A Genomic Analysis of Community-Associated C. difficile Infection Demonstrates Integration With National and International Strain Clusters and Limited Direct Transmission

BACKGROUND: Clostridioides difficile is a life-threatening gastrointestinal infection. Once predominantly associated with healthcare exposure, community-associated C. difficile infections (CA-CDI) now account for more than half of U.S. cases, and sources and transmission dynamics remain poorly defined. METHODS: We sequenced 454 C. difficile isolates, collected over a 6-month period, from CDI cases through labs serving the Greater Rochester, NY area. Cases were classified as CA or healthcare-associated (HCA) using standardized definitions. Potential transmission pairs were defined as isolates separated by 0-1 core single nucleotide polymorphism. Genomic and epidemiologic data were linked to characterize strain diversity, relatedness, and transmission patterns within the community and between community and healthcare settings. Residential addresses were geocoded to assess geographic clustering. RESULTS: Community-associated-CDI cases showed no geographic clustering and exhibited substantial genomic diversity, comprising 58 multilocus sequence types (MLST). Overall, CA isolates were less closely related than HCA isolates, although analysis by MLST revealed lineage-specific patterns. Nine closely related pairs were identified among community isolates, consistent with possible transmission. Most local genomic clusters were embedded within large, geographically diverse clades that included clinical and environmental isolates from other regions. CONCLUSIONS: Community-associated-CDI appears to arise from multiple heterogeneous sources, with transmission varying by strain type and limited evidence of direct transmission. Most isolates clustered within geographically widespread clades, consistent with repeated introductions from reservoirs, such as environmental, animal and food sources rather than sustained local spread highlighting the importance of epidemiologic context when interpreting genomic relatedness. These findings support a One Health approach to understanding CA-CDI spread.