Association between Proton Pump Inhibitors and Clostridium difficile

Transcription

1 Association between Proton Pump Inhibitors and Clostridium difficile Lauren Petrik and Nicholas Hellebusch, Pharm.D. Candidates 2013, Tatum Mead, Pharm.D. UMKC School of Pharmacy Clostridium difficile, more commonly known as C. diff, is a gram positive anaerobic spore forming bacteria that is responsible for the most common cause of hospital associated diarrhea [1]. In 2005, eighty-four in every one-hundred thousand hospitalized patients developed C. diff and twenty thousand patients were diagnosed with C. diff in an outpatient setting [2]. The mortality rate for elderly, frail patients with a confirmed diagnosis of C. diff is estimated to be as high as 25%. In the general population, C. diff can lead to death, increased length of hospital stay and costs by as much as $5,000 per patient over the 180 days following the diagnosis of C. diff [3]. Established risk factors for the development of C. diff include recent antibiotic use ( previous 90 days; particularly exposure to antibiotics shown to increase the risk of C. diff such as clindamycin, fluroquinolones, 3 rd generation cephalosporins and ampicillin), an extended period of time spent in a healthcare facility (>14 days), increased age (>65 years old), serious underlying illness (immunocompromised patients such as those with HIV or receiving chemo), and proton pump inhibitor (PPI) use. The correlation between PPI use and greater patient susceptibility to the development of C. diff has been controversial. Data suggests there is a link between PPI use and both increased C. diff development and reoccurrence rates. A reoccurrence rate of up to 42% has been shown for patients exposed to PPIs and antibiotics within days following C. diff treatment [4]. On February 8, 2012 the FDA released a statement indicating an increased risk of C. diff associated with PPIs, ranging from 1.4 to 2.75 times greater risk for patients exposed to PPIs compared to patients who did not receive a PPI [5]. The basis for the increased risk is due to decreased acidity in the stomach, resulting from the blockage of the H + /K + ATPase enzyme (also known as a proton pump) in stomach parietal cells. The high acidity of the stomach, or low ph, is the main defense mechanism the body uses to inhibit the colonization and multiplication of bacteria associated with C. diff infections [1]. The higher the ph, the greater the number of bacteria capable of survival. PPIs are the most potent acid suppressing agents on the market and are often given in the hospital for stress ulcer prophylaxis and in the outpatient setting for gastroesophageal disease or dyspepsia. Histamine receptor antagonists (H2RA) have not been studied as thoroughly as PPIs, but are also believed to increase the risk of C. diff. Some studies have shown increased risks of developing C. diff as high as 2-fold for patients taking H2RAs and having risk factors such as gender, age, a hospital stay >7 days and recent antibiotic use, compared to patients not taking H2RAs [1]. Numerous studies conducted have shown an increased association of C. diff and PPIs. Some studies have shown increased risks of developing C. diff as high as 3-fold for patients taking PPIs and having risk factors such as gender, age, a hospital stay >7 days and recent antibiotic use, compared to patients not taking a PPI [1]. C. diff development is not only related to the use of PPIs, higher dosages have been shown to further increase the risk of C. diff development [6]. Patients receiving PPI therapy showed a greater chance of developing C. diff at 77% compared to control patients receiving no PPI therapy at 43% [1]. This compelling evidence should urge healthcare providers to review the necessity to initiate and/or continue PPI therapy. Table 1 [7] below provides appropriate indications, dosing and length of treatment for PPI therapies in accordance with the American Gastroenterological Association (AGA) guidelines. Table 2 [8] below indicates which patients should receive stress ulcer prophylaxis, also in accordance with the AGA guidelines [9]. Studies have shown that as many as 53% of patients on PPIs have no such indication [4]. Even if a patient has an appropriate indication for stress ulcer prophylaxis, it is important the patient be on the lowest effective dose 1

2 and the risks versus benefits for every patient should be evaluated before therapy initiation. Following the appropriate treatment duration and/or upon discharge from a healthcare facility, patients should be reassessed for such risk factors as recent antibiotic use, extended period of time spent in a healthcare facility, increasing age, serious underlying illness, and previous PPI use, when determining necessity for continuation of acid suppression therapy. Healthcare providers can consider tapering the patient off PPI therapy to avoid rebound hypersecretion and discomfort for the patient. Patients that take a moderate to high dose PPI should have the dose reduced 50 percent every week until on the lowest dose. After one week at the lowest dose the medication can be stopped [10]. While PPI use may be an appropriate choice, healthcare providers should remind patients that available over-the-counter PPIs are to be used for short intervals ( 14 days and for no >3 rounds per year). PPIs provide greater acid suppression compared to H2RAs, thus patients are more greatly predisposed to C. diff infection on PPI therapy. Since PPIs do not provide significant efficacy over H2RAs for the treatment of stress ulcer prophylaxis, H2RA therapy should be considered a possible alternative to PPIs [9]. Table 3 [11] below provides dosage recommendations for H2RA therapy. References: 1. Aseeri, M, T Schroeder, et al. "Gastric Acid Suppression by Proton Pump Inhibitors as a Risk Factor for Clostridium difficile-associated Diarrhea in Hospitalized Patients." American Journal of Gastroenterology 103. (2008): Medline. Database. 2 Feb Aberra, F., Katz, J., & Gronczewski, C. (2012). Clostridium difficile colitis. In J. Katz (Ed.), Medscape Reference Retrieved from 3. Dubberke ER, et al. Short- and long-term attributable costs of Clostridium difficile-associated disease in nonsurgical patients> Clin Infect Dis. 2008; 46: Linsky, A, G Kalpana, et al. "Proton Pump Inhibitors and Risk for Recurrent Clostridium difficile Infection." (2010): Medline. Database. 2 Feb PL Detail-Document, Proton Pump Inhibitors (PPIs) and C. difficile. Pharmacist s Letter/Prescriber s Letter. March Howell, M, V Novack, et al. "Iatrogenic Gastric Acid Suppression and the Risk of Nosocomial Clostridium Difficlie Infection." Arch Intern Med (2010): Medline. Database.2 Feb Hester, S. Comparison of proton pump inhibitors. Pharmacist's Letter/Prescriber's Letter 2009;25(3): (Full update January 2010). 8. Hester, S. Overuse of acid suppressing drugs in the hospital. Pharmacist's Letter/Prescriber's Letter 2009;25(7): Guillamondegui, O et al. Practice management guidelines for stress ulcer prophylaxis. Chicago (IL): Eastern Association for the Surgery of Trauma (EAST); p. [58 references]. 10. Wolfe, M. "Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders." UpToDate Web.6 Mar < 11. Cupp, M. Histamine H 2 blocker oral dose comparison. Pharmacist's Letter/Prescriber's Letter 2009;25(8):

3 Table 1 Comparison of Proton Pump Inhibitors [7] Drug Indications and Adult Doses Drug Indications and Adult Doses Dexlansoprazole (Dexilant.) Omeprazole (Prilosec, Prilosec OTC) 60 mg QD for up to 8 weeks 30 mg QD for up to 6 months Symptoms from nonerosive GERD: 30 mg QD for 4 weeks for 4-8 weeks Healing gastric ulcers: 40 mg QD for 4-8 weeks for 4-8 weeks 20 mg BID for 10 days (triple therapy) or 40 mg QD for 14 days (dual therapy) Pathologic hypersecretory 60 mg QD. Max=360 mg/day Treatment of heartburn (OTC): for 14 days Omeprazole and sodium bicarbonate (Zegerid, Zegerid OTC) Pantoprazole (Protonix) EE=erosive esophagitis; GERD=gastroesophageal reflux disease Healing benign gastric ulcers: 40 mg QD for 4-8 weeks with EE: for 4-8 weeks Reduce risk of UGI bleeding in critically ill (suspension): 40 mg x1, then in 6-8 hours, then QD Treatment of heartburn (OTC): for 14 days PO: 40 mg QD for up to 8 weeks 40 mg QD Pathologic hypersecretory 40 mg BID. Max = 240 mg/day IV: with EE: 40 mg QD for 7-10 days Pathologic hypersecretory 80 mg Q12H. Max=240 mg/day 3

4 Table 1 Comparison of Proton Pump Inhibitors (continued) [7] Drug Esomeprazole (Nexium) Indications and Adult Doses PO: mg QD for 4-8 weeks 40 mg QD for 10 days (triple therapy) Reducing risk for ulcer with NSAIDs: mg QD for up to 6 months Pathologic hypersecretory 40 mg BID. Max=240 mg/day IV: 40 mg QD for 7-10 days Pathologic hypersecretory 80 mg Q12H. Max=240 mg/day Drug Indications and Adult Doses Drug Indications and Adult Doses Lansoprazole (Prevacid, Prevacid 24HR [OTC]) PO: 15 mg QD for 4 weeks Maintenance for duodenal ulcers: 15 mg QD 30 mg QD for up to 8 weeks Healing benign gastric ulcers: 30 mg QD for up to 8 weeks 15 mg QD for up to 8 weeks 30 mg Q12H for days(dual tx) or 30 mg Q8H for 14 days (triple tx) Reducing risk for ulcer with NSAIDs: 15 mg QD for up to 12 weeks Healing ulcers from NSAIDs: 30 mg QD for up to 8 weeks Treatment of heartburn (OTC): 15 mg QD for 14 days EE=erosive esophagitis; GERD=gastroesophageal reflux disease Rabeprazole (Aciphex) for up to 4 weeks Healing EE or ulcerative GERD: for 4-8 weeks Maintenance for EE or ulcerative GERD: 20 mg BID for 7 days Pathologic hypersecretory 60 mg QD. Max=120 mg/day 4

5 Table 2 - Patients Indicated for Stress Ulcer Prophylaxis [8] Coagulopathy (platelet count <50,000 mm 3, INR >1.5, or aptt >2 times control) Mechanical ventilation for >48 hours History of GI ulceration or bleeding within one year of admission Glasgow Coma score 10 Thermal injury to >35% of body surface area Partial hepatectomy Multiple trauma Transplantation perioperatively in the ICU Spinal cord injury Hepatic failure Two or more of the following risk factors: o Sepsis o ICU stay of more than one week o Occult bleeding lasting at least six days o High-dose corticosteroids (>250 mg/day of hydrocortisone) 5

6 Table 3 Histamine H 2 Blocker Oral Dose Comparison [11] Note: Dose comparison based on manufacturers' recommended oral dosing for patients with normal renal function. Consider indication, side effects, and drug interactions when choosing an H2 blocker. Doses in shaded column provide >80% duodenal or gastric ulcer healing at 8 weeks. 1-6 Abbreviations: BID=twice daily; CrCl=creatinine clearance; GERD=gastroesophageal reflux disease; HS=at bedtime; QID=four times daily Medication Maintenance, duodenal ulcer Active ulcer GERD/erosive esophagitis Cimetidine (Tagamet, generics) a 400 mg HS 800 mg HS (can divide BID for duodenal ulcer) up to 1600 mg HS (duodenal) or 300 mg QID (gastric) b 1600 mg divided BID or QID Famotidine (Pepcid, generics) c 20 mg HS 40 mg HS (can divide BID for duodenal ulcer) 20 mg BID (GERD); 20 or 40 mg BID (erosive esophagitis) Nizatidine (Axid, generics) 150 mg HS d 300 mg HS (duodenal ulcers) or divided BID (duodenal or gastric ulcers) e Ranitidine (Zantac, generics) f 150 mg HS 300 mg HS (duodenal ulcer) or 150 mg BID (duodenal or gastric ulcer) e 150 mg BID 150 mg BID (GERD); 150 mg QID (erosive esophagitis) a. Renal dosing, severe renal impairment: maximum dose 300 mg BID, increasing to TID with caution. 1 b. Optimal for most patients is 800 mg HS. Another regimen that has been used is 300 mg four times daily. A dose of 1600 mg HS may provide faster duodenal ulcer healing in smokers. 1 c. Renal dosing, CrCl <50 ml/min: reduce dose by 50% or extend dosing interval to every hours. 2 d. Renal dosing, CrCl ml/min: 150 mg every other day; CrCl <20 ml/min: 150 mg every third day. 3 e. Renal dosing, CrCl ml/min: 150 mg daily; CrCl <20 ml/min: 150 mg every other day. 3 f. Renal dosing, CrCl <50 ml/min: 150 mg QD, increasing to BID or even further with caution. 4 References for content contained within Table 3: 1. Product information for cimetidine. Mylan Pharmaceuticals, Inc. Morgantown, WV September Product information for Pepcid. Merck & Co., Inc. Whitehouse Station, NJ January Product information for Axid. Reliant Pharmaceuticals, Inc. Liberty Corner, NJ March Product information for Zantac. GlaxoSmithKline. Research Triangle Park, NC April Chase SL, Peterson AM, Wordell CJ. Therapeutic-interchange program for oral histamine H 2 -receptor antagonists. Am J Health Syst Pharm 1998;55: United States Department of Veterans Affairs. Pharmacy Benefits Management Services. Medical Advisory Panel. Drug class review. H 2 -receptor antagonists. Review.pdf. (Accessed July 6, 2009). 6