Review | Published:

Clostridium difficile-Associated Diarrhea and Proton Pump Inhibitor Therapy: A Meta-Analysis

The American Journal of Gastroenterology volume 107, pages 10011010 (2012) | Download Citation

Abstract

OBJECTIVES:

Clostridium difficile-associated diarrhea (CDAD) is a major cause of morbidity and increasing health-care costs among hospitalized patients. Although exposure to antibiotics remains the most documented risk factor for CDAD, attention has recently been directed toward a plausible link with proton pump inhibitors (PPIs). However, the results of studies on the association between CDAD and PPIs remain controversial. We have conducted a meta-analysis to summarize the association between PPIs and CDAD among hospitalized patients.

METHODS:

A systematic search of published literature on studies that investigated the association between PPIs and CDAD from 1990 to 2010 was conducted on Medline and PubMed. The identified articles were reviewed for additional references. The most adjusted risk estimates were extracted by two authors and summarized using random effects meta-analysis. We also conducted a subgroup analysis by study design. Publication bias was evaluated using the Begg and Egger tests. A sensitivity analysis using the Duval and Tweedie “trim-and-fill” method has also been performed.

RESULTS:

Twenty-three studies including close to 300,000 patients met the inclusion criteria. There was a 65% (summary risk estimate 1.69 with a 95% confidence interval (CI) from 1.395 to 1.974; P<0.000) increase in the incidence of CDAD among patients on PPIs. By study design, whether case–control study (17) or cohort study (6), there was still a significant increase in the incidence of CDAD among PPI users. The risk estimates were 2.31 (95% CI from 1.72 to 3.10; P<0.001) and 1.48 (95% CI from 1.25 to 1.75; P<0.001) for cohort and case–control studies, respectively.

CONCLUSIONS:

There is sufficient evidence to suggest that PPIs increase the incidence of CDAD. Our meta-analysis shows a 65% increase in the incidence of CDAD among PPI users. We recommend that the routine use of PPIs for gastric ulcer prophylaxis should be more prudent. Establishing a guideline for the use of PPI may help in the future with the judicious use of PPIs. Further studies, preferably prospective, are needed to fully explore the association between PPIs and CDAD.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , . The challenges posed by reemerging Clostridium difficile infection. Clin Infect Dis 2007;45:222–227.

  2. 2.

    . Playing host to the difficult Clostridium. Clin Gastroenterol Hepatol 2007;5:912–914.

  3. 3.

    , , et al. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis 2002;34:346–353.

  4. 4.

    , . Clostridium difficile-associated diarrhea in adults. CMAJ 2004;171:51–58.

  5. 5.

    , . Clostridium difficile infection associated with antineoplastic chemotherapy: a review. Clin Infect Dis 1993;17:109–113.

  6. 6.

    . Risk factors for Clostridium difficile infection. J Hosp Infect 1998;40:1–15.

  7. 7.

    . Update on the changing epidemiology of Clostridium difficile-associated disease. Nat Clin Pract Gastroenterol Hepatol 2008;5:40–48.

  8. 8.

    , , et al. Rising economic impact of clostridium difficile-associated disease in adult hospitalized patient population. Infect Control Hosp Epidemiol 2008;29:823–828.

  9. 9.

    , , et al. The emerging infectious challenge of clostridium difficile-associated disease in Massachusetts hospitals: clinical and economic consequences. Infect Control Hosp Epidemiol 2007;28:1219–1227.

  10. 10.

    , , et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med 2010;170:772–778.

  11. 11.

    , , . Possible foodborne transmission in a case of pseudomembranous colitis due to Clostridium difficile: influence of gastrointestinal secretions on Clostridium difficile infection. Gastroenterology 1982;83:465–469.

  12. 12.

    , , et al. Comparative role of antibiotic and proton pump inhibitor in experimental Clostridium difficile infection in mice. Microbiol Immunol 2007;51:1209–1214.

  13. 13.

    , , . Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol 2007;102:2047–2056.

  14. 14.

    . Quantitative methods in the review of epidemiologic literature. Epidemiol Rev 1987;9:1–30.

  15. 15.

    , . What's the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA 1998;280:1690–1691.

  16. 16.

    , . Meta-analysis in clinical trials. Controlled Clin Trials 1986;7:177–188.

  17. 17.

    . Meta-analysis and endocrinology. Endocrinol Metabol Clin North America 1997;26:31–44.

  18. 18.

    , . Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088–1101.

  19. 19.

    , , et al. Bias in meta-analysis detected by a simple, graphical test. Br Med J 1997;315:629–634.

  20. 20.

    , . Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000;56:455–463.

  21. 21.

    . Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Stat Med 2002;21:1575–1600.

  22. 22.

    , , et al. Measuring inconsistency in meta-analyses. Br Med J 2003;327:557–560.

  23. 23.

    , , et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008–2012.

  24. 24.

    , , et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004;171:33–38.

  25. 25.

    , , 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;29:626–634.

  26. 26.

    , , et al. Clostridium difficile-associated disease in a setting of endemicity: identification of novel risk factors. Clin Infect Dis 2007;45:1543–1549.

  27. 27.

    , , et al. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis 2005;40:1591–1597.

  28. 28.

    , , et al. Proton pump inhibitor therapy is a risk factor for Clostridium difficile-associated diarrhoea. Aliment Pharmacol Ther 2006;24:613–619.

  29. 29.

    , , et al. Proton pump inhibitors as a risk factor for paediatric Clostridium difficile infection. Aliment Pharmacol Ther 2010;31:754–759.

  30. 30.

    , , et al. Proton pump inhibitors as a risk factor for recurrence of Clostridium-difficile-associated diarrhea. World J Gastroenterol 2010;16:3573–3577.

  31. 31.

    , , et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med 2010;170:784–790.

  32. 32.

    , , et al. Clostridium difficile is associated with poor outcomes in patients with cirrhosis: a national and tertiary center perspective. Am J Gastroenterol 2010;105:106–113.

  33. 33.

    , , et al. Clostridium difficile PCR ribotype 078 toxinotype V found in diarrhoeal pigs identical to isolates from affected humans. Environ Microbiol 2009;11:505–511.

  34. 34.

    , , et al. Gastric acid suppression by proton pump inhibitors as a risk factor for Clostridium difficile-associated diarrhea in hospitalized patients. Am J Gastroenterol 2008;103:2308–2313.

  35. 35.

    , , . Case-control study of antibiotic use and subsequent Clostridium difficile-associated diarrhea in hospitalized patients. Infect Control Hosp Epidemiol 2008;29:44–50.

  36. 36.

    , , et al. Association of proton-pump inhibitors with outcomes in Clostridium difficile colitis. Am J Health Sys Pharm 2007;64:2359–2363.

  37. 37.

    , , et al. Clostridium difficile infection in an urban medical center: five-year analysis of infection rates among adult admissions and association with the use of proton pump inhibitors. Ann Clin Lab Sci 2007;37:241–247.

  38. 38.

    , . Increasing incidence of Clostridium difficile-associated diarrhea in African-American and Hispanic patients: association with the use of proton pump inhibitor therapy. J Natl Med Assoc 2007;99:500–504.

  39. 39.

    , , et al. Proton pump inhibitor use and risk of community-acquired Clostridium difficile-associated disease defined by prescription for oral vancomycin therapy. CMAJ 2006;175:745–748.

  40. 40.

    , , et al. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 2005;294:2989–2995.

  41. 41.

    , , et al. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea. J Hosp Infect 2003;54:243–245.

  42. 42.

    , , et al. Gastric acid suppression does not promote clostridial diarrhoea in the elderly. QJM 2000;93:175–181.

  43. 43.

    , , et al. A hospital outbreak of diarrhea due to an emerging epidemic strain of Clostridium difficile. Arch Intern Med 2006;166:2518–2524.

  44. 44.

    , , et al. Proton pump inhibitors and hospitalization for Clostridium difficile-associated disease: a population-based study. Clin Infect Dis 2006;43:1272–1276.

  45. 45.

    , , et al. Risk of Clostridium difficile-associated disease among patients receiving proton-pump inhibitors in a Quebec medical intensive care unit. Infect Control Hosp Epidemiol 2007;28:1305–1307.

  46. 46.

    , , et al. Safety of the long-term use of proton pump inhibitors. World J Gastroenterol 2010;16:2323–2330.

  47. 47.

    , , . Vegetative Clostridium difficile survives in room air on moist surfaces and in gastric contents with reduced acidity: a potential mechanism to explain the association between proton pump inhibitors and C. difficile-associated diarrhea? Antimicrob Agents Chemother 2007;51:2883–2887.

  48. 48.

    , , . Coinfection with Giardia lamblia and Clostridium difficile after use of ranitidine. Am J Med Sci 2004;327:91–93.

  49. 49.

    , , . Population dynamics of ingested Clostridium difficile in the gastrointestinal tract of the Syrian hamster. J Infect Dis 1985;151:355–361.

  50. 50.

    , , et al. Altered bowel function and duodenal bacterial overgrowth in patients treated with omeprazole. Aliment Pharmacol Ther 1996;10:557–561.

  51. 51.

    , . Review article: proton pump inhibitors and bacterial overgrowth. Aliment Pharmacol Ther 2006;23:3–10.

  52. 52.

    , , et al. Suppression of gastric acid secretion in patients with gastroesophageal reflux disease results in gastric bacterial overgrowth and deconjugation of bile acids. J Gastrointest Surg 2000;4:50–54.

  53. 53.

    , , . Germination of spores of Bacillales and Clostridiales species: mechanisms and proteins involved. Trends Microbiol 2011;19:85–94.

  54. 54.

    , . PPI use in the OTC era: who to treat, with what, and for how long? Clin Gastroenterol Hepatol 2005;3:208–215.

Download references

Author information

Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Wayne State University School of Medicine, Harper University Hospital, Detroit, Michigan, USA

    • Sailajah Janarthanan
    • , Ivo Ditah
    •  & Murray N Ehrinpreis
  2. Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA

    • Douglas G Adler

Authors

  1. Search for Sailajah Janarthanan in:

  2. Search for Ivo Ditah in:

  3. Search for Douglas G Adler in:

  4. Search for Murray N Ehrinpreis in:

Competing interests

Guarantor of the manuscript: Sailajah Janarthanan, MD.

Specific author contributions: Sailajah Janarthanan: conception of the idea, collecting data, statistical analysis, and writing the manuscript; Ivo Ditah: data collection, statistical analysis, writing the manuscript; Douglas G. Adler and Murray N. Ehrinpreis: writing and editing the manuscript.

Financial support: None.

Potential competing interests: None.

Corresponding author

Correspondence to Douglas G Adler.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ajg.2012.179

Further reading