Clostridioides difficile infections and beyond: molecular epidemiology, One Health transmission chains, under-surveilled regions, and the next generation of diagnostics, therapeutics, and vaccines
Year: 2026
Type: review
Abstract: Clostridioides difficile infection (CDI) remains the leading cause of healthcare-associated diarrhea and an urgent antimicrobial resistance threat, but the organism clinicians now face differs from the one that drove the ribotype 027 epidemics. This review is organized around a single question: which parts of the C. difficile transmission and treatment cycle are invisible to the methods used to observe them? Four developments define the answer. First, whole-genome sequencing consistently identifies genomic links between hospital cases that ward-based contact tracing cannot reconcile, and isolates from asymptomatically colonized patients are linked to subsequent cases as often as those from symptomatic patients, in some instances many months after an index encounter; we read a four-year single-center study from Guangzhou, China, in which one author participated, alongside comparable cohorts from England, Denmark and Canada. Second, One Health genomics places human and non-human compartments within a single transmission network, though the direction of transfer and the attributable fraction of human disease remain unquantified. Sequence type 11 and its ribotype 078 sublineage circulate between livestock and humans at clonal resolution, cryptic clades meet species-level divergence thresholds, and community-associated disease accounts for roughly a third of cases. Third, resistance to first-line therapy now has defined molecular mechanisms, including plasmid-borne and heme-dependent metronidazole resistance, constitutive vanG expression underlying reduced vancomycin susceptibility, and RNA polymerase substitutions conferring reduced fidaxomicin susceptibility that emerge during treatment; several of these are undetectable under standard laboratory conditions. Fourth, pathogenesis is being reframed as polymicrobial, with enterococci cross-feeding leucine and ornithine while depleting arginine as a virulence cue. We integrate these strands with age-stratified vulnerability in older and pediatric patients, with the diagnostic problem of separating infection from colonization, and with the diverging regulatory frameworks that now separate donor-derived fecal microbiota transplantation from licensed live biotherapeutic products.
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7222956168