Review
Association Between Proton Pump Inhibitor Therapy and Clostridium difficile Infection in a Meta-Analysis

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Background & Aims

In the past decade, there has been a growing epidemic of Clostridium difficile infection (CDI). During this time, use of proton pump inhibitors (PPIs) has increased exponentially. We evaluated the association between PPI therapy and the risk of CDI by performing a meta-analysis.

Methods

We searched MEDLINE and 4 other databases for subject headings and text words related to CDI and PPI in articles published from 1990 to 2010. All observational studies that investigated the risk of CDI associated with PPI therapy and used CDI as an end point were considered eligible. Two investigators screened articles independently for inclusion criteria, data extraction, and quality assessment; disagreements were resolved based on consensus with a third investigator. Data were combined by means of a random-effects model and odds ratios were calculated. Subgroup and sensitivity analyses were performed based on study design and antibiotic use.

Results

Thirty studies (25 case-control and 5 cohort) reported in 29 articles met the inclusion criteria (n = 202,965). PPI therapy increased the risk for CDI (odds ratio, 2.15, 95% confidence interval, 1.81–2.55), but there was significant heterogeneity in results among studies (P < .00001). This association remained after subgroup and sensitivity analyses, although significant heterogeneity persisted among studies.

Conclusions

PPI therapy is associated with a 2-fold increase in risk for CDI. Because of the observational nature of the analyzed studies, we were not able to study the causes of this association. Further studies are needed to determine the mechanisms by which PPI therapy might increase risk for CDI.

Section snippets

Methods

All procedures used in this meta-analysis were consistent with Preferred Reporting Items for Systematic reviews and Meta-analyses guidelines.8

Study Characteristics

Of the 688 references identified, 109 potentially relevant citations were selected based on relevance to the study topic. After screening all the titles and abstracts, 51 articles were selected for full-text review (Figure 1). Twenty-nine articles that reported PPI therapy and CDI published between 1990 and 2010 were included in the meta-analysis. Twenty-two articles were excluded (reasons for exclusion are listed in Figure 1). Table 1 summarizes the main characteristics of the included

Discussion

We found an association between CDI and PPI therapy in our meta-analysis involving 30 studies and 202,965 patients. Overall, patients on PPI therapy have approximately twice the risk of developing CDI compared with nonusers. However, the significant heterogeneity amongst the studies implies that the summary OR should be interpreted with caution. On subgroup and sensitivity analyses, the positive association between PPI therapy and the risk of CDI remained; significant heterogeneity persisted

Acknowledgments

A.D., C.P., and V.P. contributed equally to this work.

References (49)

  • M.B. Cohen

    Clostridium difficile infections: emerging epidemiology and new treatments

    J Pediatr Gastroenterol Nutr

    (2009)
  • A. Deshpande et al.

    Do fluoroquinolones predispose patients to Clostridium difficile associated disease?A review of the evidence

    Curr Med Res Opin

    (2008)
  • C. Pant et al.

    Does PPI therapy predispose to Clostridium difficile infection?

    Nat Rev Gastroenterol Hepatol

    (2009)
  • D. Moher et al.

    Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

    PLoS Med

    (2009)
  • D.F. Stroup et al.

    Meta-analysis of observational studies in epidemiology: a proposal for reportingMeta-analysis Of Observational Studies in Epidemiology (MOOSE) group

    JAMA

    (2000)
  • R.M. Klok et al.

    Meta-analysis: comparing the efficacy of proton pump inhibitors in short-term use

    Aliment Pharmacol Ther

    (2003)
  • J.P. Higgins et al.

    Quantifying heterogeneity in a meta-analysis

    Stat Med

    (2002)
  • S. Dial et al.

    Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies

    CMAJ

    (2004)
  • C. Williams et al.

    Review article: proton pump inhibitors and bacterial overgrowth

    Aliment Pharmacol Ther

    (2006)
  • M.D. Howell et al.

    Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection

    Arch Intern Med

    (2010)
  • K.J. Walker et al.

    Clostridium difficile colonization in residents of long-term care facilities: prevalence and risk factors

    J Am Geriatr Soc

    (1993)
  • J. Leonard et al.

    Systematic review of the risk of enteric infection in patients taking acid suppression

    Am J Gastroenterol

    (2007)
  • S. Janarthanan et al.

    A meta-analysis of 16 observational studies on proton pump inhibitor use and risk of Clostridium difficile associated diarrhea

    Am J Gastroenterol

    (2009)
  • B.R. Dalton et al.

    Proton pump inhibitors increase significantly the risk of Clostridium difficile infection in a low-endemicity, non-outbreak hospital setting

    Aliment Pharmacol Ther

    (2009)
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    Conflicts of interest The authors disclose no conflicts.

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