Clinical Review

Association Between Proton Pump Inhibitor Exposure and Clostridium difficile Infection in Elderly, Hospitalized Patients

Fed Pract. 2015 November;32(11):21-25

References

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Separate models were run using each case-control pair as a separate stratum in the model (125 pairs) as well as pooling similar-age strata to reduce the 125 pairs to 46 pooled sets. However, when comparing the Akaike information criterion (AIC; an objective measure to determine relative quality of multivariate models where a lower AIC value is preferred) between these individual and pooled strata models, the model that controlled for 125 individual case-control strata was overwhelmingly suggested as the better model (AIC, 175 vs 255, respectively).²⁵ Analyses were conducted with SAS 9.2 (SAS Institute Inc., Cary, NC).

Results

A total of 128 patients were positive for CDI during the 2-year study period. Three of these patients were excluded from the study due to outpatient status. The remaining  125 patients were matched 1:1 with patients negative for CDI to yield a total study population of 250 patients.

Baseline demographics are shown in Table 1. The majority of patients included were males with a median age of 66 years. Nearly half of all patients in both groups had chronic renal failure, diabetes, or anemia. Comorbidities were numerous but were not significantly different between the positive and negative CDI groups. No significant difference in immunosuppression or PPI use was detected between the 2 groups. However, there were significantly more patients taking a high-risk antibiotic or an antineoplastic agent in the positive CDI group compared with the negative CDI group. The average length of hospital stay averaged 10 to 12 days and did not statistically differ between the 2 groups.

Crude ORs (cORs) and adjusted ORs (aORs) were calculated for the primary and secondary outcome measures (Table 2). There was not a statistically significant association between PPI use and CDI (cOR 1.10, 95% confidence interval [CI] 0.67-1.82; aOR 1.19, 95% CI 0.66-2.15). Other known risk factors were also evaluated for association. A statistically significant association did not exist between CDI and immunosuppression, antidepressant use, statin use, diabetes, chronic renal failure, liver disease, or anemia. However, the statistical analysis did suggest an association between CDI and high-risk antibiotic use (aOR 2.20, 95% CI 1.22-3.99) and antineoplastic agent use (aOR 5.52, 95% CI 1.77-17.26).

A sensitivity analysis was conducted to determine whether there were differing associations with CDI by PPI dose or specific agent. In both sensitivity analyses, there were no statistically significant differences in CDI between patients who took once-daily vs twice-daily PPI dosing or those who took pantoprazole vs omeprazole.

Discussion

The objective of this study was to evaluate the association between PPI use and CDI in an aging, hospitalized population. When adjusted for known risk factors, there was no association between CDI and patients exposed to PPI therapy.

Previous studies evaluating PPI use and CDI have shown conflicting results. Large meta-analyses have shown an increase in CDI in patients exposed to a PPI, whereas other studies have shown no association. In the studies that did not link PPI use and CDI, patients were elderly, hospitalized, and had other CDI risk factors. The patients in this study were hospitalized, with a median age of  66 years. They were significantly immunosuppressed and had a very high burden of comorbidities. A possible explanation for the lack of association between PPI use and CDI is that, in patients with several existing risk factors for CDI, adding a PPI confers no additional effect on CDI risk.

Well-known risk factors, including high-risk antibiotic use and antineoplastic chemotherapy use, were confirmed by this study. Other known risk factors, including immunosuppression and diabetes, were not observed to have an association with CDI in this study. This is perhaps for the same reason that PPI exposure did not show a significant association. In a study published in 2010, Howell and colleagues showed that the risk of CDI increased as acid suppression increased in a dose-dependent fashion.⁹There was no association between PPI dose and PPI agent on the primary outcome measure.

About half of all patients in the current study were exposed to PPI therapy, which was a surprisingly high number. Although this study did not evaluate appropriate use of PPI therapy, it exposes the high rate of PPI use at the study site. It is known that PPI use has associated risks, and it is important that physicians continue to be vigilant in their prescribing habits.

Limitations and Future Directions

Several limitations of this study should be noted. A relatively narrow patient population was examined, which limits the generalizability of these findings. However, health care providers treating older, hospitalized patients with a high burden of comorbidities may find the results meaningful. This study was retrospective and included a relatively small sample size, which may limit the ability to detect a statistically significant difference.