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Ultrasensitive, quantitative Clostridioides difficile stool toxin measurement demonstrated significantly higher concentrations of toxins A and B in patients infected with the North American pulsed-field gel electrophoresis type 1/ribotype 027 (NAP-1/027) strain compared with other strains, providing in vivo confirmation of the in vitro association between NAP-1/027 and elevated toxin production., Competing Interests: Potential conflicts of interest . C. D. A. has received grant support from Merck (investigator-initiated award, paid to their institution) and an NIH Loan Repayment Award, outside the submitted work. C. P. K. reports stock ownership options with First Light; has served as an investigator for a Pfizer-sponsored research study; has served as an investigator for a Merck-sponsored research study; has served as an investigator for a Janssen-sponsored research study; has acted as a paid consultant to Artugen (scientific advisor on clinical and clinical research aspects of Clostridioides difficile infection [CDI]), Facile Therapeutics (scientific advisor on clinical and clinical research aspects of CDI), Ferring (scientific advisor on clinical and clinical research aspects of CDI), First Light Biosciences (scientific advisor on clinical and clinical research aspects of diagnosis of CDI), Finch (scientific advisor on clinical and clinical research aspects of CDI), Janssen (J&J) (scientific advisor on clinical and research aspects of CDI), Matrivax (scientific advisor on C. difficile vaccine development), Merck (scientific advisor on clinical and research aspects of CDI), Seres, Pfizer (scientific advisor on C. difficile vaccine development), and Vedanta (scientific advisor on clinical and clinical research aspects of CDI). K. W. G. has received grant support from Acurx, Paratek, Summit, and Tetraphase Pharmaceuticals (research grants paid to the university) and has received consulting fees from Acurx and Summit Pharmaceuticals. M. M., A. F., A. L., and A. B. are employees of bioMérieux. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Stool toxin concentrations may impact Clostridioides difficile infection (CDI) severity and outcomes. We correlated fecal C difficile toxin concentrations, measured by an ultrasensitive and quantitative assay, with CDI baseline severity, attributable outcomes, and recurrence., Methods: We enrolled 615 hospitalized adults (≥18 years) with CDI (acute diarrhea, positive stool nucleic acid amplification testing, and decision to treat). Baseline stool toxin A and B concentrations were measured by single molecule array. Subjects were classified by baseline CDI severity (4 scoring methods) and outcomes within 40 days (death, intensive care unit stay, colectomy, and recurrence)., Results: Among 615 patients (median, 68.0 years), in all scoring systems, subjects with severe baseline disease had higher stool toxin A+B concentrations than those without (P < .01). Nineteen subjects (3.1%) had a severe outcome primarily attributed to CDI (group 1). This group had higher median toxin A+B (14 303 pg/mL [interquartile range, 416.0, 141 967]) than subjects in whom CDI only contributed to the outcome (group 2, 163.2 pg/mL [0.0, 8423.3]), subjects with severe outcome unrelated to CDI (group 3, 158.6 pg/mL [0.0, 1795.2]), or no severe outcome (group 4, 209.5 pg/mL [0.0, 8566.3]) (P = .003). Group 1 was more likely to have detectable toxin (94.7%) than groups 2-4 (60.5%-66.1%) (P = .02). Individuals with recurrence had higher toxin A+B (2266.8 pg/mL [188.8, 29411]) than those without (154.0 pg/mL [0.0, 5864.3]) (P < .001) and higher rates of detectable toxin (85.7% versus 64.0%, P = .004)., Conclusions: In CDI patients, ultrasensitive stool toxin detection and concentration correlated with severe baseline disease, severe CDI-attributable outcomes, and recurrence, confirming the contribution of toxin quantity to disease presentation and clinical course., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Clostridioides difficile infection (CDI) is caused by Toxins A and B, secreted from pathogenic strains of C. difficle. This infection can vary greatly in symptom severity and in clinical presentation. Current assays used to diagnose CDI may lack the required sensitivity to detect the exotoxins circulating in blood. The ultrasensitive single molecule array (Simoa) assay was modified to separately detect toxin A and toxin B in serum with a limit of detection at the low picogram level. When applied to a diverse cohort, Simoa was unable to detect toxins A or B in serum from patients with CDI, including many classified as having severe disease. The detection of toxin may be limited by the inference of antitoxin antibodies circulating in serum. This result does not support the hypothesis that toxemia occurs in C. difficile infection, conflicting with the findings of other published reports., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)