Page 32 - Christiana Care Focus August 2018

Pharmacy Services | Therapeutic Notes
Acid-suppressive therapy and Clostridium difficile infection
Clostridium difficile infection (CDI) has become the most common cause of health-care-associated infections in U.S. hospitals and thus represents a significant public health concern.1 It is estimated that approximately 500,000 CDIs occur annually in the U.S., accounting for 15,000-30,000 deaths. Additionally, the annual U.S. acute care cost attributable to CDI is estimated to be 1.2-5.9 billion dollars.
Understanding the risk factors associated with CDI is essential to help guide strategies for prevention. The Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) outlines specific risk factors including advanced age, prolonged hospitalization, exposure to antimicrobial agents, antineoplastics, and gastrointestinal surgery. The role of acid-suppressive therapy in the development of CDI remains controversial.2
A proposed biologic mechanism for CDI development is the suppression of gastric acid, an important host defense mechanism for preventing germination of ingested Clostridium difficile spores. Proton pump inhibitor (PPI) use may also result in harmful changes in the human gut microbiome over time, further increasing the risk of CDI.3
A number of observational studies and meta-analyses have associated PPI use with an increased risk of CDI.4-5 However, these studies utilized various definitions for CDI and were found to have significant heterogeneity of data.
For this reason, a multicenter retrospective cohort study was recently conducted to identify risk factors associated with the development of hospital onset-Clostridium difficile infection (HO-CDI), namely acid- suppressive therapy. This study identified 1,237,537 patients through the National Healthcare Safety Network (NHSN) database across 150 hospitals in the U.S. CDI was defined as a positive stool test for toxigenic Clostridium difficile or toxin-coding genes from an unformed stool collected on hospital day > 3, in accordance with the NHSN definition for HO-CDI. Acid-suppressing/protecting medications included antacids, H2 receptor antagonists (H2RAs), PPIs, and sucralfate.5 Less than one percent of patients were classified as
References
Jamie John, Pharm.D.
HO-CDI positive, with a larger percentage of these patients receiving acid-suppressive therapy. According to the results of a multivariate logistic regression model, PPIs were found to increase the odds
of HO-CDI by 44 percent (p<0.001). Interestingly, H2RAs also significantly increased the odds of HO-CDI by 13 percent (p<0.001).6
Due to the observed association and plausible biologic mechanisms, it is prudent to focus on optimization of acid-suppressive therapy in the hospital setting. The 1999 American Society of Health-System Pharmacists therapeutic guidelines for stress ulcer prophylaxis provide the following indications: Intensive Care Unit (ICU) patients with ≥ 1 of the following: mechanical ventilation > 48 hours, coagulopathy, or history of GI ulceration or bleeding in the previous year OR ICU patients with ≥ 2 of the following: sepsis, ICU stay > 7 days, occult bleeding ≥ 6 days, high dose corticosteroids, traumatic brain injury, spinal cord injury, burn injury, or hepatic failure.7 Since these guidelines were published, improvements in the management of critically ill patients, including optimal fluid resuscitation and early enteral feeding, have significantly decreased the incidence of stress ulcers in this population. Additionally, recent data suggests that stress ulcer prophylaxis may not be necessary even in high-risk patients if adequately tolerating enteral feeding.8 Other indications for acid- suppressive therapy may include gastroesophageal reflux disease, erosive esophagitis, peptic ulcer disease, gastric hypersecretory conditions, etc.
A review of HO-CDIs from the previous three years at Christiana Care found patients on PPI therapy to be twice as likely to have HO-CDI (odds ratio [OR], 2.09; 95 percent confidence interval [CI], 1.7 1-2.55). Furthermore, the vast majority of PPI orders in the hospital setting are continued from the outpatient setting without a clear understanding of the indication for the agent. It is therefore essential to address the requirement for acid-suppressive therapy, the specific agent utilized, the appropriate dose, opportunities for de-escalation, and duration of therapy. Ultimately, minimizing inappropriate use of acid-suppressive therapy may yield a significant impact on the substantial healthcare burden associated with CDI. 
1. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile Infection in the United States. New England Journal of Medicine 2015; 372(9):825-34.
2. Mcdonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):987-994.
3. Azab M, Doo L, Doo DH, et al. Comparison of the Hospital-Acquired Clostridium difficile Infection Risk of Using Proton Pump Inhibitors versus Histamine-2 Receptor Antagonists for Prophylaxis and Treatment of Stress Ulcers: A Systematic Review and Meta-Analysis. Gut Liver. 2017.
4. Janarthanan S, Ditah I, Adler DG, et al. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol 2012; 107(7):1001-10.
5. Arriola V, Tischendorf J, Musuuza J, et al. Assessing the Risk of Hospital-Acquired Clostridium Difficile Infection With Proton Pump Inhibitor Use: A Meta-Analysis. Infect Control Hosp Epidemiol 2016; 37(12):1408-17.
6. Watson T, Hickok J, Fraker S, et al. Evaluating the risk factors for hospital-onset Clostridium difficile infections in a large healthcare system. Clin Infect Dis. 2017.
7. American Society of Health-System Pharmacists. ASHP therapeutic guidelines on stress ulcer prophylaxis. Am J Health-Syst Pharm. 1999;56:347-79.
8. Huang HB, Jiang W, Wang CY, et al. Stress ulcer prophylaxis in intensive care unit patients receiving enteral nutrition: a systematic review and meta-analysis. Crit Care. 2018;22(1):20.
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