Acid suppression has long been associated with an increased risk of developing Clostridium difficile infection (CDI), having recurrent Clostridium difficile infection, and now has been shown to increase the complication rate and mortality from Clostridium difficile infection. This risk applies to both H2-blockers and proton pump inhibitors (PPI), but the risk appears to be significantly higher for proton pump inhibitors.
Several prior studies and meta-analyses have demonstrated an increased risk of Clostridium difficile infection with proton pump inhibitor therapy.[1,2,3] Howell et al. performed a case-cohort study investigating over 101,000 patient discharges at a tertiary medical care center over a five-year period. They discovered a three-fold increased incidence of nosocomial CDI in patients receiving daily PPI therapy compared with controls not receiving any acid suppression therapy. The risk of CDI was two-fold in patients receiving daily H2-blocker therapy and 4.5-fold increased risk for patients receiving twice daily PPI therapy. The meta-analysis performed by Deshpande et al. reviewed 30 observational studies between 1990 and 2010 and concluded that PPI therapy is associated with a two-fold increased the risk for CDI.
In addition, we know that PPI use increases the risk of recurrent CDI. A retrospective, cohort study by Linsky et al. analyzed 1166 inpatients at a single center over a five year period and determined that use of PPI within 14 days of CDI diagnosis increased the rate of recurrent CDI after appropriate treatment by 42% compared with those patients not receiving PPI therapy.
The strongest risk factor for the development of CDI is recent antibiotic exposure. The risk of CDI can even persist for up to three months after exposure. The antibiotics that are considered high risk for the development of CDI include cephalosporins, carbapenems, Beta-lactamase inhibitor combination antibiotics, fluoroquinolones, clindamycin, and intravenous vancomycin. A study by Stevens et al. demonstrated that the concomitant use of a PPI and an antibiotic will increase the risk of CDI especially in patients receiving “low-risk antibiotics” and those exposed to one or two antibiotics (as opposed to three or more antibiotics). The number and duration of antibiotics does increase the risk of CDI, but concomitant PPI use does not appear to increase that risk when at least three antibiotics are administered. On the other hand, the hazard ratio of CDI is approximately 16 if a PPI is administered with a “low-risk antibiotic” or with antibiotic monotherapy compared to comparable therapy without a PPI.
Now, a recent retrospective case review of 485 cases over a four year period at a single institution suggests that acid suppression therapy increases the risk of CDI complications and mortality. In this study, about 10% of patients developed complications and nearly 5% of them died. The odds ratio of developing a CDI complication is 2.4 and the odds ratio of death from CDI is 4.74 with acid suppression therapy. Other risk factors for CDI complications included need for hospitalization, age ≥80 years, and corticosteroid use.
In the United States alone, 113 million prescriptions are written each year for PPIs which accounts for $13 billion in sales. There is certainly a role for these agents for peptic ulcer disease and chronic gastroesophageal reflux disease management, but they are undoubtedly overprescribed and can increase the risk of CDI as well as community-acquired pneumonia and hospital-acquired pneumonia. Because of these negative consequences, I advise all clinicians to be more judicious with your prescriptions of acid suppressive therapy.
Joseph Esherick, MD, FAAFP is the Associate Director of Medicine and the Medical ICU Director at the Ventura County Medical Center in Ventura, California. He is also an Associate Clinical Professor of Family Medicine at The David Geffen School of Medicine at UCLA. He received his medical degree from Yale University School of Medicine, New Haven, Connecticut, and completed a family practice residency at the Ventura County Medical Center, Ventura, California. He is board certified in family medicine and the author of the Tarascon Primary Care Pocketbook and the Tarascon Hospital Medicine Pocketbook. He is one of the lead instructors of the Hospitalist and Emergency Procedures Courses for Hospital Procedures Consultants. He is also an editorial board member for Tarascon Publishing and for Elsevier’s First Consult.
Dr. Esherick is the author of some of Tarascon Publishing’s best-selling titles including:
Tarascon Medical Procedures Pocketbook, Tarascon Hospital Medicine Pocketbookand Tarascon Primary Care Pocketbook. Hospital Medicine and Primary Care are also available for mobile (iPhone, Android and Blackberry).
_______________________________________________________ Howell M et al. Iatrogenic Gastric Acid Suppression and the Risk of Nosocomial Clostridium difficile infection. Arch Intern Med. 2010; 170: 784-790.  King R et al. Incidence of Clostridium difficile Infections in Patients Receiving Antimicrobial and Acid-Suppression Therapy. Pharmacotherapy. 2011; 31: 642-648.  Deshpande A et al. Association Between Proton Pump Inhibitor Therapy and Clostridium difficile Infection in a Meta-Analysis. Clin Gastroenterology and Hepatology. 2012; 10: 225-233.  Linsky A et al. Proton Pump Inhibitors and Risk for Recurrent Clostridium difficile Infection. Arch Intern Med. 2010; 170: 772-778.  Stevens V et al. Differential Risk of Clostridium difficile infection with proton pump inhibitor use by level of antibiotic exposure. Pharmacoepid. and Drug Safety. 2011; 20: 1035-1042.  Morrison R et al. Risk Factors Associated with Complications and Mortality in Patients with Clostridium difficile Infection. Clin Infect Dis. 2011; 53: 1173-1178.