PPIs and C. Diff

One of the most prevalent problems I see in the community is the overuse of protein pump inhibitors or PPIs.  The mechanism is thought to be by raising pH and therefore preventing gastric contents from killing C. difficle spores or gastric contents of PPI-treated patients may promote germination and outgrowth of C.difficile spores. 

Available proton pump inhibitors  include:

The FDA issued their own warning:  (from the FDA website):

FDA Drug Safety Communication: Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs)

(en Español)

Safety Announcement

[02-08-2012] The U.S. Food and Drug Administration (FDA) is informing the public that the use of stomach acid drugs known as proton pump inhibitors (PPIs) may be associated with an increased risk of Clostridium difficile–associated diarrhea (CDAD). A diagnosis of CDAD should be considered for patients taking PPIs who develop diarrhea that does not improve.


Patients should immediately contact their healthcare professional and seek care if they take PPIs and develop diarrhea that does not improve.

Facts about Proton Pump Inhibitor (PPI) Drugs

  • Marketed under various brand and generic drug names (see Tables 1 and 2) as prescription and over-the-counter (OTC) products.
  • Work by reducing the amount of acid in the stomach.
  • Prescription PPIs are used to treat conditions such as gastroesophageal reflux disease (GERD), stomach and small intestine ulcers, and inflammation of the esophagus.
  • Over-the-counter PPIs are used to treat frequent heartburn.

Clostridium difficile (C. difficile) is a bacterium that can cause diarrhea that does not improve.1 Symptoms include watery stool, abdominal pain, and fever, and patients may go on to develop more serious intestinal conditions. The disease can also be spread in the hospital. Factors that may predispose an individual to developing CDAD include advanced age, certain chronic medical conditions, and taking broad spectrum antibiotics. Treatment for CDAD includes the replacement of fluids and electrolytes and the use of special antibiotics.  

The FDA is working with manufacturers to include information about the increased risk of CDAD with use of PPIs in the drug labels.

FDA is also reviewing the risk of CDAD in users of histamine H2 receptor blockers. H2 receptor blockers are used to treat conditions such as gastroesophageal reflux disease (GERD), stomach and small intestine ulcers, and heartburn. H2 receptor blockers are marketed under various brand and generic drug names (seeTables 3 and 4) as prescription and OTC products.

Today's communication is in keeping with FDA's commitment to inform the public about the Agency's ongoing safety review of drugs. FDA will communicate any new information on PPIs or H2 receptor blockers and the risk of CDAD when it becomes available.

Additional Information for Patients and OTC Consumers: 

  • Seek immediate care if you use PPIs and develop diarrhea that does not improve. This may be a sign ofClostridium difficile–associated diarrhea (CDAD).
  • Your healthcare professional may order laboratory tests to check if you have CDAD.
  • Do not stop taking your prescription PPI drug without talking to your healthcare professional.
  • Discuss any questions or concerns about your PPI drug with your healthcare professional.
  • If you take an OTC PPI drug, follow the directions on the package carefully.
  • Report any side effects you experience to the FDA MedWatch program using the information in the "Contact FDA" box at the bottom of the page.


Additional Information for Healthcare Professionals 

  • A diagnosis of CDAD should be considered for PPI users with diarrhea that does not improve.
  • Advise patients to seek immediate care from a healthcare professional if they experience watery stool that does not go away, abdominal pain, and fever while taking PPIs.
  • Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
  • Report adverse events involving PPIs to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of the page.


Data Summary

FDA has reviewed reports from the FDA's Adverse Event Reporting System (AERS) and the medical literature for cases of Clostridium difficile-associated diarrhea (CDAD) in patients undergoing treatment with PPIs. Many of the adverse event reports involved patients who were elderly, had chronic and/or concomitant underlying medical conditions, or were taking broad spectrum antibiotics that could have predisposed them to developing CDAD. Although these factors could have increased their risk of CDAD, the role of PPI use cannot be definitively ruled out in these reviewed reports. Patients who have one or more of these risk factors may have serious outcomes from CDAD with concomitant PPI use.

FDA also reviewed a total of 28 observational studies described in 26 publications. Twenty-three of the studies showed a higher risk of C. difficile infection or disease, including CDAD, associated with PPI exposure compared to no PPI exposure.2-27 Although the strength of the association varied widely from study to study, most studies found that the risk of C. difficile infection or disease, including CDAD, ranged from 1.4 to 2.75 times higher among patients with PPI exposure compared to those without PPI exposure. In the five studies that provided information on clinical outcomes, colectomies, and rarely deaths, were reported in some patients 4,6,11,12,21

The published studies varied in their ability to assess the association between C. difficile infection or CDAD and prior PPI use. There were limited data on the relationship between the risk of C. difficile infection or CDAD and PPI dose and duration of use. There also was little information on the use of OTC PPIs in community settings in these studies. Nevertheless, the weight of evidence suggests a positive association between the use of PPIs and C. difficile infection and disease, including CDAD.



  1. U.S. National Library of Medicine. National Institutes of Health. Health topics-Clostridium difficileinfections. http://vsearch.nlm.nih.gov/vivisimo/cgi-bin/query-meta?v%3Aproject=medlineplus&query=clostridium+difficile+infections. Accessed January 31, 2012.
  2. Al-Tureihi FIJ, Hassoun A, Wolf-Klein G, et al. Albumin, length of stay, and proton pump inhibitors: key factors in Clostridium difficile-associated disease in nursing home patients. J Am Med Dir Assoc.2005;6:105-108.
  3. Cunningham R, Dale B, Undy B, et al. Proton pump inhibitors as a risk factor for Clostridium difficilediarrhoea. J Hosp Infect. 2003;(54):243-245.
  4. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171(1):33-38.
  5. Dial S, Delaney JAC, Barkun A, et al. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 2005;294(23):2989-2995.
  6. Muto C, Pokrywka M, Shutt K, et al. A large outbreak of Clostridium difficile associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp Epidemiol. 2005;26:273-280.
  7. Pepin J, Saheb N, Coulombe M-A, et al. Emergence of fluoroquinolones as the predominant risk factor forClostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis. 2005;41(9):1254-1260.
  8. Shah S, Lewis A, Leopold D, et al. Gastric acid suppression does not promote clostridial diarrhoea in the elderly. QJM .2000;93:175-181.
  9. Dial S, Delaney JAC, Schneider V, et al. Proton pump inhibitor use and risk of community-acquiredClostridium difficile-associated disease defined by prescription for oral vancomycin therapy. CMAJ. 2006;175(7):745-748.
  10. Dial S, Kezouh A, Dascal A, et al. Patterns of antibiotic use and risk of hospital admission for Clostridium difficile infection among elderly people in Quebec. CMAJ. 2008;179:767-772.
  11. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of Clostridium diffcile-associated diarrhea with high morbidity and mortality. N Engl J Med. 2005;353:2442-2449.
  12. Akhtar AJ, Shaheen M. 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(5):500-504.
  13. Aseeri M, Schroeder T, Kramer J, 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(9):2308-2313.
  14. Beaulieu M, Williamson D, Pichette G, 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(11):1305-1307.
  15. Cadle R, Mansouri M, Logan N, et al. Association of proton-pump inhibitors with outcomes in Clostridium difficile colitis. Am J Health Syst Pharm. 2007;64(22):2359-2363.
  16. Dalton B, Lye-Maccannell T, Henderson E, et al. Proton pump inhibitors increase significantly the risk ofClostridium difficile infection in a low-endemicity, non-outbreak hospital setting. Aliment Pharmacol Ther. 2009;29(6):626-634.
  17. Dubberke ER, Reske KA, Yan Y, et al. Clostridium difficile-associated disease in a setting of endemicity: identification of novel risk factors. Clin Infect Dis. 2007;45(12):1543-1549.
  18. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomialClostridium difficile infection. Arch Intern Med. 2010;170(9):784-790.
  19. Janarthanan S, Ditah I, Kutait A, et al. A meta-analysis of 16 observational studies on proton pump inhibitor use and risk of Clostridium difficile associated diarrhea [abstract]. American College of Gastroenterology Conference 2010;Abstract 378.
  20. Jayatilaka S, Shakov R, Eddi R, 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(3):241-247.
  21. Kazakova SV, Ware K, Baughman B, et al. A hospital outbreak of diarrhea due to an emerging epidemic strain of Clostridium difficileArch Intern Med. 2006;166(22):2518-2524.
  22. Kim JW, Lee KL, Jeong JB, et al. Proton pump inhibitors as a risk factor for recurrence of Clostridium-difficile-associated diarrhea. World J Gastroenterol. 2010;16(28):3573-3577.
  23. Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol. 2007;102(9):2047-2056.
  24. Linsky A, Gupta K, Lawler EV, et al. Proton pump inhibitors and risk for recurrent Clostridium difficileinfection. Arch Intern Med. 2010;170(9):772-778.
  25. Lowe DO, Mamdani MM, Kopp A, et al. Proton pump inhibitors and hospitalization for Clostridium difficile-associated disease: a population-based study. Clin Infect Dis. 2006;43(10):1272-1276.
  26. Turco R, Martinelli M, Miele E, et al. Proton pump inhibitors as a risk factor for paediatric Clostridium difficile infection. Aliment Pharmacol Ther. 2010;31(7):754-759.
  27. Yearsley K, Gilby L, Ramadas A, et al. Proton pump inhibitor therapy is a risk factor for Clostridium difficile-associated diarrhoea. Aliment Pharmacol Ther. 2006;24(4):613-9.





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