Genomic investigation of MRSA bacteremia relapse reveals diverse genomic profiles but convergence in bacteremia-associated genes

BackgroundRecurrence of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a high risk complication for patients. Distinguishing persistent lineages from new infections is not standardized across clinical studies. MethodsWe investigated factors contributing to recurrence of MRSA bacteremia among subjects in Philadelphia, Pennsylvania. Subject demographics and clinical history were collected and paired with whole-genome sequences of infection isolates. Recurrent bacteremia episodes were recorded and defined as relapse infections (same lineage) or new infections by genomic criteria, where a relapse contains isolates <=25 single nucleotide polymorphisms (SNP) different, and by clinical criteria. All isolates were assessed for pairwise SNP distances, common mutations, and signatures of within-host adaptation using the McDonald-Kreitman test. Clusters of transmission between relapse-associated isolates and other subject lineages were identified. ResultsAmong 411 sequential subjects with MRSA bacteremia, 32 experienced recurrent bacteremia episodes, with 24 subjects having exclusively relapse infections, six with infections exclusively from a new strain, and two patients with both relapse and new infections. No concordance between a genomic and a clinical definition of relapse was evident (Cohens Kappa = 0.18, CI: -0.41). Recurrence-associated lineages exhibited signatures of positive selection(G- test:<0.01) . Genes with SNPs occurring in multiple relapse lineages have roles in antibiotic resistance and virulence, including 5 lineages with mutations in mprF and 3 lineages with mutations in rpoB, which corresponded with evolved phenotypic changes in daptomycin and rifampin resistance. ConclusionsRecurrent infections have a diverse strain background. Relapses can be readily distinguished from newly acquired infections using genomic sequencing but not clinical criteria.