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PPIs and the risk of Clostridium difficile infection

A National Prescribing Centre (NPC) Rapid Review in 2010 highlighted two US studies investigating PPI use and CDI. The Rapid Review stated PPIs have undoubted benefits in certain GI conditions. However gastric acid suppression has been a suggested risk factor for CDI, since gastric juices that have a greater acidity are more effective at killing the bacterium and neutralising its toxin then less acidic gastric juices [1].

A study published in 2005 based on the UK General Practice Research Database (GPRD), found that people with CDI were about three times more likely to have been prescribed a PPI in the previous 3 months than people without CDI[2]. Other studies found that hospital inpatients taking daily PPIs were over 70% more likely to develop CDI than non-users. Patients who received more frequent PPIs had more than a doubling of this risk [1],[3]. The results may have important public health implications, as they suggest that compared with no acid suppression at least one additional case of nosocomial CDI should be expected for every 533 patients who receive a daily PPI, after controlling for other risk factors.

Although this seems a relatively large Number-Needed-to-Harm (NNH), the magnitude of exposure is large. They found, similar to others’ estimates, 60% of patients received acid-suppressive therapy.

In the absence of an RCT several important steps are recommended. Firstly ensure patients receive the least intense acid-suppressive therapy appropriate for their clinical condition, secondly minimise exposure in low risk, non-critically ill patients for stress ulcer prophylaxis and thirdly ensure prophylactic medications are not continued beyond discharge[3].

PPIs are often prescribed without a clear indication and CDI is more common in those exposed to PPIs than those who are not exposed. PPI use concurrent with treatment for CDI was associated with a 42% increased relative risk of recurrent infection 15 to 90 days afterwards. Risks were highest among those older than 80 years and those receiving antibiotics not targeted to CDI. Although C. difficile spores are acid-resistant, vegetative forms are susceptible to acidity. Elevated gastric pH levels may allow or facilitate conversion from spore to vegetative forms of C. difficile in the upper GI tract. Other mechanisms include impairment of leukocytes and other immune responses and antimicrobial properties of PPIs[4]. Older age, antibiotics after diagnosis of CDI and use of PPIs are the most frequent risk factors for recurrence[5].

Adapted from PrescQIPP Bulletin 92, Safety of long term proton pump inhibitors (PPIs), May 2015.


[1] NPC Rapid Review. Increased risk of C. difficile infections and of fractures: two more good reasons to review PPI prescribing. 3 June 2010.

[2] Dial S, Delaney JAC, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk of Community-Acquired Clostridium difficile-associated disease. JAMA 2005; 294: 2989-2995.

[3] Howell M, Novack V, Grgurich P et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med 2010; 170 (9): 784-790.

[4] Linsky A, Kalpana G, Lawler EV et al. Proton Pump Inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med 2010; 170(9): 772-778.

[5] Abou Chakra CN, Pepin J, Sirard S, Valiquette L. Risk factors for recurrence, complications and mortality in Clostridium difficile Infection: a systematic review. PLoS ONE 2014 Jun 4;9(6): e98400.