Proton pump inhibitors and risk of Clostridium difficile infection: a multi-country study using sequence symmetry analysis

Expert Opin Drug Saf. 2016 Dec;15(12):1589-1595. doi: 10.1080/14740338.2016.1238071. Epub 2016 Sep 27.


Objective: To determine the association between incident proton pump inhibitor (PPI) use and Clostridium difficile infections across multiple countries Method: National data covering the total population in Australia and Korea, the Canadian population over 65 years and a 3 million person random sample data set from Taiwan were assessed, as were data from a worker insurance population and a hospital inpatient/outpatient population in Japan. Sequence symmetry analysis was used to assess the association with oral vancomycin dispensing as the outcome of interest.

Results: 54,957 patients were included. Positive associations were observed in Australia; adjusted sequence ratio (ASR) 2.48 (95% CI 1.90, 3.12), Korea ASR 2.15 (95%CI 2.11, 2.19), Canada ASR 1.45 (95% CI 1.16, 1.79), Japan hospital dataset ASR 3.21 (95%CI 2.12, 4.55) and Japan worker insurance dataset ASR 5.40 (95% CI 2.73, 8.75). The pooled result was ASR 2.40 (95%CI 1.88, 3.05) and 3.16 (95%CI 1.95, 5.10) when limited to Japan, Korean and Taiwan. Results did not vary by individual PPI. The temporal analysis showed effects within the first two weeks of PPI initiation.

Conclusion: Our study confirms the association between PPI initiation and C. difficile infections across countries in the Asia-Pacific region.

Keywords: Asia; Clostridium difficile; Proton pump inhibitors; adverse event; sequence symmetry analysis.

MeSH terms

  • Aged
  • Anti-Bacterial Agents / therapeutic use
  • Clostridioides difficile / isolation & purification*
  • Clostridium Infections / drug therapy
  • Clostridium Infections / epidemiology*
  • Clostridium Infections / etiology
  • Databases, Factual
  • Humans
  • Proton Pump Inhibitors / adverse effects
  • Proton Pump Inhibitors / therapeutic use*
  • Vancomycin / therapeutic use


  • Anti-Bacterial Agents
  • Proton Pump Inhibitors
  • Vancomycin