Proton Pump Inhibitors (PPIs) & C. Diff Infection Risk: Concerning?

Although PPIs are generally safe medications for most people, some users are concerned with increased risk of infection – particularly C. diff (Clostridium difficile).

I happen to be: (A) a PPI user (esomeprazole 20 mg, b.i.d.) and (B) someone who’s concerned with potential increased risk of C. diff – so I reviewed the literature on this topic.

PPIs & C. diff infection (Research)

Included below are overviews of studies examining the risk of Clostridium difficile infection (CDI) associated with proton-pump inhibitors (PPIs).

Systematic reviews & meta-analyses

Systematic reviews/meta-analyses generally provide the best evidence because they factor in all quality data – so these should be the primary focus for those hoping to learn whether PPIs increase C. diff risk.

Positive association between PPIs & Clostridium Difficile infection (2021) (R)

Tawam et al.: “Currently available data suggest a positive association between PPIs and CDI.”

• Aim: Review and summarize data on the link between PPIs & CDI.
• Methods: Review meta-analyses and systematic reviews from 2000-2020 examining the link between PPIs and C. diff infection.
• Data: 8 meta-analyses and systematic reviews met inclusion criteria for this review – including studies from U.S., Europe, Asia, and Canada in adults.

Studies analyzed for this review

Oshima et al. (2018)

• Systematic review & meta-analysis
• 67 studies
• Inpatient/outpatient adults and pediatrics
• Comparison: PPI vs. non-PPI users
• diff risk: High

Cao et al. (2018)

• Meta-analysis
• 50 studies (342,532 patients)
• Inpatient/outpatient/ICU patients
• PPI users vs. non-PPI users
• diff Risk: Minimal

Trifan et al. (2017)

• Meta-analysis
• 56 studies (356,683 patients)
• Inpatient/outpatient adults
• PPI users vs. non-PPI users
• diff risk: Moderate

Arriola et al. (2016)

• Meta-analysis
• 23 studies (10,307 patients)
• Inpatient or ICU adults
• PPI users vs. non-PPI users
• diff risk: Moderate

Tleyjeh et al. (2012)

• Systematic review & meta-analysis
• 47 studies
• Inpatient/outpatient adults
• PPI users vs. non-PPI users
• diff risk: Moderate

Janarthanan et al. (2012)

• Meta-analysis
• 23 studies (288,620 patients)
• PPI users vs. non-PPI users
• diff risk: Moderate

Deshpande et al. (2012)

• Meta-analysis
• 30 studies (202,965 patients)
• Inpatient/outpatient
• PPI users vs. non-users
• diff risk: High

Leonard et al. (2007)

• Systematic review
• 12 studies (2,948 patients)
• Inpatient adults
• PPI users vs. non-PPI users
• diff risk: Moderate

What were the results?

• All 8 systematic reviews reported an increase in developing CDI as compared to groups who were not prescribed PPIs.
• Patients included in studies did NOT take antibiotics which is a well-known confounder.
• Odds ratios were sorted into 3 categories: (1) minimal risk (OR = 1.1 to <1.5); (2) moderate risk (OR = 1.5-2); (3) high risk (OR = 2+).
• Results indicated a statistically significant association between PPIs & CDI ranging from mild to high risk – however, most studies found “moderate risk.”

Proton pump inhibitor use & risk for recurrent C. diff infection (2021) (R)

Note: This study examined risk for “recurrent” C. diff infection – not merely a single/isolated C. diff infection.

D’Silva et al.: “We found significantly higher odds of recurrent CDI among users of PPIs that persisted across multiple sensitivity analyses.”

• Aim: Perform a systematic review & meta-analysis evaluating the association between PPI use and recurrent CDI.
• Methods: Review cohort and case-control studies involving adults with prior CDI who did or did not receive PPI therapy – followed by assessment for recurrent CDI. Odds ratios were calculated using a random effects model and additional subgroup analyses were performed.
• 16 studies were included in the meta-analysis (57,477 patients with CDI).
• 6,870 of 57,477 (12%) of the CDI patients received PPIs.

What were the results?

• PPI users exhibited a 24% rate of recurrent CDI 18% in non-PPI users.
• A meta-analysis that pooled unadjusted odds ratios revealed higher odds of recurrent CDI among PPI recipients.
• Analyses restricted to multivariate studies that combined adjusted ORs also revealed higher odds of recurrent CDI in PPI users.

Comparison of hospital-acquired C. diff infection risk of PPIs vs. H2RAs for stress ulcers (2017) (R)

Note: This study specifically compared rates of hospital-acquired C. diff infection between PPIs & H2RAs among those using them for stress ulcer prophylaxis/treatment.

Azab et al.: “The use of PPIs for the prevention and treatment of stress ulcers was associated with increased risk of hospital-acquired CDI occurrence compared to H2RA use.”

• Aim: Evaluate comparative hospital-acquired CDI risk associated with PPIs vs. H2RAs.
• Methods: Find relevant studies through 2016 (CDI risk from PPIs vs. H2RAs).
• Data: 12 observational studies (74,132 patients) that reported hospital-acquired CDI occurrence with H2RAs & PPIs in stress ulcer prevention/treatment.

What were the results?

• PPIs increased the risk of CDI by 38.6% relative to H2RAs in stress ulcer prevention/treatment.
• Subgroup analyses confirmed consistency of a greater CDI risk with PPIs than H2RAs.
• Evidence quality: Low.

Other relevant studies (re: PPIs & C. diff risk)

PPI use & risk of community-associated C. diff infection (2021) (R)

Inghammar et al.: “Use of PPIs was associated with moderately increased risk of community-associated CDI.”

• Aim: Determine whether PPIs increase risk of community-associated CDI.
• Method: Adults in Denmark (2010-2013) were evaluated via medical register data on C. diff testing, filled prescriptions, and patient characteristics.
• All episodes of CDI were identified in the Danish National Microbiological Database.
• Self-controlled case-series analyses were employed to estimate IRRs and control for confounds.

What were the results?

• 3,583 cases of community-associated CDI were identified
• 964 of the 3,583 cases were among PPI users
• 324 cases occurred within 6 months of PPI discontinuation
• 123 cases occurred 6-12 months after PPI discontinuation
• PPIs were associated with a doubled risk of community-associated CDI
• Risk diminished after PPI discontinuation but remained elevated up to 1 year after treatment ended

Effects of PPI use on risk of C. diff infection (2019) (R)

Park et al. (2019): “PPI use was associated with an increased risk of developing CDI and the risk of CDI was dose-dependent.”

• Retrospective cohort study
• Investigated association, dose, duration, and types of PPIs associated with CDI
• 309,073 patients hospitalized (PPI users = 125,922 vs. non-PPI users = 183,151)
• Incidence of CDI in PPI users = 6.84 per 10,000 person-days vs. control = 3.24 per 10,000 person-days
• Risk of CDI based on specific PPI: esomeprazole (HR = 1.79); pantoprazole (HR = 2.02); lansoprazole (HR = 1.32); dexlansoprazole (HR = 0.86)
• High-dose PPI = 1.95-fold increased risk
• Interestingly no significant difference found between patients using PPIs for longer than 6 days and non-users
• Risk of CDI increased 4.2-fold in those who used PPIs for less than 6 days vs. non-users
• The mean time from PPI exposure to C. diff test was ~6.7 days (median: 5 days)

Studies suggesting no association between PPIs & C. diff…

The studies below found no association between PPI use and risk of C. difficile infection (CDI).

That said, there are limitations with these studies, including (but not limited to): evaluating healthcare facility-onset CDI only; retrospective cohort designs; confounds; etc.

Falek et al. (2016): “Exposure to antibiotics was the most important risk factor for healthcare facility-onset CDI in the ICU. PPIs did not increase risk for CDI in the ICU regardless of use of antibiotics.” (R)

• Retrospective cohort study
• Examined association between PPI use and CDI in the ICU
• 18,134 patients (271 or 1.5% developed CDI at the ICU)
• No association between CDI and PPIs in those who didn’t receive antibiotics
• PPIs associated with a decreased risk of CDI in antibiotic recipients
• No evidence of increased risk of CDI among higher-dose PPI users

Beaulieu et al. (2007): “The hypothesis that use of gastric acid-suppressive agents may predispose individuals to develop CDAD has not been confirmed.” (R)

• Retrospective cohort study
• Evaluated risk of C. difficile-associated disease (CDAD) associated with PPI use
• 827 medical records analyzed
• PPIs & CDAD risk (HR = 1.02 & AHR = 0.90)

Pepin et al. (2005): “Proton pump inhibitors (AHR = 1.00) were not associated with CDAD.” (R)

• Evaluated risk of C. diff-associated diarrhea (CDAD) associated with PPI use
• 5,619 individuals (2003-2004)
• 293 patients with C. diff-associated diarrhea (CDAD)
• Fluoroquinolones emerged as the most important risk factor for CDAD in Quebec during an epidemic caused by a hyper-virulent strain of C. difficile

Shah et al. (2000): “Gastric acid suppression does not promote Clostridial diarrhea in the elderly.” (R)

• Retrospective cohort study
• Examined risk of C. diff diarrhea in patients treated with gastric acid suppressants
• 126 cases with positive C. diff diarrhea (1995-1996) vs. 126 negative controls
• Positive C. diff cases were associated with antibiotic use, disability, and hypoalbuminemia.
• There was no evidence that PPIs or H2RAs increased susceptibility to C. diff in the elderly.

What does the totality of research suggest re: PPIs & C. diff?

PPIs are associated with moderately increased risk of Clostridium difficile infection (CDI).

As of current, the highest-level evidence is derived from a systematic review & meta-analysis of 8 prior systematic reviews/meta-analyses by Tawam et al. (2021).

• Tawam et al. found a positive association between PPIs and Clostridium Difficile infection (CDI) and noted that the association was found in all 8 studies evaluated.
• Average risk level, according to Tawam et al., for C. difficile infection (CDI) with PPIs was “moderate” (ranging from “low” to “high” in prior reviews).

A separate systematic review by D’Silva et al. (2021) examined the prevalence of recurrent CDI among PPI users and found “significantly higher odds of recurrent CDI among PPI users.”

Another systematic review by Azab et al. (2021) examined risk of CDI in stress ulcer prophylaxis/treatment associated with PPIs vs. H2RAs – and found significantly increased risk of CDI (~38.6%) with PPI use vs. H2RAs.

Inghammar et al. (2021) reported that PPIs were associated with “moderately increased risk” of community-associated Clostridium Difficile infection (CDI).

Park et al. (2019) reported that PPI use is associated with increased risk of CDI – and that the association is dose-dependent.

Various studies from 2000-2016 found no significant association between PPIs and Clostridium difficile infection (CDI) – and one study found a decreased risk of CDI associated with PPI use, however, these findings were not substantiated in systematic reviews/meta-analyses.

Moreover, the studies that found no association and/or inverse association between PPIs and C. difficile infection had substantially more limitations than the studies finding positive associations (including: smaller sample sizes; specific settings (e.g. ICU); confounds; etc.).

That said, just because PPIs appear to moderately increase risk of CDI in associational studies does NOT mean that PPIs somehow cause CDI or actually increase CDI risk.

Limitations associated with this research includes: observational studies; confounding variables (despite statistical adjustment); heterogeneity among studies reviewed; lack of information regarding dose/duration of PPI therapy; unknown compliance to PPI therapy; publication bias; etc.

There are zero randomized controlled trials (RCTs) comparing rates of CDI in healthy PPI (monotherapy) users vs. a placebo control.

For this reason, it’s more difficult to conclusively state that PPIs 100% increase C. difficile risk.

Still, we must consider that: (A) the highest-level review found an association between PPI use and increased C. difficile infection; and (B) there’s biological plausibility – it’s biologically plausible that PPIs could increase risk of C. difficile infection via numerous mechanisms (e.g. increased gastric/colonic pH; induction of dysbiosis; immunomodulation; etc.).

Overall, there’s stronger evidence indicating that PPIs increase risk of C. difficile infection (CDI) than suggests otherwise.

How might PPIs increase risk of C. diff infection? (Hypothesized mechanisms)

Unclear.  Nerandzic et al. (2009) examined potential mechanisms to explain the association between PPI therapy and C. diff infection. (R)

• Hypothesis: (1) Raising pH with PPIs prevents gastric contents from killing C. diff spores and (2) gastric contents of PPI-treated patients may promote germination and outgrowth of C. diff spores.
• Methods: Examine germination and outgrowth of 6 different C. diff strains in acidic gastric contents derived from elderly subjects with nasogastric tubes.

What were the findings?

• Germination did NOT occur in unmodified gastric contents of patients but did occur with the addition of taurocholic acid and amino acids.
• diff spores survived in acidic gastric contents and did NOT undergo germination and outgrowth probably due to lack of essential germinants such as taurocholic acid.

Conclusion: These findings do not suggest a mechanism by which PPI therapy might promote Clostridium Difficile infection (CDI). In the absence of a clear mechanism by which PPIs might promote CDI, it’s possible that these agents do not promote CDI.

Limitations: In vitro examinations (rather than in vivo) within gastric/intestinal contents; gastric fluid only from elderly males with nasogastric tubes placed for clinical indications; all subjects were fasting (which might impact germination).

Wombell et al. (2018) stated that the exact mechanism by which PPIs lead to increased C. diff acquisition remains unanswered but appears to be multifactorial. (R)

At this time, it remains unknown as to how PPIs might increase the risk of C. diff infection. Included below are mechanisms hypothesized by researchers.

Elevated gastric and/or colonic pH

PPIs increase gastric pH above 4 and may also increase colonic pH to enable bacterial overgrowth – including of pathogenic flora like C. diff within the upper/lower GI tract.

• High gastric pH increases vegetative bacteria counts in the small/large intestine.
• Though H+/K+ ATPases are concentrated primarily in the stomach – they’ve also been identified in the colon. (R)
• An alkaline colonic pH (as a result of PPI action on colonic proton pumps) may be a primary mechanism by which PPIs increase risk of C. diff.
• Gupta et al. (2016) found a “strong association between C. difficile infection and alkaline stool pH.” (R)

Altered gene expression

PPIs might decrease the expression of genes that maintain colonocyte integrity – which could create an environment favorable to C. diff proliferation.

• Hegarty et al. (2014) observed significant changes in 322 colonocyte transcripts – including genes with potential implications for susceptibility to CDI – following omeprazole exposure in a human colonic cell line. (R)

Vegetative C. difficile survival

Elevated gastric pH (above 4) has been hypothesized to enable the survival of the “vegetative form” of C. difficile – the live, disease-inducing form of C. diff which germinates from the spore under specific conditions.

• C. difficile spores are thought to be acid resistant, but vegetative forms of C. difficile are usually susceptible to acidity.
• Survival of vegetative forms of C. diff (that would normally be killed by stomach acid) may yield inevitable C. diff infection in a subset of PPI users due to the ongoing elevation of gastric pH (reduction of stomach acid).

Spore C. difficile survival

Elevated gastric pH (above 4) has been hypothesized to enable the survival of C. difficile “spores” – or dormant forms of C. difficile.

• difficile spores are understood to be acid resistant and incapable of germination within the stomach.
• In theory, PPI-related reductions in gastric acid should have minimal (if any) impact on C. difficile spores.
• Cunningham et al. found that C. difficile spores were unaffected following exposure to physiologically-relevant nitrite concentrations at an elevated pH of 5 (about the same level in the stomach of PPI users). (R)
• It was stated that when pH is increased from a PPI, gastric nitrite is unable to generate ROS and neutralize/inhibit C. difficile spores.
• As a result, individuals who take PPIs may be more susceptible to accumulation of more C. difficile spores, subsequent germination, and overall CDI potential.

Gut microbiota dysbiosis

PPIs are understood to significantly modify gut bacteria – such that they may induce a state of dysbiosis. A state of dysbiosis might increase risk of C. diff infection via numerous mechanisms.

• Naito et al. found that PPIs significantly increased the presence of Streptococcaceae and Enterococcaceae – which are risk factors for C. diff infection. (R)
• Seto et al. noted that PPI use decreases observed operational taxonomic unit (OTU) levels after 1 week and 1 month. (The OTU decreases were similar to what’s observed in treatment-naïve C. difficile infection patients.) (R)
• Kanno et al. found that PPIs enabled significant proliferation of most groups of intestinal microflora as a result of gastric acid reduction. (R)
• Amir et al. report that PPI treatment markedly alters gastric and esophageal microbial populations (e.g. increased Enterobacteriaceae). (R)

Abnormal immune response

PPIs are associated with abnormal immune responses – and abnormal immune expression/function could increase susceptibility to C. diff infection.

• Altered immune responses could be due to altered homeostatic physiology as a direct response to the PPIs over time and/or onset of dysbiosis, nutrient deficiencies, and/or immunoreactivity to PPI/metabolite deposits (such as within the kidney).
• Omeprazole impairs production of reactive oxygen intermediates by neutrophils – which might alter host defenses and reduce bactericidal activity (associated with an increase of intracellular Ca2+ concentrations in resting neutrophils). (R)
• Long-term PPI use is associated with increased microbial product translocation, innate immune activation, reduced immunologic recovery in HIV patients. (R)
• Long-term PPI therapy disrupts neutrophil leukocyte functions in the lung. (R)
• Long-term PPI therapy may reduce RBC and WBC counts as well as hemoglobin levels. (R)
• Proton pump inhibitors appear to increase the risk of autoimmune diseases – possibly via immunoreactivity to PPI/metabolite deposits within the kidneys. (R)

Antimicrobial effects

PPIs are known to have antimicrobial effects – which could increase the risk of C. diff. (R)

How? Elimination of probiotic bacteria allows pathogenic bacteria like C. diff to proliferate unchecked due to lack of competition.

Enhancement of C. diff toxin expression

Some researchers believe that PPIs might interact directly with C. difficile by: (A) promoting toxin production or (B) inducing virulence behaviors –distinct from effects on gastric pH.

• The generation of toxins is involved in C. difficile infection development and gastric acid is understood to help deactivate/neutralize bacterial toxins.
• Stewart & Hegarty evaluated the effects of PPIs on C. difficile toxin gene expression – finding an elevated/alkaline pH yielded ~35-fold increase in C. difficile toxin A gene expression relative to a low/acidic pH. (R)
• Omeprazole was shown to enhance C. difficile toxin expression by ~120-fold.
• At a pH of 5, C. difficile toxins A & B increased: (1) ~34-fold without PPI exposure vs. ~138-152-fold with PPI exposure.
• Evidence indicates that PPIs probably have: (1) pH-dependent and (2) independent – effects on C. difficile toxin production which increases its virulence.

How common is C. diff infection in PPI users?

Although C. diff infection (CDI) may be more common among PPI users than non-PPI users, it’s still relatively “rare” in terms of prevalence.

Based on all data from ICD-coded hospitalizations, the approximate cumulative incidence rate of C. difficile infection (CDI) for all ages is ~50 cases per 100,000 population per year (0.05%). (R)

Cao et al. reviewed 50 studies and reported a relative risk for CDI of: 1.29 (inpatients) and 1.17 (outpatients) – among PPI users. (R)

(For reference: A relative risk of “1” means there’s no difference between PPI users and non-users in CDI risk. And below “1” would indicate protection with PPI therapy.)

This means that although PPIs increase relative risk of C. difficile infection (CDI) – the likelihood of getting CDI while on PPIs is still low.

Risk factors for C. diff infection on PPIs

Poor hygiene: Suboptimal hand washing (e.g. not washing hands, infrequently washing hands, etc.) is probably the biggest risk factor for developing C. difficile infection. Failing to clean the bathroom (especially surfaces), storing a toothbrush in the bathroom, infrequently washing clothes, etc. could also increase C. diff infection risk.

High-dose PPI: There’s evidence that risk of developing C. diff on PPIs is dose-dependent. (R) Higher doses of PPIs are associated with increased risk of C. diff infection relative to lower doses.

PPI therapy duration (?): It’s unclear as to how duration of PPI therapy might influence risk of C. difficile infection (CDI) – as the data are relatively mixed.

• Short-term: Park et al. found a significant increase in CDI risk (~4.2-fold) in those who use PPIs for less than 6 days – but zero increased risk among those who use PPIs for over 6 days.
• Long-term: Some researchers think that long-term PPI use may increase risk of C. diff infection relative to short-term use – and this makes logical sense given that many physiological adaptations occurring under PPI therapy become more pronounced with long-term use.
• Post-PPI: Inghammar et al. found that PPI users are at increased risk of CDI up to ~1 year after stopping the PPI (324 cases within 6 months & 123 cases at 6-12 months).

Antibiotic use: Antibiotic use is associated with higher rates of C. difficile infection (CDI) than PPIs. Combining antibiotics and PPIs significantly increases risk more than either the antibiotics or PPIs in isolation (i.e. monotherapy).

Dysbiosis: Preliminary evidence suggests that gut microbiota dysbiosis may increase risk of C. difficile infection. (R)

Older age: Older age is considered a key risk factor for CDI development.

Hospitalization: Hospitalization is considered another key risk factor for C. diff infection.

Prior C. diff infection: Risk of C. difficile infection is higher among individuals who were previously infected.

Immune system impairment: Individuals with preexisting immunodeficiencies (e.g. HIV/AIDS; cancer) or using immunosuppressive agents (e.g. methotrexate, prednisone, etc.) may be more susceptible to C. difficile infection.

Amino acid supplementation: Some research suggests that high concentrations of amino acids may increase risk of C. diff infection while using PPIs.

Nutrient deficiencies (?): Some researchers hypothesize that PPI-induced hypomagnesemia (low magnesium) might alter gut motility and possibly CDI risk.

Specific PPI (?): Risk might be higher with certain PPIs relative to others.

• This could be due to slight variations in potency or dosages among users of those PPIs – but it’s possible that specific PPIs affect risk slightly more/less than other PPIs.
• Based on one study, highest-to-lowest risk PPIs were: pantoprazole (HR = 2.02); esomeprazole (HR = 1.79); lansoprazole (HR = 1.32); and dexlansoprazole (HR = 0.86).

How to minimize risk of C. difficile infection on PPIs… (Hypotheses)

Included below are tactics that might help reduce risk of C. difficile infection while using PPIs. Keep in mind that these tactics are not guaranteed to help – and that you should consult a medical doctor if necessary before pursuing certain ideas.

1. Hand washing: Regularly wash your hands after using the bathroom or when around any germs. Hand washing is the top way to prevent C. difficile infection.
2. Hygiene: In addition to hand washing, manage overall hygiene by regularly: showering/bathing, washing clothes, cleaning bedsheets, etc. (Definitely avoid storing the toothbrush in the bathroom – as a fecal plume effect might introduce fecal particulates to your toothbrush, causing an infection.)
3. Cleaning: Cleaning the house (particularly surfaces in the bathroom, kitchen, etc.) – might help reduce risk of C. difficile infection.
4. Minimal effective PPI dose: Use the lowest necessary dose of a PPI to control symptoms. Some research suggests that risk of C. difficile on PPIs is dose-dependent such that higher doses are associated with increased C. difficile risk.
5. Minimal PPI therapy duration: Avoid using PPIs for longer than is medically necessary. Consult a medical doctor and/or pharmacist to ensure that you’re not using PPIs for longer than medically indicated and/or safe.
6. Avoid antibiotics (if possible): If prescribed or taking antibiotics, consult a medical doctor to ensure that the antibiotics are 100% medically-necessary. If the antibiotics aren’t absolutely necessary – they should be avoided. (Antibiotics are often overprescribed/overused and significantly increase C. difficile infection risk – and the risk is further amplified with PPI therapy.)
7. Probiotics: One proposed mechanism by which PPIs may increase risk of C. difficile infection (CDI) during PPI therapy is via microbiota dysbiosis within the intestine, GI tract, and colon. A high-quality probiotic during PPI therapy may introduce bacteria that effectively out-compete or eradicate C. difficile – such as to prevent infection.

• • Saccharomyces boulardii: S. boulardii is technically a fungus/yeast (not bacteria) that elicits “probiotic” effects in the gastrointestinal tract. Some evidence suggests that it may prevent and/or eradicate C. difficile infection. (R) (This is an affiliate link to the product that I use.)
  • PRO-15: This is a probiotic that I take to maintain healthy gut bacteria while using proton pump inhibitors (PPIs). (This is an affiliate link to the product that I use.)

8. Magnesium carbonate (?): Because some researchers think PPI-induced hypomagnesemia may increase risk of C. difficile infection while on PPIs (due to altering GI motility), it might make sense to supplement with a non-acidic form of magnesium like magnesium carbonate. (This is an affiliate link to the exact product that I use.)
9. Avoid amino acid excess (?): One mechanistic study found that excessive concentrations of amino acids may help facilitate the growth of C. difficile bacteria. Arguably the best ways to avoid excessive amino acids are to: avoid unnecessary amino acid supplementation, avoid overeating (total calories), and avoid excessive protein intake.
10. Avoid PPIs (if possible): Many people on PPIs don’t really need them. One study reported that over 50% of PPI users who developed C. difficile infection (CDI) had zero valid indications for PPI therapy. (R) If you can get relief from H2RAs (histamine-2 receptor antagonists) – then this would be better regarding C. diff risk.
11. Continue these practices for ~1 year (after stopping PPI): Evidence suggests that risk of C. difficile infection (CDI) remains elevated up to 1 year after PPI cessation. (R)

Do PPIs cause C. diff infection?

There’s no evidence to suggest that PPIs directly cause C. diff infection. PPIs aren’t loaded with C. diff bacteria such that C. diff ends up deposited into the stomach from PPIs.

However, PPIs can reduce gastric acid which increases susceptibility to C. difficile colonization – particularly among high-dose users.

Add in a few other synergies such as: administration of antibiotics and poor hygiene (failing to wash hands after using the bathroom) – and C. difficile infection risk will further increase.

C. difficile infection generally occurs when individuals touch: food, surfaces, or objects that are contaminated with fecal matter (poop) from a person who has C. difficile.

What are the symptoms of C. diff infection?

Mild-to-moderate infection

• Watery diarrhea (3+ times per day)
• Mild abdominal cramping & tenderness

Severe infection

• Watery diarrhea (10-15+ times per day)
• Abdominal cramping & pain
• Appetite loss
• Rapid heart rate
• Dehydration
• Fever
• Nausea
• Increased white blood cell count
• Kidney failure
• Swollen abdomen
• Weight loss
• Blood or mucus in stool

What should you do if you think you’ve developed C. diff on PPIs?

1. Emergency medical care: Consult a medical doctor as soon as possible – as C. difficile could progress and inflict physiological damage or turn fatal.
2. Stop PPIs (if possible): McDonald et al. recommend considering the cessation of unnecessary PPI use at the time of C. diff diagnosis. (R)
3. Proper treatment: The most commonly used antibiotics for the treatment of C. diff include Fidaxomicin and Vancomycin. These will be administered by a medical doctor/pharmacist until the infection is eradicated.

Have you developed C. diff while using PPIs?

If you’ve experienced C. diff while on PPIs, feel free to leave a comment about the experience.

• Age, BMI, sex
• PPI specifics: Daily dosage; duration of treatment; specific drug; once vs. twice daily dosing
• Did you use other substances with the PPI? (medications, supplements, drugs like caffeine, nicotine, alcohol, cannabis, etc.)
• Did you use any antibiotics prior to C. diff onset?
• Medical conditions
• Prior C. difficile infection?
• Recent hospitalization or nursing home visit?
• How is your general hygiene? (e.g. hand washing; cleaning habits; etc.)

What was the time from PPI therapy initiation to C. difficile symptoms/diagnosis?

What were the first signs/symptoms of C. difficile infection?

How strongly do you believe the PPI led to C. difficile infection? (Conviction: Low; moderate; high)