Proton pump inhibitors: Potential adverse effects

Current Opinion in Gastroenterology

Volumn 28, Issue 6, 2012, Pages 615-620

  Abraham, Neena S ^a  

^a BAYLOR COLLEGE OF MEDICINE   (United States)

Author keywords

B12 deficiency; bone fractures; Clostridium difficile; hypomagnesemia; pneumonia; proton pump inhibitor side effects

Indexed keywords

CALCIUM; CLOPIDOGREL; OMEPRAZOLE; PROTON PUMP INHIBITOR; REACTIVE OXYGEN METABOLITE;

CARDIOVASCULAR RISK; CLINICAL TRIAL (TOPIC); CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM DIFFICILE INFECTION; CYANOCOBALAMIN DEFICIENCY; CYTOSOL; DRUG ANTAGONISM; DRUG SCREENING; FRACTURE; GASTRIC HYPERACIDITY; GASTROINTESTINAL HEMORRHAGE; HUMAN; HYPOMAGNESEMIA; INFECTION RISK; INTERSTITIAL NEPHRITIS; INTESTINE INFECTION; LEUKOCYTE FUNCTION; MAGNESIUM DEFICIENCY; META ANALYSIS (TOPIC); NEUTROPHIL; PNEUMONIA; PRESCRIPTION; REVIEW; RISK REDUCTION; SIDE EFFECT; STOMACH CARCINOID; STOMACH PH; TREATMENT DURATION; TREATMENT INDICATION;

AGE FACTORS; CARCINOID TUMOR; CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM INFECTIONS; DRUG INTERACTIONS; FRACTURES, BONE; GASTROINTESTINAL HEMORRHAGE; HUMANS; MAGNESIUM DEFICIENCY; NEPHRITIS, INTERSTITIAL; PNEUMONIA; PROTON PUMP INHIBITORS; RISK FACTORS; STOMACH NEOPLASMS; VITAMIN B 12 DEFICIENCY;

EID: 84868369288     PISSN: 02671379     EISSN: 15317056     Source Type: Journal    
DOI: 10.1097/MOG.0b013e328358d5b9     Document Type: Review

References (114)

1. Pallarito K. How safe are popular reflux drugs? Experts debate evidence linking acid-blockers to possible bone, heart problems. US News World Report 4 November 2009. http://health.usnews.com/health-news/familyhealth/bones-joints- and-muscles/articles/2009/11/04/how-safe-are-popularreflux-drugs. [Accessed 28 March 2012].
2. Dries AM, Richardson P, Cavazos J, Abraham NS. Therapeutic intent of proton pump inhibitor prescription among elderly nonsteroidal anti-inflammatory drug users. Aliment Pharmacol Ther 2009; 30:652-661.
3. Sheen E, Triadafilopoulos G. Adverse effects of long-term proton pump inhibitor therapy. Dig Dis Sci 2011; 56:931-950.
4. Dutta SK. Vitamin B12 malabsorption and omeprazole therapy. J Am Coll Nutr 1994; 13:544-545.
5. Saltzman JR, Kemp JA, Golner BB, et al. Effect of hypochlorhydria due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B12 absorption. J Am Coll Nutr 1994; 13:584-591.
6. Thorens J, Forehlich F, Schwizer W, et al. Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. Gut 1996; 39:54-59.
7. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med 1994; 120:211-215.
8. Hirschowitz BI, Worthington J, Mohnen J. Vitamin B12 deficiency in hypersecretors during long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2008; 27:1110-1121.
9. Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Curr Gastroenterol Rep 2010; 12:448-457.
10. Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol 2004; 57:422-428.
11. Dharmarajan TS, Kanagala MR, Murakonda P, et al. Do acid-lowering agents affect vitamin B12 status in older adults? J Am Med Dir Assoc 2008; 9:162-167.
12. Rozgony NR, Fang C, Kuczmarski MF, Bob H. Vitamin B(12) deficiency is linked with long-term use of proton pump inhibitors in institutionalized older adults: could a cyanocobalamin nasal spray be beneficial? J Nutr Elder 2010; 29:87-99.
13. Yang YX, Metz DC. Safety of proton pump inhibitor exposure. Gastroenterology 2010; 139:1115-1127.
14. Cundy T, Dissanayake A. Severe hypomagnesaemia in long-term users of proton-pump inhibitors. Clin Endocrinol (Oxf) 2008; 69:338-341.
15. Reimer C, Sondergaard B, Hilsted L, Bytzer P. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009; 137:80-87; 87.
16. Waldum HL, Qvigstad G, Fossmark R, et al. Rebound acid hypersecretion from a physiological, pathophysiological and clinical viewpoint. Scand J Gastroenterol 2010; 45:389-394.
17. McColl KE, Gillen D. Evidence that proton-pump inhibitor therapy induces the symptoms it is used to treat. Gastroenterology 2009; 137:20-22.
18. McCarthy DM. Adverse effects of proton pump inhibitor drugs: clues and conclusions. Curr Opin Gastroenterol 2010; 26:624-631.
19. Niklasson A, Lindstrom L, Simren M, et al. Dyspeptic symptom development after discontinuation of a proton pump inhibitor: a double-blind placebocontrolled trial. Am J Gastroenterol 2010; 105:1531-1537.
20. Metz DC, Pilmer BL, Han C, Perez MC. Withdrawing PPI therapy after healing esophagitis does not worsen symptoms or cause persistent hypergastrinemia: analysis of dexlansoprazole MR clinical trial data. Am J Gastroenterol 2011; 106:1953-1960.
21. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association medical position statement on the management of gastroesophageal reflux disease. Gastroenterology 2008; 135:1383-1391.
22. Sierra F, Suarez M, Rey M, Vela MF. Systematic review: proton pump inhibitorassociated acute interstitial nephritis. Aliment Pharmacol Ther 2007; 26:545-553.
23. Perazella MA, Markowitz GS. Drug-induced acute interstitial nephritis. Nat Rev Nephrol 2010; 6:461-470.
24. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97:934-959.
25. Laine L, Ahnen D, McClain C, et al. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000; 14:651-668.
26. Abraham NS. Prescribing proton pump inhibitor and clopidogrel together: current state of recommendations. Curr Opin Gastroenterol 2011; 27:558-564.
27. Tantry US, Kereiakes DJ, Gurbel PA. Clopidogrel and proton pump inhibitors: influence of pharmacological interactions on clinical outcomes and mechanistic explanations. JACC Cardiovasc Interv 2011; 4:365-380.
28. Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation 2010; 122:2619-2633.
29. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363:1909-1917.
30. Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009; 101:714-719.
31. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009; 373:309-317.
32. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360:354-362.
33. Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009; 302:849-857.
34. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360:363-375.
35. Cayla G, Hulot JS, O'Connor SA, et al. Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. JAMA 2011; 306:1765-1774.
36. Bliden KP, Tantry US, Storey RF, et al. The effect of ticagrelor versus clopidogrel on high on-treatment platelet reactivity: combined analysis of the ONSET/OFFSET and RESPOND studies. Am Heart J 2011; 162:160-165.
37. Wiviott SD, Braunwald SE, McCabe SCH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357:2001-2015.
38. Khalili H, Huang ES, Jacobson BC, et al. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ 2012; 344:e372.
39. Targownik LE, Lix LM, Metge CJ, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008; 179:319-326.
40. Vestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int 2006; 79:76-83.
41. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006; 296:2947-2953.
42. Targownik LE, Lix LM, Leung S, Leslie WD. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology 2010; 138:896-904.
43. Gray SL, LaCroix AZ, Larson J, et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative. Arch Intern Med 2010; 170:765-771.
44. Kaye JA, Jick H. Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 2008; 28:951-959.
45. Corley DA, Kubo A, Zhao W, Quesenberry C. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among atrisk patients. Gastroenterology 2010; 139:93-101.
46. Ngamruengphong S, Leontiadis GI, Radhi S, et al. Proton pump inhibitors and risk of fracture: a systematic review and meta-analysis of observational studies. Am J Gastroenterol 2011; 106:1209-1218.
47. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336:924-926.
48. Theisen J, Nehra D, Citron D, et al. Suppression of gastric acid secretion in patients with gastroesophageal reflux disease results in gastric bacterial overgrowth and deconjugation of bile acids. J Gastrointest Surg 2000; 4:50-54.
49. Zedtwitz-Liebenstein K, Wenisch C, Patruta S, et al. Omeprazole treatment diminishes intra- and extracellular neutrophil reactive oxygen production and bactericidal activity. Crit Care Med 2002; 30:1118-1122.
50. Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol 2007; 102:2047-2056.
51. 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; 10:225-233.
52. Linsky A, Gupta K, Lawler EV, et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med 2010; 170:772-778.
53. Laheij RJ, Sturkenboom MC, Hassing RJ, et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004; 292:1955-1960.
54. Gulmez SE, Bansal D, Sotos J, et al. Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study. Arch Intern Med 2007; 167:950-955.
55. Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med 2008; 149:391-398.
56. Sultan N, Nazareno J, Gregor J. Association between proton pump inhibitors and respiratory infections: a systematic review and meta-analysis of clinical trials. Can J Gastroenterol 2008; 22:761-766.
57. Pallarito K. How safe are popular reflux drugs? Experts debate evidence linking acid-blockers to possible bone, heart problems. US News World Report 4 November 2009. http://health.usnews.com/health-news/familyhealth/bones-joints- and-muscles/articles/2009/11/04/how-safe-are-popularreflux-drugs. [Accessed 28 March 2012].
58. Targownik LE, Metge C, Roos L, Leung S. The prevalence of and the clinical and demographic characteristics associated with high-intensity proton pump inhibitor use. Am J Gastroenterol 2007; 102:942-950.
59. Dries AM, Richardson P, Cavazos J, Abraham NS. Therapeutic intent of proton pump inhibitor prescription among elderly nonsteroidal anti-inflammatory drug users. Aliment Pharmacol Ther 2009; 30:652-661.
60. Sheen E, Triadafilopoulos G. Adverse effects of long-term proton pump inhibitor therapy. Dig Dis Sci 2011; 56:931-950.
61. Dutta SK. Vitamin B12 malabsorption and omeprazole therapy. J Am Coll Nutr 1994; 13:544-545.
62. Saltzman JR, Kemp JA, Golner BB, et al. Effect of hypochlorhydria due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B12 absorption. J Am Coll Nutr 1994; 13:584-591.
63. Thorens J, Forehlich F, Schwizer W, et al. Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. Gut 1996; 39:54-59.
64. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med 1994; 120:211-215.
65. Hirschowitz BI, Worthington J, Mohnen J. Vitamin B12 deficiency in hypersecretors during long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2008; 27:1110-1121.
66. Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Curr Gastroenterol Rep 2010; 12:448-457.
67. Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol 2004; 57:422-428.
68. Dharmarajan TS, Kanagala MR, Murakonda P, et al. Do acid-lowering agents affect vitamin B12 status in older adults? J Am Med Dir Assoc 2008; 9:162-167.
69. Rozgony NR, Fang C, Kuczmarski MF, Bob H. Vitamin B(12) deficiency is linked with long-term use of proton pump inhibitors in institutionalized older adults: could a cyanocobalamin nasal spray be beneficial? J Nutr Elder 2010; 29:87-99.
70. Yang YX, Metz DC. Safety of proton pump inhibitor exposure. Gastroenterology 2010; 139:1115-1127.
71. Cundy T, Dissanayake A. Severe hypomagnesaemia in long-term users of proton-pump inhibitors. Clin Endocrinol (Oxf) 2008; 69:338-341.
72. Reimer C, Sondergaard B, Hilsted L, Bytzer P. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009; 137:80-87; 87.
73. Waldum HL, Qvigstad G, Fossmark R, et al. Rebound acid hypersecretion from a physiological, pathophysiological and clinical viewpoint. Scand J Gastroenterol 2010; 45:389-394.
74. McColl KE, Gillen D. Evidence that proton-pump inhibitor therapy induces the symptoms it is used to treat. Gastroenterology 2009; 137:20-22.
75. McCarthy DM. Adverse effects of proton pump inhibitor drugs: clues and conclusions. Curr Opin Gastroenterol 2010; 26:624-631.
76. Niklasson A, Lindstrom L, Simren M, et al. Dyspeptic symptom development after discontinuation of a proton pump inhibitor: a double-blind placebocontrolled trial. Am J Gastroenterol 2010; 105:1531-1537.
77. Metz DC, Pilmer BL, Han C, Perez MC. Withdrawing PPI therapy after healing esophagitis does not worsen symptoms or cause persistent hypergastrinemia: analysis of dexlansoprazole MR clinical trial data. Am J Gastroenterol 2011; 106:1953-1960.
78. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association medical position statement on the management of gastroesophageal reflux disease. Gastroenterology 2008; 135:1383-1391.
79. Sierra F, Suarez M, Rey M, Vela MF. Systematic review: proton pump inhibitorassociated acute interstitial nephritis. Aliment Pharmacol Ther 2007; 26:545-553.
80. Perazella MA, Markowitz GS. Drug-induced acute interstitial nephritis. Nat Rev Nephrol 2010; 6:461-470.
81. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97:934-959.
82. Laine L, Ahnen D, McClain C, et al. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000; 14:651-668.
83. Abraham NS. Prescribing proton pump inhibitor and clopidogrel together: current state of recommendations. Curr Opin Gastroenterol 2011; 27:558-564.
84. Tantry US, Kereiakes DJ, Gurbel PA. Clopidogrel and proton pump inhibitors: influence of pharmacological interactions on clinical outcomes and mechanistic explanations. JACC Cardiovasc Interv 2011; 4:365-380.
85. Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation 2010; 122:2619-2633.
86. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363:1909-1917.
87. Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009; 101:714-719.
88. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009; 373:309-317.
89. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360:354-362.
90. Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009; 302:849-857.
91. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360:363-375.
92. Cayla G, Hulot JS, O'Connor SA, et al. Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. JAMA 2011; 306:1765-1774.
93. Bliden KP, Tantry US, Storey RF, et al. The effect of ticagrelor versus clopidogrel on high on-treatment platelet reactivity: combined analysis of the ONSET/OFFSET and RESPOND studies. Am Heart J 2011; 162:160-165.
94. Wiviott SD, Braunwald SE, McCabe SCH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357:2001-2015.
95. Khalili H, Huang ES, Jacobson BC, et al. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ 2012; 344:e372.
96. Targownik LE, Lix LM, Metge CJ, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008; 179:319-326.
97. Vestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int 2006; 79:76-83.
98. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006; 296:2947-2953.
99. Targownik LE, Lix LM, Leung S, Leslie WD. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology 2010; 138:896-904.
100. Gray SL, LaCroix AZ, Larson J, et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative. Arch Intern Med 2010; 170:765-771.
101. Kaye JA, Jick H. Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 2008; 28:951-959.
102. Corley DA, Kubo A, Zhao W, Quesenberry C. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among atrisk patients. Gastroenterology 2010; 139:93-101.
103. Ngamruengphong S, Leontiadis GI, Radhi S, et al. Proton pump inhibitors and risk of fracture: a systematic review and meta-analysis of observational studies. Am J Gastroenterol 2011; 106:1209-1218.
104. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336:924-926.
105. Theisen J, Nehra D, Citron D, et al. Suppression of gastric acid secretion in patients with gastroesophageal reflux disease results in gastric bacterial overgrowth and deconjugation of bile acids. J Gastrointest Surg 2000; 4:50-54.
106. Zedtwitz-Liebenstein K, Wenisch C, Patruta S, et al. Omeprazole treatment diminishes intra- and extracellular neutrophil reactive oxygen production and bactericidal activity. Crit Care Med 2002; 30:1118-1122.
107. Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol 2007; 102:2047-2056.
108. 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; 10:225-233.
109. Linsky A, Gupta K, Lawler EV, et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med 2010; 170:772-778.
110. Laheij RJ, Sturkenboom MC, Hassing RJ, et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004; 292:1955-1960.
111. Gulmez SE, Bansal D, Sotos J, et al. Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study. Arch Intern Med 2007; 167:950-955.
112. Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med 2008; 149:391-398.
113. Sultan N, Nazareno J, Gregor J. Association between proton pump inhibitors and respiratory infections: a systematic review and meta-analysis of clinical trials. Can J Gastroenterol 2008; 22:761-766.
114. Targownik LE, Metge C, Roos L, Leung S. The prevalence of and the clinical and demographic characteristics associated with high-intensity proton pump inhibitor use. Am J Gastroenterol 2007; 102:942-950.