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

Abstract

<i>Staphylococcus aureus</i> is a major bacterial pathogen in humans, and a dominant cause of severe bloodstream infections. Globally, antimicrobial resistance (AMR) in <i>S. aureus</i> remains challenging. While human risk factors for infection have been defined, contradictory evidence exists for the role of bacterial genomic variation in <i>S. aureus</i> 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 <i>S. aureus</i> 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 <i>dfrB</i> were significantly associated with bacteraemia-vs-carriage (<i>P=</i>10^-8.9-10^-9.3). Pooling variation within genes, bacteraemia-vs-carriage was associated with the presence of <i>mecA</i> (HMP=10^-5.3) as well as the presence of SCCmec (HMP=10^-4.4). Among <i>S. aureus</i> 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 <i>prsA</i>, where kmers representing conserved sequence allele were associated with CA carriage (<i>P=</i>10^-7.1-10^-19.4), while in <i>gyrA</i>, a ciprofloxacin resistance-conferring mutation, L84S, was associated with HA carriage (<i>P=</i>10^-7.2). In an extensive study of <i>S. aureus</i> bacteraemia and nasal carriage in the UK, we found strong evidence that all <i>S. aureus</i> lineages are equally capable of causing bloodstream infection, and of being carried in the healthcare environment. Genomic variation in the foldase protein <i>prsA</i> is a novel genomic marker of healthcare origin in <i>S. aureus</i> 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.