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Sandra Dial, MD, MSc; J. A. C. Delaney, MSc; Alan N. Barkun, MD, MSc; Samy Suissa, PhD

JAMA. 2005;294:2989-2995.

Context  Recent reports suggest an increasing occurrence and severity of Clostridium difficile–associated disease. We assessed whether the use of gastric acid–suppressive agents is associated with an increased risk in the community.

Objective  To determine whether the use of gastric acid–suppressive agents increases the risk of C difficile–associated disease in a community population.

Design, Setting, and Patients  We conducted 2 population-based case-control studies using the United Kingdom General Practice Research Database (GPRD). In the first study, we identified all 1672 cases of C difficile recorded between 1994 and 2004 among all patients registered for at least 2 years in each practice. Each case was matched to 10 controls on calendar time and the general practice. In the second study, a subset of these cases defined as community-acquired, that is, not hospitalized in the prior year, were matched on practice and age with controls also not hospitalized in the prior year.

Main Outcome Measures  The incidence of C difficile and risk associated with gastric acid–suppressive agent use.

Results  The incidence of C difficile in patients diagnosed by their general practitioners in the General Practice Research Database increased from less than 1 case per 100 000 in 1994 to 22 per 100 000 in 2004. The adjusted rate ratio of C difficile–associated disease with current use of proton pump inhibitors was 2.9 (95% confidence interval [CI], 2.4-3.4) and with H₂-receptor antagonists the rate ratio was 2.0 (95% CI, 1.6-2.7). An elevated rate was also found with the use of nonsteroidal anti-inflammatory drugs (rate ratio, 1.3; 95% CI, 1.2-1.5).

Conclusions  The use of acid-suppressive therapy, particularly proton pump inhibitors, is associated with an increased risk of community-acquired C difficile. The unexpected increase in risk with nonsteroidal anti-inflammatory drug use should be investigated further.

Author Affiliations: Division of Critical Care and Respiratory and Clinical Research (Dr Dial); Division of Clinical Epidemiology (Mr Delaney and Dr Suissa); Divisions of Gastroenterology and Clinical Epidemiology, McGill University Health Centre (Dr Barkun); Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec (Mr Delaney and Drs Barkun and Suissa).

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