Proton Pump Inhibitor Use and Clostridium difficile Infection: The Final Word

There has been a huge increase in the prescription of PPIs globally, and almost 113 million were prescribed in the last decade, which continues to increase rapidly.[2] Epidemiological studies have stated that acid-related disorders are snowballing, especially in India, due to lifestyle and dietary habits transformation.[3] Hence more patients seek to resort to acid-relief medications. Due to their widespread usage in clinical practice, PPIs are prone to be misused. Most (91%) oral PPI prescriptions in inpatient and outpatient cases are inappropriate.[4] A study by Churi et al. showed intravenous (IV) PPIs being inappropriately prescribed to 89.2% of internal medicine ward patients and 34.04% of surgery ward patients.[5]Numerous medication utilization studies have documented the widespread and improper use of PPIs, which may harm one's health.[2] Although PPIs are widely preferred, they remain controversial; in 2017, US Food and Drug Administration (FDA) warned about PPIs use and the risk of developing Clostridium difficile infections.[6]

This article will shed light on using PPIs and an imminent threat to developing C. difficile infections.

Dissecting the Causality of PPIs and C. difficile Infection with Scientific Evidence [6,7,8]

The incidence and severity of C. difficile infection have recently increased, making it a global health problem. A 7.1-26.6% prevalence rate has been found in studies on C. difficile-associated diarrhoea (CDAD) in India.

C. difficile is an anaerobic, gram-positive, spore-forming that spreads via the faecal-oral route before germinating in the gastrointestinal tract and developing vegetative cells that can produce toxins. These toxins (Toxin A and Toxin B) exhibit enterotoxic and cytotoxic activities, respectively, and contribute to the pathogenicity of C. difficile.

Potential Mechanism for PPI-associated C. difficile Infections: Several studies indicate that alkaline gut could lead to the growth of C. difficile:

• Gupta P et al. examined the effect of alkaline stool and the risk of C. difficile infections. The study included 228 patients with signs and symptoms of C. difficile infections, of whom 86.7% tested positive for C. difficile infections and had an alkaline stool.
• Edwards A. N et al. studied the impact of pH on growth, sporulation, motility, and toxin production in C. difficile. The study concluded that sporulation frequency was the lowest under acidic pH, while alkaline colonic pH increased C. difficile infections.

These studies may explain the high prevalence of C. difficile infections in patients with alkaline stools because low gastric pH prevents C. difficile spores from sporulating. In contrast, high gastric and alkaline intestine pH promotes C. difficile survival and enables sporulation and germination of the bacterium's vegetative form. Hence acid suppression treatments like PPIs encourage the survival and proliferation of vegetative C. difficile, which raises the risk of contracting C. difficile infections.

C. difficile infection manifestations could be life-threatening, including significant dehydration, abdominal distension, hypoalbuminemia with peripheral oedema, and subsequent circulatory shock. Other severe complications of C. difficile infections include toxic megacolon, colon perforation, intestinal paralysis, kidney failure, systemic inflammatory response syndrome, septicaemia, and death.

Systematic Review and Meta-analysis Substantiating PPIs as the Risk Factor for Developing C. difficile Infections [6]

Many studies, including systematic reviews and meta-analyses, have pointed out that PPIs can be a potential risk factor for developing C. difficile infections. Some significant studies are:

• Janarthanan et al. looked at 23 studies, including 6 cohort studies and 17 case-control studies conducted in the United States, Canada, Europe, and South Korea. Patients in these studies used PPIs for at least three months before developing acute onset diarrhoea with laboratory-confirmed C. difficile infections. Finally, the study discovered that approximately 65% of PPI users were more likely to develop C. difficile infections than non-users, substantiating that using PPIs can lead to C. difficile infections.
• Deshpande et al. evaluated 30 observational studies in their meta-analysis, including 5 cohorts and 25 case-control studies with 202,965 patients from the United States, United Kingdom, Canada, and South Korea. The combined results of the aforementioned studies revealed a greater incidence of C. difficile infections with PPI therapy than non-PPI users (OR 2.15; 95% CI 1.81-2.70; P<0.00001), pointing out that the use of PPIs use can be a risk factor for developing C. difficile infections.
• Trifan et al. conducted a meta-analysis that comprised 56 studies (40 case-control and 16 cohort) and 356,683 patients. All 56 studies comparing PPI users to non-users found statistically significant results with an OR of 1.99 (CI: 1.73-2.30, P<0.001). The study concluded that PPI users are nearly twice as likely as non-users to contract C. difficile infections.
• Cao et al. conducted a meta-analysis of 50 studies, revealing a substantial link between PPI use and C. difficile infections. The study discovered that patients on PPIs in medicine units had a higher chance of developing C. difficile infections than ICU patients, with an odds ratio of 1.26; (95% CI: 1.12-1.39), indicating that PPI use can raise the risk of C. difficile infections development.
• Oshima et al. performed a systematic review and meta-analysis that included adults and children. There were 67 studies, and these trials were conducted in both inpatient and outpatient settings. The findings revealed an OR of 2.34; (95% CI 1.94-2.82; P<0.00001), demonstrating a statistically significant increase in the risk of C. difficile with PPI usage compared to individuals who did not take PPIs. The study concluded that the use of PPI causes an increase in the incidence of C. difficile infections in adults and children and that it should not be prescribed to a patient of any age unless medically necessary.

Deprescribing PPIs: Prudent Approach from Clinical Guidelines: Although PPIs have been a drug of choice for many gastric-related disorders, several practising guidelines have stressed deprescribing PPIs in the long run.

• According to the American Geriatrics Society (AGS) Beers Criteria, after at least four weeks of PPI treatment and improvement of gastrointestinal symptoms, there is a strong recommendation to discontinue or reduce the PPI dose.[9]
• The American Gastroenterological Association (AGA) recommends deprescribing PPIs without indication for chronic PPIs and tapering twice-daily dosing to once-daily PPI.[10]
• The Canadian Clinical Practice Guidelines also recommend deprescribing PPIs (reducing dose, stopping, or using “on-demand” dosing) in adults who have completed a minimum of 4 weeks of PPI treatment for heartburn or mild to moderate gastroesophageal reflux disease or esophagitis, and whose symptoms are resolved.[11]

Clinical Message: Although PPIs have been widespread and their presence is ubiquitous across various clinical practice settings, they still possess adverse effects that clinicians may need to be aware of while prescribing them. C. difficile infections are one such mammoth burden posed by PPIs if used over a long time. Evidence has pointed out that high pH in the gut induced by PPIs gives a breeding ground for C. difficile infections that can have dire repercussions on patients’ health and well-being. Several studies have corroborated that patients taking PPIs could develop C. difficile infections compared to non-users, thus pointing out the fact that PPIs should be used judiciously and deprescribed when their need is not medically well-justified.

References

1. Strand, D. S., Kim, D., & Peura, D. A. (2017). 25 Years of Proton Pump Inhibitors: A Comprehensive Review. Gut and liver, 11(1), 27–37. https://doi.org/10.5009/gnl15502

2. Al-Dosari, B. S., Binafeef, B. M., & Alsolami, S. A. (2021). Prescribing pattern of proton pump inhibitors among patients admitted to medical ward at King Abdulaziz University Hospital, Jeddah, Saudi Arabia: A retrospective study. Saudi Medical Journal, 42(12), 1313-1319. https://doi.org/10.15537/smj.2021.42.12.20210488

3. Desai, & S Anand. (2021, June). Clinical Practice of Prescribing Proton Pump Inhibitors by Physicians: An Indian Perspective. Journal of the Indian Medical Association, 119(6), 91–96.

4. Verma, Nitish & Tayal, Vandana & Roy, Vandana. (2019). Proton Pump Inhibitors: Prescribing Practices, Appropriateness of Use, and Cost Incurred in a Tertiary Care, Public, Teaching Hospital in New Delhi, India. MAMC Journal of Medical Sciences. 5. 113. 10.4103/mamcjms.mamcjms_40_19.

5. Churi S, Jogani A. Prospective Assessment of Prescribing Pattern of Intravenous Proton Pump Inhibitors in an Indian Tertiary-Care Teaching Hospital. Indian J Pharmacy Pract 2014; 7:3.

6. Tawam, D., Baladi, M., Jungsuwadee, P., Earl, G., & Han, J. (2021). The Positive Association between Proton Pump Inhibitors and Clostridium Difficile Infection. Innovations in Pharmacy, 12(1). https://doi.org/10.24926/iip.v12i1.3439

7. Soman, R., & Sunavala, A. (2012). Clostridium difficile infection--is it coming at us?. The Journal of the Association of Physicians of India, 60, 9–10.

8. Czepiel, J., Dróżdż, M., Pituch, H., Kuijper, E. J., Perucki, W., Mielimonka, A., Goldman, S., Wultańska, D., Garlicki, A., & Biesiada, G. (2019). Clostridium difficile infection: review. European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical Microbiology, 38(7), 1211–1221. https://doi.org/10.1007/s10096-019-03539-6

9. Toth, J., Jadhav, S., Holmes, H.M. et al. Prescribing trends of proton pump inhibitors, antipsychotics, and benzodiazepines of medicare part d providers. BMC Geriatr 22, 306 (2022). https://doi.org/10.1186/s12877-022-02971-2

10. Targownik, L. E., Fisher, D. A., & Saini, S. D. (2022). AGA Clinical Practice Update on De-Prescribing of Proton Pump Inhibitors: Expert Review. Gastroenterology, 162(4), 1334–1342. https://doi.org/10.1053/j.gastro.2021.12.247

11. Farrell, B., Pottie, K., Thompson, W., Boghossian, T., Pizzola, L., Rashid, F. J., Rojas-Fernandez, C., Walsh, K., Welch, V., & Moayyedi, P. (2017). Deprescribing proton pump inhibitors: Evidence-based clinical practice guideline. Canadian family physician Medecin de famille canadien, 63(5), 354–364.