Why should proton pump inhibitors (PPIs) be discontinued in patients with Clostridioides difficile (C. difficile) infection?

Why Discontinue PPIs in C. difficile Infection

PPIs should be discontinued in patients with C. difficile infection when there is no clear clinical indication, as they are epidemiologically associated with increased CDI risk, recurrence, and mortality, though causality remains unproven. 1, 2

The Evidence for PPI Discontinuation

Guideline Recommendations

The major infectious disease societies provide nuanced guidance on this issue:

• IDSA/SHEA (2018) states that while there is an epidemiologic association between PPI use and CDI, there is insufficient evidence to recommend discontinuation of PPIs specifically as a CDI prevention measure. 1 However, they emphasize that unnecessary PPIs should always be discontinued as part of good stewardship practice. 1

• WSES (2019) recommends consideration should be given to stopping PPIs when they are not necessary, especially in patients at high risk of CDI. 1 They note that PPIs are overprescribed in surgical settings and stewardship activities to discontinue unneeded PPIs are strongly warranted. 1, 2

• Taiwan guidelines (2020) acknowledge the epidemiologic association but state there still lacks robust evidence to support discontinuation of PPI as a primary prevention measure for CDI. 1

The Clinical Algorithm for Decision-Making

When managing a patient with active CDI on PPIs, follow this approach:

1. Evaluate whether a legitimate indication for PPI therapy exists (e.g., active peptic ulcer disease, severe GERD with esophagitis, high-dose NSAID use with GI bleeding risk). 2

2. If no clear indication exists, discontinue the PPI immediately. 2, 3

3. If a legitimate indication exists, consider the risk-benefit ratio carefully:

   • Use the minimum effective dose required to treat symptoms 2
   • Consider temporary discontinuation during acute CDI treatment if clinically feasible 2
   • Reassess necessity daily during hospitalization 1

Why This Matters: The Supporting Evidence

Association with CDI Risk and Outcomes

The epidemiologic data consistently demonstrates:

• Meta-analyses show PPI use increases CDI risk with odds ratios ranging from 1.26 to 2.34. 1, 4 A 2018 meta-analysis of 50 studies found OR = 1.26 (95% CI 1.12-1.39) for developing CDI. 1

• PPIs increase risk of recurrent CDI (OR 1.73,95% CI 1.39-2.15). 4

• The risk is synergistic with antibiotic use. When PPIs are combined with antibiotics, the CDI risk is further amplified. 1 Notably, the hazard ratio for PPI-associated CDI was highest (15.7) when only one antibiotic was prescribed, suggesting PPIs may be particularly problematic in lower-risk antibiotic scenarios. 5

• Most critically, a 2022 study demonstrated that daily PPI use was an independent risk factor for mortality in CDI patients, with duration-dependent increases in death rates. 6 This study showed PPI-induced gut dysbiosis (decreased Ruminococcus gnavus and Prevotella copri, increased Parabacteroides merdae and C. difficile) correlated with mortality. 6

The Confounding Problem

Despite consistent associations, causality has not been definitively proven due to extensive confounding in observational studies. 7 Patients on PPIs often have:

• Greater underlying illness severity 1
• Longer hospital stays 1
• More comorbidities that independently increase CDI risk 7

However, the 2021 Danish nationwide cohort study using self-controlled case-series design (which controls for fixed confounders) found adjusted IRR of 2.03 (95% CI 1.74-2.36) for community-associated CDI with PPI use, with risk remaining elevated up to 1 year after discontinuation. 8

Critical Management Principles

What to Do in Active CDI

• Discontinue the inciting antibiotic agent as soon as possible, as this influences risk of CDI recurrence. 1, 3

• Discontinue unnecessary PPIs immediately as part of comprehensive CDI management. 2, 3

• If continued antibiotic therapy is required for another infection, switch to agents less frequently implicated with CDI (parenteral aminoglycosides, sulfonamides, macrolides, or tetracyclines). 9, 3

• Avoid high-risk antibiotics entirely (clindamycin, third-generation cephalosporins, fluoroquinolones, penicillins). 9

Common Pitfalls to Avoid

• Do not continue PPIs "just in case" during CDI treatment without a documented indication. 2, 3

• Do not assume all patients need stress ulcer prophylaxis – most hospitalized patients do not meet criteria for PPI use. 1

• Remember that the risk-benefit calculation changes in CDI – the potential harm of continuing an unnecessary PPI now includes increased mortality risk. 6

The bottom line: While guidelines stop short of mandating PPI discontinuation due to imperfect causality evidence, the consistent association with worse outcomes (including mortality) means any PPI without clear indication should be stopped in CDI patients. 2, 3, 6