Abstract and Introduction
Abstract
OBJECTIVES: Observational studies suggest that proton pump inhibitors (PPIs) are a risk factor for incident Clostridium difficile infection (CDI). Data also suggest an association between PPIs and recurrent CDI, although large-scale studies focusing solely on hospitalized patients are lacking. We therefore performed a retrospective cohort analysis of inpatients with incident CDI to assess receipt of PPIs as a risk factor for CDI recurrence in this population.
METHODS: Using electronic medical records, we identified hospitalized adult patients between 1 December 2009 and 30 June 2012 with incident CDI, defined as a first positive stool test for C. difficile toxin B and who received appropriate treatment. Electronic records were parsed for clinical factors including receipt of PPIs, other acid suppression, non-CDI antibiotics, and comorbidities. The primary exposure was in-hospital PPIs given concurrently with C. difficile treatment. Recurrence was defined as a second positive stool test 15–90 days after the initial positive test. C. difficile recurrence rates in the PPI exposed and unexposed groups were compared with the log-rank test. Multivariable Cox proportional hazards modeling was performed to control for demographics, comorbidities, and other clinical factors.
RESULTS: We identified 894 inpatients with incident CDI. The cumulative incidence of CDI recurrence in the cohort was 23%. Receipt of PPIs concurrent with CDI treatment was not associated with C. difficile recurrence (hazard ratio (HR)=0.82; 95% confidence interval (CI)=0.58–1.16). Black race (HR=1.66, 95% CI=1.05–2.63), increased age (HR=1.02, 95% CI=1.01–1.03), and increased comorbidities (HR=1.09, 95% CI=1.04–1.14) were associated with CDI recurrence. In light of a higher 90-day mortality seen among those who received PPIs (log-rank P=0.02), we also analyzed the subset of patients who survived to 90 days of follow-up. Again, there was no association between PPIs and CDI recurrence (HR=0.87; 95% CI=0.60–1.28). Finally, there was no association between recurrent CDI and increased duration or dose of PPIs.
CONCLUSIONS: Among hospitalized adults with C. difficile, receipt of PPIs concurrent with C. difficile treatment was not associated with CDI recurrence. Black race, increased age, and increased comorbidities significantly predicted recurrence. Future studies should test interventions to prevent CDI recurrence among high-risk inpatients.
Introduction
Proton pump inhibitors (PPIs) are a risk factor for incident Clostridium difficile infection (CDI). PPIs are among the most common drugs in the world; in the America, esomeprazole was the third most prescribed drug by sales in 2011. They are highly effective in treating gastric acid-related disorders but are often prescribed without a documented indication. Other established risk factors for CDI include older age, antibiotics, hospitalization, and gastrointestinal tract abnormalities; PPIs appear to act synergistically with other risk factors to increase the risk of incident C. difficile among both inpatients and outpatients.
Up to 30% of patients with CDI recur after completing treatment and limited data suggests that PPIs may be a risk factor for recurrent as well as incident CDI. A study combining inpatients and outpatients at eight Veterans Affairs medical centers in New England suggested that PPIs were associated with a moderately increased risk of recurrent CDI. Two smaller studies reached similar conclusions although with heterogeneity in their estimates of risk.
The factors that influence C. difficile recurrence differs between inpatients and outpatients. Inpatients with incident CDI are older, have more comorbidities, and are more often exposed to antibiotics compared with outpatients. Inpatients with CDI are more likely to have been exposed to PPIs compared with outpatients; when PPIs are given, there are differences between inpatients and outpatients in indications for use, duration, dosage, and method of administration. Furthermore, inpatients have more severe C. difficile and are more likely to be exposed to hypervirulent subtypes such as the North American Pulsed Field type 1 strain.
For these reasons, factors that influence Clostridium difficile recurrence may have distinct strengths of association in the inpatient setting as opposed to the outpatient setting. Yet studies to date have not focused on PPIs as a risk factor for recurrence exclusively among inpatients with CDI. We therefore sought to study the relationship between in-hospital use of PPIs and recurrent CDI in a retrospective cohort analysis of inpatients with CDI.