Acid-Suppressing Drugs Associated with Serious Infectious Diarrhea

Proton pump inhibitors (PPIs) and histamine 2-receptor antagonists (H2As) suppress the production of acid in the stomach and are therefore known as acid suppressants. They are widely (and often unnecessarily) used for treating heartburn. Additionally, all prescription H2As and PPIs (except dexlansoprazole [DEXILANT] and pantoprazole [PROTONIX]) are effective, approved treatments for a gastrointestinal ulcer.

It has long been known that acid suppressants come with serious side effects. A recent study[1] published in the medical journal JAMA Internal Medicine confirmed that acid suppressants are associated with a particularly dangerous side effect: recurrent (a repeated episode of ) Clostridium difficile infection. The study is important because C. difficile infection often can be severe and life-threatening and because acid suppressants are used so widely and liberally, despite few long-term benefits for many users.

C. difficile infection

C. difficile is a bacterium that can live in the large intestine (also called the colon). Most people whose colons contain C. difficile do not develop any illness. This is because the colon normally is filled with millions of other bacteria that play key roles in maintaining a healthy bowel. These “good” bacteria block the overgrowth of potentially diseasecausing bacteria such as C. difficile.

However, when people are treated with antibiotics, many of these good bacteria in the colon are killed. Left unchecked by these good bacteria, the C. difficile can multiply and produce a toxin that causes watery diarrhea and stomach cramps. In severe cases, C. difficile infection can cause fever, nausea, bloody stools and other symptoms.

An estimated half a million Americans were diagnosed with a C. difficile infection in 2011, and 29,000 of them died within 30 days of the initial diagnosis.[2] Approximately 83,000 infected people experienced at least one repeat episode.[3]

Stomach acid serves as a barrier to bacteria entering the body, killing most organisms that are swallowed. It is speculated that suppressing the amount of acid in the stomach might enable certain bacteria, such as C. difficile, to survive the stomach’s environment and make their way to the colon, which can lead to infection.[4]

It is therefore not surprising that an association has been found previously between stomach acidsuppressing medications and C. difficile infection in patients.[5],[6] This evidence prompted the Food and Drug Administration (FDA) in 2012 to alert the public and health care professionals that PPIs could increase the risk of C. difficile infection, and the agency required a (not very prominent) warning of this risk to be included in the labels of all PPI medications.[7] In the same announcement, the FDA stated that it was “reviewing” the evidence linking H2As with C. difficile infection, but the agency has not yet disclosed its conclusion, nor has it required any information on a possible association to be included in the labels of any H2As.

JAMA Internal Medicine Study

What has not been determined definitively is whether acid suppressants increase the risk of repeat C. difficile infection in those with a previous bout of the disease, with studies on the topic showing conflicting results. The JAMA Internal Medicine study set out to combine and analyze data from prior studies together in order to determine whether acid-suppressing medications increase the risk of a repeat C. difficile infection.[8]

The new study looked at more than 7,700 patients with C. difficile infection across 16 different previous observational studies. The patients had received PPIs, H2As, both H2As and PPIs, unspecified acid suppressants, or no acid suppressants. More than half of the patients were using acid suppressants.

The analysis showed that, after adjusting for differences in age and health status, patients who were taking acid suppressants were 38 percent more likely to experience a repeat bout of C. difficile infection. Some of the analyzed studies defined recurrence as a repeat C. difficile infection within 60 days of the initial bout, whereas others defined it as a repeat infection within 90 days. Acid suppressants increased the risk of a repeat C. difficile infection within both time periods.

The study authors also analyzed separately the risk of repeat C. difficile infection in eight studies that evaluated only patients using PPIs, and they found an even higher 66 percent increased risk of repeat infection with use of these drugs. In contrast, a separate analysis of the seven studies that assessed patients using PPIs or H2As plus one study that only examined patients using H2As did not find an increased risk of repeat C. difficile infection with use of these acid suppressants. The relevance of this latter finding is unclear. Although H2As are less potent acid suppressants than PPIs[9] and may therefore truly involve less risk of certain side effects, they also have been associated with C. difficile infection in previous studies.[10]

Nonetheless, the recent study’s findings of an increased risk of repeat C. difficile infection with use of acid suppressants is concerning because of the widespread overuse of these medications, especially PPIs. One study has shown that up to two thirds of all prescriptions for PPIs are given for unapproved or unproven uses.[11]

What You Can Do

Avoiding unnecessary antibiotic use is the best way to prevent C. difficile infection. If you have minor cold-like symptoms, such as those occurring with a sinus infection or a sore throat, that last just a few days, the cause is almost always viral. If it is indeed a viral infection, antibiotics will be completely ineffective and will only put you at risk for side effects and antibiotic resistance.

If you have heartburn (gastroesophageal reflux disease), there are many nondrug approaches you can adopt to try to relieve your symptoms. Avoiding excessive amounts of alcohol, coffee, chocolate or foods high in fat and, for nighttime heartburn, avoiding food too close to bedtime and raising the head of the bed at night, can go a long way toward relieving heartburn symptoms.

If your symptoms persist, you can try drugs that are safer than PPIs and H2As and still effective. Overthe- counter antacids (MAALOX, TUMS) are the oldest and safest treatments for heartburn and have few side effects (except in people who have kidney disease, who should avoid antacids until consulting a health care provider).

If antacids do not work, then H2As should be tried before resorting to PPIs because H2As are less potent suppressors of stomach acid and cause fewer serious side effects. Certain H2As, however, interact dangerously with other drugs,[12] so you should always tell your doctor about all the medications you are taking before starting an H2A.

If you do eventually require a PPI for your symptoms, you should first discuss the risks of treatment with your doctor. Having such a discussion with a doctor is especially important given that PPIs are heavily overused, often for conditions for which they have not been approved as effective treatments.[13] To see a complete discussion of risks with PPIs other than C. difficile infection, see our in-depth article on PPIs in the November 2011 issue of Worst Pills, Best Pills News.[14]

References

[1] Tariq R, Singh S, Gupta A, et al. Association of gastric acid suppression with recurrent Clostridium difficile infection: A systematic review and meta-analysis. JAMA Intern Med. 2017 Mar 27. doi: 10.1001/jamainternmed.2017.0212.

[2] Centers for Disease Control and Prevention. Healthcare-associated Infections: Clostridium difficile Infection. Clinicians page. https://www.cdc.gov/hai/organisms/cdiff/cdiff_clinicians.html. Accessed May 3, 2017.

[3] Ibid.

[4] Tariq R, Singh S, Gupta A, et al. Association of gastric acid suppression with recurrent Clostridium difficile infection: A systematic review and meta-analysis. JAMA Intern Med. 2017 Mar 27. doi: 10.1001/jamainternmed.2017.0212.

[5] Tleyjeh IM, Abdulhak AB, Riaz M, et al. The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis. PLoS One. 2013;8(3):e56498.

[6] Deshpande A, Pant C, Pasupuleti V, et al. Association between proton pump inhibitor therapy and Clostridium difficile infection in a meta-analysis. Clin Gastroenterol Hepatol. 2012;10(3):225-233.

[7] Food and Drug Administration. FDA drug safety communication: Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). February 8, 2012. https://www.fda.gov/Drugs/DrugSafety/ucm290510.htm. Accessed May 3, 2017.

[8] Tariq R, Singh S, Gupta A, et al. Association of gastric acid suppression with recurrent Clostridium difficile infection: A systematic review and meta-analysis. JAMA Intern Med. 2017 Mar 27. doi: 10.1001/jamainternmed.2017.0212.

[9] Huang JQ, Hunt RH. Pharmacological and pharmacodynamic essentials of H(2)-receptor antagonists and proton pump inhibitors for the practising physician. Best Pract Res Clin Gastroenterol. 2001;15(3):355-70.

[10] Tleyjeh IM, Abdulhak AB, Riaz M, et al. The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis. PLoS One. 2013;8(3):e56498.

[11] Ahrens D, Chenot JF, Behrens G, et al. Appropriateness of treatment recommendations for PPI in hospital discharge letters. Eur J Clin Pharmacol. 2010;66(12):1265-71.

[12] Mayo Clinic. Drugs and Supplements: Histamine H2 Antagonist. http://www.mayoclinic.org/drugs-supplements/histamine-h2-antagonist-oral-route-injection-route-intravenous-route/before-using/drg-20068584. Accessed May 3, 2017.

[13] Heidelbaugh JJ, Kim AH, Chang R, Walker PC. Overutilization of proton-pump inhibitors: What the clinician needs to know. Therap Adv Gastroenterol. 2012;5(4):219-232.

[14] Proton pump inhibitors: Dangerous and habit-forming heartburn drugs. Worst Pills, Best Pills News. November 2011. /newsletters/view/772. Accessed May 3, 2017.