Can proton pump inhibitors (PPIs) cause Clostridioides difficile (C. diff) colitis in patients with a history of gastrointestinal issues or recent antibiotic use?

Does PPI Cause C. diff Colitis?

Yes, PPIs are associated with an increased risk of C. difficile infection, with multiple meta-analyses showing 1.7-1.8 times higher odds of developing CDI, though the true causal relationship remains unclear and should not lead to discontinuation of PPIs when medically indicated. 1

Strength of Association

The evidence consistently demonstrates a clinical association between PPI use and CDI across multiple high-quality meta-analyses:

• Three major meta-analyses involving over 300,000 patients showed increased risk of incident CDI with PPIs (OR 1.69-1.74), with even higher risk for recurrent CDI (OR 2.51). 1

• The 2019 World Journal of Emergency Surgery guidelines confirmed pooled analysis of 50 studies showing significant association (OR 1.26,95% CI 1.12-1.39). 1

• The risk is further amplified when PPIs are combined with non-C. difficile antibiotics (OR 1.96), with number needed to harm ranging from 28-50 in hospitalized patients on concurrent antibiotics versus 899-3925 in the general population. 1

Critical Limitations of the Evidence

Despite consistent associations, the IDSA/SHEA 2018 guidelines emphasize that no randomized controlled trials or quasi-experimental studies have proven causality, and several methodologic concerns limit practical application: 1

• Substantial heterogeneity across studies and publication bias in 2 of 3 meta-analyses 1
• Role of unknown confounders and lack of dose-response relationships 1
• The association may reflect underlying severity of illness rather than direct causation 1

FDA-Mandated Warnings

Both omeprazole and lansoprazole FDA labels explicitly warn that published observational studies suggest PPI therapy may be associated with increased risk of C. difficile-associated diarrhea, especially in hospitalized patients, and recommend using the lowest dose and shortest duration appropriate to the condition being treated. 2, 3

Risk Stratification by Clinical Context

The risk varies substantially based on antibiotic exposure and patient setting:

• Hospitalized patients on concurrent antibiotics: Highest risk group with number needed to harm of 28-50 1
• Hospitalized patients without antibiotics: Intermediate risk with number needed to harm of 202-367 1
• Community-associated CDI: 31% of patients who developed CDI without antibiotic exposure had received a PPI 1
• Patients with fewer antibiotics show paradoxically higher PPI-associated risk: Adjusted hazard ratio of 15.7 (CI 6.4-38.8) with one antibiotic versus 2.7 (CI 1.2-5.9) with five or more antibiotics, suggesting clinically relevant interaction 4

Recurrent CDI Risk

The association with recurrent CDI is particularly concerning, with adjusted hazard ratio of 1.42 (95% CI 1.11-1.82) for PPI exposure during incident CDI treatment. 5 However, two of three studies examining recurrent CDI did not show this association, indicating mixed evidence. 1

Clinical Management Algorithm

When PPIs Should NOT Be Discontinued Despite CDI Risk

The following patients require continued PPI therapy regardless of CDI concerns: 1, 6

• Barrett's esophagus
• Severe erosive esophagitis (LA Grade C or D)
• Eosinophilic esophagitis with PPI response
• History of upper GI bleeding, especially with ongoing anticoagulant/antiplatelet therapy
• High-risk NSAID/aspirin users requiring gastroprotection
• Secondary prevention of gastric/duodenal ulcers
• Idiopathic pulmonary fibrosis

When to Consider PPI De-prescribing

All patients without definitive indication for chronic PPI should be considered for trial of de-prescribing, including those with non-erosive reflux disease and mild erosive esophagitis. 1, 6

Specific Recommendations for CDI Prevention

The Taiwan guidelines state that while epidemiologic association exists between PPI use and CDI, there still lacks robust evidence to support discontinuation of PPI as a primary prevention measure for CDI. 1

However, stewardship activities to discontinue unneeded PPIs are warranted given the consistent observational data. 1

Common Pitfalls to Avoid

• Do not globally discontinue PPIs in patients at high risk for CDI or recurrent CDI regardless of need for PPI, as this requires further causal proof and may lead to serious complications including upper GI bleeding. 1, 6

• Do not assume all acid suppressants carry equal risk: Histamine-2 receptor antagonists showed decreased risk of CDI compared to PPI use in meta-analysis. 1

• Consider CDI diagnosis in any patient on PPI therapy who develops diarrhea that does not improve, particularly in hospitalized patients. 2, 3

• Up to 70% of PPI use may be inappropriate, highlighting the importance of periodic reassessment of indication for continued therapy. 6