Contribution to Clostridium Difficile Transmission of Symptomatic Patients With Toxigenic Strains Who Are Fecal Toxin Negative

Background: The role of symptomatic patients who are toxigenic strain positive (TS+) but fecal toxin negative (FT-) in transmission of Clostridium difficile is currently unknown. Methods: We investigated the contribution of symptomatic TS+/FT- and TS+/FT+ patients in C. difficile transmission in 2 UK regions. From 2-step testing, all glutamate dehydrogenase (GDH)-positive specimens, regardless of fecal toxin result, from Oxford (April 2012 through April 2013) and Leeds (July 2012 through April 2013) microbiology laboratories underwent culture and whole-genome sequencing (WGS), using WGS to identify toxigenic strains. Plausible sources for each TS+/FT+ case, including TS+/FT- and TS+/FT+ patients, were determined using WGS, with and without hospital admission data. Results: A total of 1447 of 12772 (11%) fecal samples were GDH positive, 866 of 1447 (60%) contained toxigenic C. difficile, and fecal toxin was detected in 511 of 866 (59%), representing 235 Leeds and 191 Oxford TS+/FT+ cases. TS+/FT+ cases were 3 times more likely to be plausibly acquired from a previous TS+/FT+ case than a TS+/FT- patient. Fifty-one of 265 (19%) TS+/FT+ cases diagnosed >3 months into the study were genetically related (≤2 single-nucleotide polymorphisms) to ≥1 previous TS+/FT+ case or TS+/FT- patient: 27 (10%) to only TS+/FT+ cases, 9 (3%) to only TS+/FT- patients, and 15 (6%) to both. Only 10 of 265 (4%) were genetically related to a previous TS+/FT+ or TS+/FT- patient and shared the same ward simultaneously or within 28 days. Conclusions: Symptomatic TS+/FT- patients were a source of C. difficile transmission, although they accounted for less onward transmission than TS+/FT+ cases. Although transmission from symptomatic patients with either fecal toxin status accounted for a low overall proportion of new cases, both groups should be infection control targets.