Antimicrobial resistance determinants are associated with Staphylococcus aureus bacteraemia and adaptation to the healthcare environment: a bacterial genome-wide association study.

Bernadette C Young,Daniel J Wilson,Heather Godwin,Jane Charlesworth,Laura Dunn,James R Price,Matthew Scarborough,Chieh-Hsi Wu,Elian Liu,Robert Tilley,Rowena Fung,Sarah Oakley,Kyle Knox,Derrick W Crook,Timothy E A Peto ,A Sarah Walker ,Antonina A Votintseva ,T Phuong Quan ,Ruth R Miller ,N Claire Gordon ,Martin Llewelyn ,Kevin N Cole ,Sarah G Earle

doi:10.1099/mgen.0.000700

Abstract

Staphylococcus aureus is a major bacterial pathogen in humans, and a dominant cause of severe bloodstream infections. Globally, antimicrobial resistance (AMR) in S. aureus remains challenging. While human risk factors for infection have been defined, contradictory evidence exists for the role of bacterial genomic variation in S. aureus disease. To investigate the contribution of bacterial lineage and genomic variation to the development of bloodstream infection, we undertook a genome-wide association study comparing bacteria from 1017 individuals with bacteraemia to 984 adults with asymptomatic S. aureus nasal carriage. Within 984 carriage isolates, we also compared healthcare-associated (HA) carriage with community-associated (CA) carriage. All major global lineages were represented in both bacteraemia and carriage, with no evidence for different infection rates. However, kmers tagging trimethoprim resistance-conferring mutation F99Y in dfrB were significantly associated with bacteraemia-vs-carriage (P=10-8.9-10-9.3). Pooling variation within genes, bacteraemia-vs-carriage was associated with the presence of mecA (HMP=10-5.3) as well as the presence of SCCmec (HMP=10-4.4). Among S. aureus carriers, no lineages were associated with HA-vs-CA carriage. However, we found a novel signal of HA-vs-CA carriage in the foldase protein prsA, where kmers representing conserved sequence allele were associated with CA carriage (P=10-7.1-10-19.4), while in gyrA, a ciprofloxacin resistance-conferring mutation, L84S, was associated with HA carriage (P=10-7.2). In an extensive study of S. aureus bacteraemia and nasal carriage in the UK, we found strong evidence that all S. aureus lineages are equally capable of causing bloodstream infection, and of being carried in the healthcare environment. Genomic variation in the foldase protein prsA is a novel genomic marker of healthcare origin in S. aureus but was not associated with bacteraemia. AMR determinants were associated with both bacteraemia and healthcare-associated carriage, suggesting that AMR increases the propensity not only to survive in healthcare environments, but also to cause invasive disease.

Highlights

Staphylococcus aureus is a common coloniser of human mucosal surfaces and skin and a major human pathogen [1, 2]
It is possible that other between-group differences, such co-m orbid illnesses, may account for the different prevalence of methicillin-r esistant S. aureus (MRSA) observed between patients with bacteraemia and asymptomatic carriers, and we have not been able to measure patient factors confounding between MRSA carriage and invasive infection
In a study of over 2000 isolates from S. aureus bacteraemia and nasal carriage in the UK, we found strong evidence that all S. aureus lineages are capable of causing bloodstream infection, and of being carried in the healthcare environment

Summary

Introduction

Staphylococcus aureus is a common coloniser of human mucosal surfaces and skin and a major human pathogen [1, 2]. It is a leading cause of hospital and community acquired infection and one of the leading causes of bloodstream infection worldwide [1,2,3,4]. S. aureus possesses diverse and variable virulence mechanisms facilitating tissue invasion, inflammation and evasion of host immune factors. These include a thick peptidoglycan wall, polysaccharide capsule, toxins [9, 10], complement control proteins [11], and bound adhesins [12]. With the exception of specific toxinoses such as toxic shock syndrome [13,14,15], and the role of Panton-Valentine leucocidin (PVL) in skin or soft tissue infections [16] and pyomyositis [17], evidence linking bacterial genetic variability to clinical disease phenotype is inconclusive

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