A multisite genomic epidemiology study of Clostridioides difficile infections in the USA supports differential roles of healthcare versus community spread for two common strains

is the leading cause of healthcare-associated infectious diarrhoea. However, it is increasingly appreciated that healthcare-associated infections derive from both community and healthcare environments, and that the primary sites of transmission may be strain-dependent. We conducted a multisite genomic epidemiology study to assess differential genomic evidence of healthcare vs community spread for two of the most common strains in the USA: sequence type (ST) 1 (associated with ribotype 027) and ST2 (associated with ribotype 014/020). We performed whole-genome sequencing and phylogenetic analyses on 382 ST1 and ST2 isolates recovered from stool specimens collected during standard clinical care at 3 geographically distinct US medical centres between 2010 and 2017. ST1 and ST2 isolates both displayed some evidence of phylogenetic clustering by study site, but clustering was stronger and more apparent in ST1, consistent with our healthcare-based study more comprehensively sampling local transmission of ST1 compared to ST2 strains. Analyses of pairwise single-nucleotide variant (SNV) distance distributions were also consistent with more evidence of healthcare transmission of ST1 compared to ST2, with 44 % of ST1 isolates being within two SNVs of another isolate from the same geographical collection site compared to 5.5 % of ST2 isolates ( -value=