methicillin-susceptible SAB (1366 of 1430, 95.5%). We identified 5 distinct, reproducible clinical subphenotypes: (A) SAB associated with older age and comorbidity, (B) nosocomial intravenous catheter-associated SAB in younger people without comorbidity, (C) community-acquired metastatic SAB, (D) SAB associated with chronic kidney disease, and (E) SAB associated with injection drug use. Survival and microbiologic outcomes differed between the subphenotypes. Mortality was highest in subphenotype A and lowest in subphenotypes B and E. Microbiologic outcomes were worse in subphenotype C. In a secondary analysis of the ARREST trial, adjunctive rifampicin was associated with increased mortality in subphenotype B and improved microbiologic outcomes in subphenotype C.CONCLUSIONS: We have identified reproducible and clinically relevant subphenotypes within SAB and provide proof of principle of differential treatment effects. Through clinical trial enrichment and patient stratification, these subphenotypes could contribute to a personalized medicine approach to SAB.

AB - BACKGROUND: Staphylococcus aureus bacteremia (SAB) is a clinically heterogeneous disease. The ability to identify subgroups of patients with shared traits (subphenotypes) is an unmet need to allow patient stratification for clinical management and research. We aimed to test the hypothesis that clinically relevant subphenotypes can be reproducibly identified among patients with SAB.METHODS: We studied 3 cohorts of adults with monomicrobial SAB: a UK retrospective observational study (Edinburgh cohort, n = 458), the UK ARREST trial (n = 758), and the Spanish SAFO trial (n = 214). Latent class analysis was used to identify subphenotypes using routinely collected clinical data without considering outcomes. Mortality and microbiologic outcomes were then compared between subphenotypes.RESULTS: Included patients had predominantly methicillin-susceptible SAB (1366 of 1430, 95.5%). We identified 5 distinct, reproducible clinical subphenotypes: (A) SAB associated with older age and comorbidity, (B) nosocomial intravenous catheter-associated SAB in younger people without comorbidity, (C) community-acquired metastatic SAB, (D) SAB associated with chronic kidney disease, and (E) SAB associated with injection drug use. Survival and microbiologic outcomes differed between the subphenotypes. Mortality was highest in subphenotype A and lowest in subphenotypes B and E. Microbiologic outcomes were worse in subphenotype C. In a secondary analysis of the ARREST trial, adjunctive rifampicin was associated with increased mortality in subphenotype B and improved microbiologic outcomes in subphenotype C.CONCLUSIONS: We have identified reproducible and clinically relevant subphenotypes within SAB and provide proof of principle of differential treatment effects. Through clinical trial enrichment and patient stratification, these subphenotypes could contribute to a personalized medicine approach to SAB.

KW - Adult

KW - Aged

KW - Anti-Bacterial Agents/therapeutic use

KW - Bacteremia/microbiology

KW - Comorbidity

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Phenotype

KW - Retrospective Studies

KW - Staphylococcal Infections/microbiology

KW - Staphylococcus aureus/classification

KW - United Kingdom/epidemiology

KW - bacteraemia

KW - patient stratification

KW - adjunctive treatment

KW - subphenotypes

KW - Staphylococcus aureus

U2 - 10.1093/cid/ciae338

DO - 10.1093/cid/ciae338

M3 - Article

C2 - 38916975

SN - 1058-4838

VL - 79

SP - 1153

EP - 1161

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

IS - 5

ER -

Clinical sub-phenotypes of Staphylococcus aureus bacteraemia

Abstract

Keywords / Materials (for Non-textual outputs)

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Optimising Innate Host Defence to Combat Antimicrobial Resistance

Cite this