Proton Pump Inhibitor (PPI) Use and Clostridium difficile

21 Dec

While following one of our patients we suggested discontinuing her PPI if it was feasible.  This led to a discussion on the data linking Clostridium difficile infection (CDI) and acid suppressive agents.  Here’s our take on the issue.

“The hippies knew, acid is good, man.” Dr. Mark Crislip.

PPI use at our institution, and I’m sure many others, is widespread.   In 2009 US News reported that PPI sales in the US amounted to 13.9 billion dollars! PPIs are well tolerated and effective.  PPIs, like antibiotics however, are not without harm.

In 2007, a systematic review was published in the American Journal of Gastroenterology. (2)  The review evaluated 11 observational studies (n=126,999).  The team at McMaster found an associated between acid suppression and C. difficile infection with a combined OR of 2.05 (1.47 – 2.85). Ten of the studies showed a positive association between PPI use and CDI.

Infection & Colonization

A recent article by Loo and colleagues (3) found that proton pump inhibitor use along with use of antibiotics and older age were significant risk factors for nosocomial CDI.   The prospective study took place in six Canadian hospitals in Quebec and Ontario and involved 4,143 patients.  Of those patients 117 (2.8%) and 123 (3.0%) patients developed health care associated C. difficile infection or colonization.  Previous use of proton-pump inhibitors was associated with Clostridium difficile infection [OR 2.64 95% CI (1.71-4.09)].  The study also showed PPIs [OR 1.71 (1.15 – 2.52)] & H2 blockers [2.14 (1.24 – 3.70)] were also associated with C difficile colonization.

Dose Response

Another trial displayed that increasing levels of acid-suppressive therapy was related to increasing rates of nosocomial CDI (4).  Howell’s group analyzed data collected prospectively for ‘other reasons.’  They analyzed 101,796 hospital discharges over 5 years.  Increasing the level of acid suppression increased the risk of health care associated C difficile.  [no acid suppression=reference Odds Ratio = 1(CI), H2 blocker only OR = 1.53 (1.12 – 2.10), daily PPI OR = 1.74 (1.39 – 2.18), PPI more frequently OR = 2.36 (1.79 – 3.11)].  Although this was an observational study the findings are impressive; receiving a daily PPI was associated with a >70% increase in the odds of developing C difficile. The study essentially provides a dose-response curve for acid suppressants and CDI.  Very cool data.

 Recurrent CDI

Amy Linsky et al (5) found that proton pump inhibitor use during CDI treatment was associated with an increased risk of recurrence within 15-90 days.  Hazard ratio 1.42 [CI 1.11-1.82; P=0.008].  This retrospective cohort study used the New England VA database and reviewed 1,549 patients with findings of C difficile toxin.  The increased risk of recurrent CDI was significantly higher in patients older than 80 years.

PPIs and Neutrophils

A small open label study done on 10 healthy subjects found that omeprazole impaired production of reactive oxygen intermediates by neutrophils.   The study linked single doses of omeprazole to decreased bactericidal activity of neutrophils (6).   This provides another proposed mechanism of the association between the class of drugs and pathogen.


Based on the above data it’s likely that gastric acidity plays a major role in protecting against infection from Clostridium difficile. Studies have shown that more acidic gastric juices were more effective than less-acidic gastric juices in killing C difficile and neutralizing its toxin.  (7)  The association is likely mutlifactorial (think swiss cheese). Curbing inappropriate PPI use could vastly improve the care we provide our patients.

One of our tenets as clinicians is to first, do no harm.  There are definitely multiple patient groups that would benefit from PPI therapy: patients with upper GI bleeds, GERD, erosive esophagitis, patients on dual anti-platelet medications or NSAIDs, H. Pylori eradication, and patients at high risk of stress ulcers.   I was unable to find a consensus guideline suggesting when PPIs should and shouldn’t be used; this is part of the problem.  PPIs are very effective and easy to prescribe.  However, we should be aware of the potential collateral damage associated with their use.  There’s data suggesting PPI use is associated with increased risk of fractures, pneumonia, and Clostridium difficile (email for more references)We should attempt to use agents with the least collateral damage for the shortest duration possible.

During stewardship rounds we suggest discontinuation of PPIs or de-escalation of PPIs to H2RAs if possible.  If there’s a clear indication for PPI use it at the lowest effective dose, for the shortest duration possible. This sounds familiar doesn’t it? :)



The FDA issued a Safety Announcement last week supporting the above post.

Feb 15, 2012




  1. Thorens, J., Froehlich, F., Schwizer, W., Saraga, E., Bille, J., Gyr, K., Duroux, P., et al. (1996). Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. Gut, 39(1), 54-59. Retrieved from
  2. Leonard, J., Marshall, J. K., & Moayyedi, P. (2007). Systematic review of the risk of enteric infection in patients taking acid suppression. American Journal of Gastroenterology, 102(9), 2047-2056; quiz 2057. Retrieved from
  3. Loo, V. G., Bourgault, A.-M., Poirier, L., Lamothe, F., Michaud, S., Turgeon, N., Toye, B., et al. (2011). Host and pathogen factors for Clostridium difficile infection and colonization. The New England Journal of Medicine, 365(18), 1693-703. Retrieved from
  4. Howell, M. D., Novack, V., Grgurich, P., Soulliard, D., Novack, L., Pencina, M., & Talmor, D. (2010). Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Archives of Internal Medicine, 170(9), 784-790. Retrieved from
  5. Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA. (2010). Proton pump inhibitors and risk for recurrent Clostridium difficile infection.  Archives of Internal Medicine, 170(9), 772-778. Retrieved from
  6. Zedtwitz-Liebenstein, K., Wenisch, C., Patruta, S., Parschalk, B., Daxböck, F., & Graninger, W. (2002). Omeprazole treatment diminishes intra- and extracellular neutrophil reactive oxygen production and bactericidal activity. Critical Care Medicine, 30(5), 1118-1122. Retrieved from
  7. Gurian, L., Ward, T. T., & Katon, R. M. (1982). Possible foodborne transmission in a case of pseudomembranous colitis due to Clostridium difficile: influence of gastrointestinal secretions on Clostridium difficile infection. Gastroenterology. Retrieved from

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