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Original Investigation
June 2017

Association of Gastric Acid Suppression With Recurrent Clostridium difficile InfectionA Systematic Review and Meta-analysis

Author Affiliations
  • 1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
  • 2Division of Gastroenterology and Hepatology, University of California, San Diego, La Jolla
  • 3Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota
JAMA Intern Med. 2017;177(6):784-791. doi:10.1001/jamainternmed.2017.0212
Key Points

Question  Does concomitant use of gastric acid suppressant medications (proton pump inhibitors and histamine H2 receptor blockers) increase the risk of recurrent Clostridium difficile infection?

Findings  In this meta-analysis of 16 studies comprising 7703 patients, the use of gastric acid suppressants was associated with a significantly increased risk of recurrent C difficile infection. Subgroup analyses of studies with potential confounders also confirmed an increased risk of recurrent C difficile infection with use of these medications.

Meaning  It may be reasonable to stop gastric acid suppressants in patients with C difficile infection; limiting unnecessary use of these medications may help to decrease both recurrent C difficile infection and health care costs.


Importance  Gastric acid suppression has been associated with an increased risk of primary Clostridium difficile infection (CDI), but the risk of recurrent CDI in patients taking gastric acid suppressant medications is unclear.

Objective  To perform a systematic review and meta-analysis to evaluate the association between gastric acid suppressants and recurrent CDI.

Data Sources  MEDLINE, EMBASE, the Cochrane Central Register, the Cochrane Database, and Web of Science were searched from January 1, 1995, to September 30, 2015, for studies assessing the association between gastric acid suppressant exposure and recurrent CDI. Search terms included Clostridium difficile, pseudomembranous colitis, proton pump inhibitor, and histamine H2 blocker.

Study Selection  Case-control studies, cohort studies, and clinical trials that included patients with CDI who did or did not receive gastric acid suppressant therapy and who were evaluated for recurrent CDI were included, with no restriction on study setting (inpatient or outpatient).

Data Extraction and Synthesis  The Newcastle-Ottawa scale was used to assess the methodologic quality of included studies. In this scale, case-control and cohort studies were scored on selection, comparability, and ascertainment of the outcome of interest. Data were independently abstracted to a predetermined collection form by 2 investigators. Summary odds ratio estimates with 95% CIs were calculated using the random-effects model and software to calculate the pooled effect size of studies reporting multivariate analyses.

Main Outcomes and Measures  Risk of recurrent infection in patients with CDI and its association with use of gastric acid suppressant medication.

Results  Sixteen observational studies were included, together reporting 7703 patients with CDI; among these, 1525 patients (19.8%) developed recurrent CDI. The rate of recurrent CDI in patients with gastric acid suppression was 22.1% (892 of 4038 patients) compared with 17.3% (633 of 3665) in patients without gastric acid suppression, which indicated an increased risk by meta-analysis (odds ratio [OR], 1.52; 95% CI, 1.20-1.94; P < .001). There was significant heterogeneity among the studies, with an I2 value of 64%. Subgroup analyses of studies adjusting for age and potential confounders confirmed an increased risk of recurrent CDI with use of gastric acid suppressants (OR, 1.38; 95% CI, 1.08-1.76; P = .02).

Conclusions and Relevance  Meta-analyses of observational studies suggest that patients who receive gastric acid suppressants may be at increased risk for recurrent CDI. These data should be interpreted with caution because they may be confounded owing to the observational design of the individual studies. It may be reasonable to re-evaluate the need for these medications in patients with CDI.