Comparing clinical, microbiological and genetic definitions of relapse in patients with subsequent episodes of MRSA bone and joint infection

Background Differentiation of a relapse from a new infection is challenging in patients with a recurrent bone or joint infection (BJI). We compared clinical, microbiological, and genomic definitions of relapse among patients with methicillin resistant Staphylococcus aureus (MRSA) BJI. Methods All MRSA isolates obtained from BJIs between July 2018 and December 2022 from patients with at least 2 episodes of BJI from two U.S. hospitals underwent whole-genome sequencing. Distinct intrasubject lineages (ISLs) were defined as MRSA genomes from the same individual differing by <100 single nucleotide polymorphisms. Clinical, microbiological, and population genomic criteria were each separately compared to a gold standard for relapse vs. new infection of genomically defined ISLs. The level of agreement was calculated with Cohen’s kappa. A multivariable analysis was performed to define factors associated with the occurrence of recurrent episodes with different ISLs. Results We included 264 isolates from 80 subjects with a range of 2-5 episodes spanning 16 - 1,403 days. In total, 29 subjects (36%) had >1 ISL. Multilocus sequence type (ST) 8 was the most common (n=147, 55.7%). In multivariable analysis, female sex and antibiotic susceptibility differences in MRSA strains were associated with >1 ISL. Compared to the genomic definition of relapse (same ISL), the level of agreement was poor (Cohen’s kappa = -0.16) for the clinical definition, fair for the microbiological definition (Cohen’s kappa = 0.29), and substantial for the MLST definition (Cohen’s kappa = 0.63). Conclusions Clinical and microbiological criteria were not accurate in distinguishing a relapse of BJI from a new infection.