Burden of Clostridioides difficile Infection and Risk Factors for Recurrences in an Italian Tertiary Care University Hospital: A Prospective Observational Study

<b>Background:</b><i>Clostridioides difficile</i> infection (CDI) remains a challenging condition, particularly in severe or recurrent cases. This study aimed to identify factors associated with recurrent CDI (rCDI), severe disease (defined by ZAR score or ESCMID criteria), death during CDI, and bloodstream infections (BSI) or candidemia within 8 weeks of CDI onset. <b>Methods:</b> We conducted a prospective study at an Italian university hospital that included all adult CDI cases diagnosed between November 2022 and December 2024. Statistical analyses were performed with IBM SPSS Statistics. A <i>p</i>-value < 0.05 was considered statistically significant in univariate analyses. For the multivariable analysis, we selected the variables that were statistically significant in the univariate analysis and considered the most clinically relevant. <b>Results:</b> A total of 161 CDI cases were identified. Recurrence occurred in 13%, higher than the 4% reported in a previous retrospective cohort at the same center (2013-2022). In univariate analysis, independent predictors of recurrent CDI (rCDI) were therapeutic regimens including oral vancomycin (<i>p</i> = 0.008; OR 6.17; 95% CI 1.36-27.97), peripheral vascular disease (PVD) (<i>p</i> < 0.001; OR 5.92; 95% CI 2.07-16.94), and dysphagia (<i>p</i> = 0.034; OR 4.61; 95% CI 1.25-17.07), whereas fidaxomicin use was associated with a protective effect (<i>p</i> = 0.016; OR 0.17; 95% CI 0.04-0.78). In multivariable analysis, oral vancomycin use (<i>p</i> = 0.008; OR 15.03) and peripheral vascular disease (<i>p</i> = 0.002; OR 7.27) remained independently associated with rCDI. Overall, 15 of 161 patients (9.3%) died during the CDI episode (either presenting CDI or rCDI), with all deaths directly attributable to CDI. Mortality during CDI was associated with age > 77 years (median value of the study population), transfer from a nursing home or long-term care facility within the previous 3 months, lymphoma, hematological malignancy, peripheral vascular disease, connective tissue disease, immobilization syndrome, dysphagia, elevated lactate levels (>1 mmol/L), septic shock, severe or severe-complicated CDI according to ESCMID criteria, severe-complicated CDI according to ESCMID criteria, leukocytosis (WBC > 15,000/mm³) during CDI, ZAR score ≥ 2, concomitant BSI, and concomitant pneumonia. During follow-up, 11 of 127 (8.7%) patients developed a BSI. BSI was associated with corticosteroid use and osteomyelitis. Only four patients developed candidemia due to <i>Candida albicans</i> during follow-up. <b>Conclusions:</b> Our study confirms that <i>Clostridioides difficile</i> infection remains a major clinical challenge, particularly due to its high recurrence rate and the burden of severe forms. The evidence strongly supports the preferential use of fidaxomicin, which should now be regarded as the standard of reference in clinical practice.