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We sought to determine nationwide, population-based trends in rates of Clostridium difficile (C. difficile) infection among hospitalized inflammatory bowel disease (IBD) patients in the United States, and to determine its mortality and economic impact.We analyzed discharge records from the Nationwide Inpatient Sample, and used the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes to identify Crohn's disease (CD) and ulcerative colitis (UC) cases, and cases of C. difficile infection between 1998 and 2004. Temporal patterns of C. difficile incidence in IBD patients were compared to non-IBD gastroenterology patients and all-hospitalized patients. The impact of C. difficile on in-hospital mortality and resource utilization was quantified using multiple regression analysis.The prevalence of C. difficile among UC patients (37.3 per 1,000, 95% confidence interval [CI] 34.0–40.7 per 1,000) was higher than that among CD patients (10.9 per 1,000, 95% CI 9.9–12.0 per 1,000), non-IBD gastrointestinal (GI) patients (4.8 per 1,000, 95% CI 4.6–5.0 per 1,000), and general medical patients (4.5 per 1,000, 95% CI 4.2–4.7 per 1,000). C. difficile incidence nearly doubled among UC patients (26.6 per 1,000 to 51.2 per 1,000) over 7 yr. After adjustment for confounders, C. difficile infection was associated with greater mortality among patients with UC (odds ratio [OR] 3.79, 95% CI 2.84–5.06), but not CD (OR 1.66, 95% CI 0.75–3.66). C. difficile was also associated with 65% and 46% longer lengths of stay, which correlated with 63% and 46% higher average hospital charges, for CD and UC patients, respectively.C. difficile infection is a growing public health issue among hospitalized IBD patients, especially those with UC, and is associated with higher mortality and resource utilization, prompting the need for better preventative measures and early detection.