1. In this systematic review and meta-analysis of observational data, gastric acid suppression was associated with increased risk of recurrent Clostridium difficile infection (CDI).
2. Gastric acid suppression’s link with recurrent CDI was observed in subgroup analysis of studies that examined only proton-pump inhibitors, but not in studies that included H2-receptor blockers. CDI detection by ELISA was also more strongly linked to gastric acid suppression than PCR assays.
Evidence Rating Level: 2 (Good)
Study Rundown: Clostridium difficile infection is becoming increasingly prevalent in both healthcare facilities and the community, and results in significant cost, morbidity, and death. Medications for gastric acid suppression such as proton-pump inhibitors (PPIs) and H2-receptor blockers (H2Bs) have been described as risk factors for primary CDI, though associations are often confounded by age and comorbid conditions. This study sought to evaluate the risk of recurrent CDI with gastric acid suppression through systematic review and meta-analysis of available studies.
Overall, the rate of recurrent CDI in patients with gastric acid suppression was increased compared to patients who are not on these agents. This remained significant after adjusting for known confounders. The included studies were significantly heterogeneous, with variation in techniques to test for presence of C. diff, timeline definitions for “recurrent” CDI, and choice of medications evaluated. Only studies that focused on PPIs remained significant, while studies that examined both PPIs and H2Bs did not demonstrate any increased risk of recurrent CDI. The evaluation for known covariates for CDI and gastric acid suppression use, and adjustment for these factors in the analysis was the main strength of this study. The limitations of this study include the heterogeneity in study design and outcome definitions. The lack of data on antibiotic use or the dose and duration for gastric acid suppressive agents also limit the generalizability of the results.
In-Depth [systematic review and meta-analysis]: This study undertook systematic review to obtain case-control, cohort, and clinical trials from 1995 to 2015 that included patients with CDI who did or did not receive gastric acid suppression therapy, and evaluated for recurrent CDI. Studies were excluded if there was insufficient data to determine odds ratios for recurrence. Primary outcome was recurrent CDI, but included many studies with varied definitions for recurrent infections (e.g. within 30, 56, 60, or 90 days).
A total of 16 studies were included, consisting of 15 observational studies and one post-hoc analysis of 2 clinical trials. Together these studies represented 7703 patients with CDI, 52.4% of whom were receiving gastric acid suppression. Rate of recurrent CDI was 22.1% in those receiving acid suppression and 17.3% in those who did not (OR 1.52, 95%CI 1.20-1.94). Controlling for covariates including age and comorbid conditions yielded an adjusted odds ratio of 1.38 (95%CI 1.08-1.76), suggesting higher rates of recurrent CDI among those on acid suppression therapy. In studies where H2Bs were included, there was no significant association with recurrent CDI, while studies that only evaluated PPIs still demonstrated significant association (OR 1.66, 95%CI 1.18-2.34). Use of ELISA to detect C. difficile was also found to preserve the observed association (OR 2.54, 95%CI 1.76-3.67), while PCR assays did not.
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