Association between gastric acid suppression and risk of primary C. diff infection

May 19, 2017

Use of gastric acid suppression medications has been associated with increased risk of primary Clostridium difficile, or C. diff, infection. But is there an association between these medications and recurrent C. diff infection as well? That was the question posed by Mayo Clinic researchers in a recent JAMA Internal Medicine article.

Gastric acid suppressant medications, including proton pump inhibitors (PPIs) and H-2 receptor blockers, are established therapies for gastroesophageal reflux disease, peptic ulcer disease or functional dyspepsia. Also available over-the-counter, these medications are sometimes prescribed for unnecessary indications, leading to overuse.

Clostridium difficile infection (CDI) is the most common cause of hospital-acquired diarrhea. Studies examining whether there's an association between use of gastric acid suppressant medications and CDI have yielded conflicting data. Some of these studies failed to control for variables such as age and comorbid conditions. However, meta-analyses and systematic reviews have demonstrated that patients exposed to PPIs are at an increased risk of primary CDI. In 2012, the Food and Drug Administration issued a warning that PPIs are associated with increased risk of CDI.

Recurrent CDI after a primary infection is a major problem, with the risk being as high as 50 to 60 percent after three or more infections. Studies attempting to establish whether there's an association between gastric acid suppression and recurrent CDI have also yielded conflicting results and a wide range of risk estimates. To better address this question, Mayo researchers performed a comprehensive, systematic review and meta-analysis.

Mayo researchers examined case control studies, cohort studies and clinical trials that included a population of patients with CDI who did or did not receive gastric acid suppressant therapy (either PPIs or H-2 receptor blockers) and evaluated the occurrence of recurrent CDI, with no restrictions on study setting (inpatient or outpatient). They excluded studies that did not evaluate recurrent CDI as an outcome, studies in which there were insufficient data to determine an estimate of an odds ratio (OR) and 95 percent confidence intervals, and those that were only available in abstract form.

Characteristics of included studies
Characteristics of included studies

Using these criteria, the meta-analysis was narrowed to include a total of 16 studies: 15 observational studies and one post hoc analysis of two clinical trials of treatment of CDI that evaluated use of gastric acid suppressants. These 16 studies involved 7,703 patients with CDI, 1,525 (19.8 percent) of whom developed recurrent CDI.


The meta-analysis yielded several key findings. "We found that use of gastric acid suppression medications is associated with a statistically significant increased risk of development of recurrent C. diff in patients with one or more prior episodes of C. diff," says Sahil Khanna, M.B.B.S., a gastroenterologist at Mayo Clinic and senior author of the study.

  • The rate of recurrent CDI in patients with gastric acid suppression was 22.1 percent (892 of 4,038 patients) compared with 17.3 percent (633 of 3,665) in patients without gastric acid suppression, which indicated an increased risk by meta-analysis (OR, 1.52; 95 percent confidence interval (CI), 1.20 to 1.94; P < 0.001).
  • There was significant heterogeneity among the studies, with an I2 value of 64 percent.
  • 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 percent CI, 1.08 to 1.76; P = 0.02).

Additional conclusions and recommendations

  • Patients who develop CDI may require discontinuation of these medications to prevent recurrence of CDI if there is no clear indication to use these medications.
  • Unnecessary use of gastric acid suppressants in both the inpatient and outpatient settings without proper indication should be limited.
  • Decreasing unnecessary use of gastric acid suppressants may help reduce the rates of primary and recurrent CDI as well as health care costs.

"If you are starting a patient on gastric acid reducing medications," advises Dr. Khanna, "whether it's for bad reflux or peptic ulcer, always think about setting a stopping point and evaluate this decision every six to 12 months, due to the potential of side effects such as primary and recurrent C. difficile infections."

Study limitations

Dr. Khanna notes that these data should be interpreted with caution, because they may be confounded due to the observational design of the individual studies. "Large, prospective studies that control for confounding variables are required to more fully understand the possible association between gastric acid suppression and recurrent C. diff infection."

The authors stress that future research should focus on evaluating the effect of concomitant use of antibiotics with PPIs, dosage and duration of gastric acid suppressants, and CDI recurrence. A randomized clinical trial evaluating the effect of continuing the use of gastric acid suppressants versus stopping them in patients with no serious indications will help to further assess the true association between gastric acid suppressants and the risk of recurrent CDI.

Clinical services and clinical trials available to patients with C. diff

Mayo Clinic has a C. difficile infection clinic, for patients with complex and recurrent infection. "Patients treated in this clinic are evaluated to see if they are candidates for stool transplant and if they would benefit from enrolling in clinical trials," explains Dr. Khanna.

Mayo Clinic researchers are conducting studies testing the use of capsules for primary CDI, phase 1 studies for recurrent CDI focusing on capsule-based treatment currently unavailable elsewhere, and upcoming phase 3 enema-based trials. Mayo researchers are also about to begin studying the use of a vaccine to prevent CDI.

For more information

Tariq R, et al. Association of gastric acid suppression with recurrent Clostridium difficile infection: A systematic review and meta-analysis. JAMA Internal Medicine. In press.

Treatment of Recurrent Clostridium Difficile Infection With RBX7455.