Laboratory-Detected Clostridioides difficile Stool-Test Positivity and Mortality in Sepsis: A Retrospective Cohort Study.

BACKGROUND: Sepsis disrupts intestinal microbiota, and broad-spectrum antibiotics may worsen dysbiosis. Clostridioides difficile (C. difficile) infection (CDI) is a prevalent nosocomial enteric pathogen among critically ill patients, yet its prognostic implications in sepsis remain inadequately studied. METHODS: We retrospectively analyzed 13,484 adult sepsis hospitalizations from MIMIC-IV. The exposure was any laboratory-detected C. difficile-positive stool test during the index hospitalization. Cox regression, detailed early-antibiotic adjustment, stabilized inverse probability weighting, timing- and assay-based sensitivity analyses, and a post hoc nested-model comparison assessed association and incremental prediction. Archived positive-subgroup machine-learning models were retained as exploratory risk-stratification analyses. RESULTS: Detailed early-antibiotic adjustment substantially attenuated the association: the 30-day hazard ratio (HR) was 0.98 (95% CI, 0.87-1.11; p = 0.767) and the 90-day HR was 1.08 (95% CI, 0.99-1.18; p = 0.103). Early, landmark, PCR-only, and toxin-positive analyses were also nonsignificant, whereas the stabilized-weighted 90-day estimate remained modest (HR, 1.13; 95% CI, 1.03-1.24; p = 0.010), indicating inconsistency across analyses. Predictive models showed strong performance (C-index: 0.81 for in-hospital mortality; 0.68 for 30-day mortality). CONCLUSIONS: While laboratory-detected C. difficile stool-test positivity is associated with worse unadjusted outcomes in sepsis, this relationship is substantially attenuated and inconsistent after rigorous adjustment. Accordingly, laboratory positivity may serve as a marker of a complex clinical phenotype. Evidence for its independent prognostic utility remains limited, and its incremental predictive value beyond conventional severity measures is minimal.