Background: Clostridium difficile infection (CDI) is a leading cause of healthcare-associated diarrhea worldwide. In this study, risk factors associated with the development of severe-complicated and recurrent outcomes in CDI patients in different age groups, including the non-elderly, were assessed in a third-level hospital. Methods: CDI cases were detected by clinical data and polymerase-chain-reaction (PCR). Clinical, demographic, epidemiological, and microbiological risk factors for CDI were evaluated. Results: During the study period, 248 out of 805 patients with nosocomial diarrhea were diagnosed with CDI and the majority were severe-complicated cases (87.90%). Female gender (OR 3.19, 95% CI 1.19–8.55, p = 0.02) and lymphoma (OR 3.95, 95% CI 1.03–15.13, p = 0.04) were risk factors for severe-complicated CDI. Mature adulthood (51–60 years) (OR 5.80, 95% CI 1.56–21.62, p = 0.01), previous rifampicin use (OR 7.44, 95% CI 2.10–26.44, p = 0.00), and neoplasm (solid malignant neoplasm or hematological malignancies) (OR 4.12, 95% CI 1.01–16.83, p = 0.04) were risk factors for recurrent infection. Autoimmune disorders (OR 6.62, CI 95% 1.26–34.73, p = 0.02), leukemia (OR 4.97, 95% CI 1.05–23.58, p = 0.04), lymphoma (OR 3.79, 95% CI 1.03–12.07, p = 0.04) and previous colistin treatment (OR 4.97, 95% CI 1.05–23.58, p = 0.04) were risk factors for 30-day mortality. Conclusion: Newly identified risk factors for recurrent CDI were rifampicin treatment and age between 51 and 60 years; colistin treatment was identified as a risk factor for 30-day mortality. Previously identified risk factors for severe-complicated CDI were confirmed, but with a major impact on non-elderly patients.
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