Proton-pump inhibitors and the risk of Clostridium difficile–associated diarrhea in high-risk antibiotics users: A population-based case-crossover study

Purpose: Given the severity and high-costs demand of Clostridium difficile–associated diarrhea (CDAD), management of risk factors is very important. Although the association between proton-pump inhibitors (PPIs) and CDAD has been established, little is known among high-risk antibiotics users. This study aimed to identify the association between PPIs and CDAD in high-risk antibiotics users by using a case-crossover design. Methods: We conducted a case-crossover study using a nationwide population-based cohort in South Korea. Participants who developed CDAD from 1 January 2003 to 31 December 2013 and had prior prescription records of both PPIs and high-risk antibiotics were included. The hazard period was 49 days, and the three prior control periods had the same duration as the hazard period. The status of exposure to PPIs was assessed during the hazard and control periods in each patient and discordant pairs of exposure were used to estimate the matched odds ratio (OR). Results: In total, 200 participants with CDAD who had histories of both PPIs and high-risk antibiotics use were included. A twofold increased risk for CDAD due to PPI use was observed (OR = 2.0; 95% confidence interval, 1.2-3.2). The time-invariant variables including age group, sex, and comorbidities were proven not to modify the association between PPIs and CDAD. Conclusions: Our study suggested that PPIs increase the risk of developing CDAD in high-risk antibiotics users. Thus, PPIs should be used cautiously in patients requiring high-risk antibiotics in the situation of medical treatment to prevent further incidence of CDAD.