Clostridioides difficile is an anaerobic, spore-forming, toxin-producing bacterium that is the primary cause of healthcare-associated infectious colitis worldwide [1]. The clinical spectrum of C. difficile infection (CDI) ranges from self-limiting diarrhea to fulminant pseudomembranous colitis, toxic megacolon, and death [2]. In Korea, widespread use of broad-spectrum antibiotics has increased the incidence and burden of healthcare-associated CDI [3]. Early prediction and risk stratification of severe CDI are essential for timely initiation of targeted oral vancomycin therapy [4]. A recent nationwide survey showed that most Korean physicians tailored CDI treatment according to the disease severity [5].

However, observational studies of CDI frequently suffer from circular reasoning and reverse causality. Variables such as intensive care unit (ICU) admission, length of ICU stay, and prolonged hospitalization are often inappropriately modeled as independent “risk factors” for disease severity. Because ICU admission contributes to the definition of severe-complicated CDI in the severity classification used in this study, ICU-related variables occurring at or after CDI onset cannot serve as temporal antecedent predictors of that outcome and were therefore excluded from the predictor modeling. Moreover, because total hospital stay encompasses the post-diagnostic course, it reflects disease consequences rather than antecedent causes. Eliminating these post-infection variables is important to identify independent baseline factors associated with subsequent severe CDI.

Disease severity was classified according to established criteria [6]. Severe CDI was defined as a serum albumin < 3.0 g/dL plus white blood cell (WBC) count ≥ 15,000/mm³ or abdominal tenderness. Severe-complicated CDI was defined by hypotension, fever ≥ 38.5°C, ileus, mental changes, WBC ≥ 35,000 or < 2,000/mm³, lactate > 2.2 mmol/L, end-organ failure, or ICU admission. Confirmed episodes that met neither definition were categorized as non-severe CDI (controls).

Exposure and confounding variables were distinguished using temporal and causal hierarchies. Exposure variables were defined as antecedent clinical, pharmacological, and environmental factors preceding CDI onset that directly perturb gut microbial ecology or host defenses. These included prior antimicrobial exposures within 12 weeks before diagnosis (narrow-spectrum cephalosporins, extended-spectrum cephalosporins, β-lactamase inhibitor combinations, carbapenems, fluoroquinolones, teicoplanin, penicillin), a history of prior recurrent CDI episodes, healthcare-associated acquisition (symptom onset > 48 h after admission or within 4 weeks of discharge), and concomitant proton pump inhibitor use. Recurrence after the index CDI episode was not included in this variable.

Confounding variables were defined as pre-existing host characteristics and chronic comorbidities that independently influence both the propensity for high-risk antibiotic exposure and host vulnerability to severe infection without acting as direct causal intermediates: baseline age (continuous years), sex (male vs. female), Charlson comorbidity index (CCI) [7], and specific chronic medical conditions verified using standardized diagnostic codes in Korean healthcare databases (chronic renal disease, pneumonia, cerebrovascular disease, malignancy, diabetes mellitus, heart failure, chronic respiratory disease, atherosclerosis, biliary tract disease, liver cirrhosis, and nutritional deficiency) [8]. The CCI was used for descriptive characterization but was not entered simultaneously with individual component comorbidities in the multivariable model to avoid redundant adjustment.

ICU and total hospital stays were classified as post-infection clinical courses and intermediate outcomes, and both were strictly excluded from the multivariable baseline risk-factor association model.

Clinicians should maintain heightened vigilance regarding severe CDI when treating patients with chronic kidney disease, prior CDI history, or recent exposure to β-lactamase inhibitor combinations, narrow-spectrum cephalosporins, or teicoplanin. These high-risk individuals may warrant closer clinical monitoring and prompt assessment of CDI severity to guide treatment in accordance with the current clinical guidelines. These findings support continued antimicrobial stewardship and appropriate de-escalation of broad-spectrum antimicrobial therapy when clinically feasible.

The Institutional Review Board of the National Health Insurance Service Ilsan Hospital approved this retrospective cohort study (approval number: NHIMC 2024-03-043) and waived the requirement for informed consent because anonymized data were used.