Association between Use of Proton Pump Inhibitors and the Risk of Clostridium Difficile Infection: A Meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

 ZHUMiao-miao ^1,2 , LIHui-lan ^1,2,3 , LUOJia ^1,2 , LINCong ^1,2 ,  ZHANGZan-ling ^1,2

1. Department of Pharmacy, Xiangya Hospital Central South University, Changsha 410008, China;
2. Institute of Pharmaceutical Research, Central South University, Changsha 410008, China;
3. Pharmacy Faculty Central South University, Changsha 410013, China;

Corresponding author：

ZHANGZan-ling, Email: zanlingzhang2015@126.com

Keywords：

Proton pumps inhibitor; Clostridium difficile; Case-control study; Cohort study; Meta-analysis

DOI：

10.7507/1672-2531.20160045

Video：

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Objective To systematically review the association between use of proton pumps inhibitors (PPIs) and clostridium difficile infection (CDI), so as to provide evidence for doctors' prescription. Methods We electronically searched databases including PubMed, The Cochrane Library (Issue 8, 2015), Web of Science, Ovid, CBM, CNKI, VIP, WanFang Data to collect case-control studies and cohort studies about the association between use of PPIs and CDI from January 1990 to October 2015. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then meta-analysis was performed using RevMan 5.3 software. Results A total of 47 articles involving 50 studies with 309620 cases were included. According to whether infected by clostridium difficile or not, these cases were divided into the case group (n=15913) and the control group (n=293707). The result of meta-analysis showed that the CDI rate of the PPIs therapy group was higher than that of the control group (OR=1.99, 95%CI 1.72 to 2.31, P<0.01, I²=87%) but a significant heterogeneity was found among studies. So subgroup analyses were performed according to the type of study design, type of patients, sample size and NOS scores of included studies. The results showed that, within different subgroups, the CDI rate of the PPIs therapy group was higher than that of the control group with significance, but the heterogeneity among studies was still existed. Conclusion Current evidence shows the use of PPI is associate with a 2-fold increase of the risk of CDI. Due to limited quality of the included studies, the above conclusion needs to be verified by more high quality studies.

Citation： ZHUMiao-miao, LIHui-lan, LUOJia, LINCong, ZHANGZan-ling. Association between Use of Proton Pump Inhibitors and the Risk of Clostridium Difficile Infection: A Meta-analysis. Chinese Journal of Evidence-Based Medicine, 2016, 16(3): 278-285. doi: 10.7507/1672-2531.20160045 Copy

1.	Kelly CP, La Mont JT. Clostridium difficile-more difficult than eve. N Engl J Med, 2008, 359(18):1932-1940.
2.	McDonald EG, Milligan J, Frenette C, et al. Contiunous proton pump inhibitor therapy and the associated risk of recurrent clostridium difficile infection. JAMA Intern Med, 2015, 175(5):784-791.
3.	Zilberberg MD, Reske K, Olsen M, et al. Risk factors for recurrent clostridium difficile infection (CDI) hospitalization among hospitalized patients with an initial CDI episode:a retrospective cohort study. BMC Infect Dis, 2014(14):306-312.
4.	Bauer MP, Notermans DW, van Benthem BH, et al. Clostridium difficile infection in Europe:a hospital-based survey. Lancet, 2011, 377(9759):63-73.
5.	Wells GA, Shea B, O'Connell D, et al. Th e Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Available at:http://www.ohri.ca/programs/clinicalepidemiology/oxford.htm.
6.	Yuhara H, Steinmaus C, Cohen SE, et al. Is diabetes mellitus an independent risk factor for colon cancer and rectal cancer? Am J Gastroenterol, 2011, 106(11):1911-1921.
7.	Dial S. Risk of clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors:cohort and case-control studies. CMAJ, 2004, 171(1):33-38.
8.	Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial clostridium difficile infection. Arch Intern Med, 2010, 170(9):784-790.
9.	Dalton BR, Lye-Maccannell T, Henderson EA, et al. Proton pump inhibitors increase significantly the risk of clostridium difficile infection in a low-endemicity, non-outbreak hospital setting. Aliment Pharmacol Ther, 2009, 29(6):626-634.
10.	Shah S, Lewis A, Leopold D, et al. Gastric acid suppression does not promote clostridial diarrhoea in the elderly. QJM, 2000, 93(4):175-181.
11.	Yip C, Loeb M, Salama S, et al. Quinolone use as a risk factor for nosocomial clostridium difficile-associated diarrhea. Infect Control Hosp Epidemiol, 2001, 22(3):572-575.
12.	Cunningham R, Dale B, Undy B, et al. Proton pump inhibitors as a risk factor for clostridium difficile diarrhoea. J Hosp Infect, 2003, 54(3):243-245.
13.	Dial S, Delaney JA, Barkun AN, et al. Use of gastric acid-suppressive agents and the risk of community-acquired clostridium difficile-associated disease. JAMA, 2005, 294(3):2989-2995.
14.	Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med, 2005, 353(8):2442-2449.
15.	Modena S, Bearelly D, Swartz K, et al. Clostridium difficile among hospitalized patients receiving antibiotics:a case-control study. Infect Control Hosp Epidemiol, 2005, 26(3):685-690.
16.	Muto CA, Pokrywka M, Shutt K, et al. A large outbreak of clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp Epidemiol, 2005, 26(3):273-280.
17.	Kazakova SV, Ware K, Baughman B, et al. A hospital outbreak of diarrhea due to an emerging epidemic strain of clostridium difficile. Arch Intern Med, 2006, 166(7):2518-2524.
18.	Lowe DO, Mamdani MM, Kopp A, et al. Proton pump inhibitors and hospitalization for clostridium difficile-associated disease:a population-based study. Clin Infect Dis, 2006, 43(4):1272-1276.
19.	Yearsley KA, Gilby LJ, Ramadas AV, et al. Proton pump inhibitor therapy is a risk factor for clostridium difficile-associated diarrhea. Aliment Pharmacol Ther, 2006, 24(4):613-619.
20.	Akhtar AJ, Shaheen M. Increasing incidence of clostridium difficile-associated diarrhea in African-American and Hispanic patients:association with the use of proton pump inhibitor therapy. J Natl Med Assoc, 2007, 99(4):500-504.
21.	Cadle RM, Mansouri MD, Logan N, et al. Association of proton-pump inhibitors with outcomes in clostridium difficile colitis. Am J Health Syst Pharm, 2007, 64(22):2359-2363.
22.	Dubberke ER, Reske KA, Yan Y, et al. Clostridium difficile——associated disease in a setting of endemicity:identification of novel risk factors. Clin Infect Dis, 2007, 45(12):1543-1549.
23.	Jayatilaka S, Shakov R, Eddi R, et al. Clostridium difficile infection in an urban medical center:five-year analysis of infection rates among adult admissions and association with the use of proton pump inhibitors. Ann Clin Lab Sci, 2007, 37(6):241-247.
24.	Mcfarland LV, Clarridge JE, Beneda HW, et al. Fluoroquinolone use and risk factors for clostridium difficile-associated disease within a Veterans Administration Health Care System. Clin Infect Dis, 2007, 45(9):1141-1151.
25.	Aseeri M, Schroeder T, Kramer J, et al. Gastric acid suppression by proton pump inhibitors as a risk factor for clostridium difficile-associated diarrhea in hospitalized patients. Am J Gastroenterol, 2008, 103(9):2308-2313.
26.	Baxter R, Ray GT, Fireman BH. Case-control study of antibiotic use and subsequent clostridium difficile-associated diarrhea in hospitalized patients. Infect Control Hosp Epidemiol, 2008, 29(7):44-50.
27.	Kim JW. Proton pump inhibitors as a risk factor for recurrence of clostridium-difficile-associated diarrhea. World J Gastroenterol, 2010, 16(28):3573-3577.
28.	Kim YG, Jang BI, Choi EJ, et al. Proton pump inhibitors with recurrent clostridium difficile associated disease:a case-control analysis matched by propensity score. J Clin Gastroenterology, 2012, 46(5):397-400.
29.	Linsky A, Gupta K, Lawler EV, et al. Proton pump inhibitors and risk for recurrent clostridium difficile infection. Arch Intern Med, 2010, 170(9):772-778.
30.	Linney S, Fernandes T, Einarson T, et al. Association between use of proton pump inhibitors and a clostridium difficile-associated disease outbreak:case-control study. Can J Hosp Pharm, 2010, 63(1):31-37.
31.	Dial S. Proton pump inhibitor use and risk of community-acquired clostridium difficile-associated disease defined by prescription for oral vancomycin therapy. CMAJ, 2006, 175(7):745-748.
32.	Kutty PK, Woods CW, Sena AC, et al. Risk factors for and estimated incidence of community-associated clostridium difficile infection, North Carolina, USA. Emerg Infect Dis, 2010, 16(2):197-204.
33.	Marwick CA, Yu N, Lockhart MC, et al. Community-associated clostridium difficile infection among older people in Tayside, Scotland, is associated with antibiotic exposure and care home residence:cohort study with nested case-control. J Antimicrob Chemother, 2013, 68(12):2927-2933.
34.	Novack L, Kogan S, Gimpelevich L, et al. Acid suppression therapy does not predispose to clostridium difficile infection:the case of the potential bias. PLoS One, 2014, 9(10):e110790.
35.	Mori N, Aoki Y. Clinical characteristics and risk factors for community-acquired clostridium difficile infection:A retrospective, case-control study in a tertiary care hospital in Japan. J Infect Chemother, 2015, 21(12):864-867.
36.	Barletta JF, El-Ibiary SY, Davis LE, et al. Proton pump inhibitors and the risk for hospital-acquired clostridium difficile infection. Mayo Clin Proc, 2013, 88(10):1085-1090.
37.	Bishara J, Farah R, Mograbi J, et al. Obesity as a risk factor for clostridium difficile Infection. Clin Infect Dis, 2013, 57(4):489-493.
38.	Pakyz AL, Jawahar R, Wang Q, et al. Medication risk factors associated with health care-associated clostridium difficile infection:a multilevel model case-control study among 64 US academic medical centres. J Antimicrob Chemother, 2014, 69(4):1127-1131.
39.	Soes LM, Holt HM, Böttiger B, et al. Risk factors for clostridium difficile infection in the community:a case-control study in patients in general practice, Denmark, 2009-2011. Epidemiol Infect, 2014, 142(07):1437-1448.
40.	Barletta JF, Sclar DA. Proton pump inhibitors increase the risk for hospital-acquired clostridium difficile infection in critically ill patients. Crit Care Med, 2014, 18(6):714-717.
41.	Sahay T, Ananthakrishnan AN. Vitamin D deficiency is associated with community-acquired clostridium difficile infection:a case-control study. BMC Infect Dis, 2014, 14(2):661-666.
42.	Aldrete SDM, Magee MJ, Friedman-Moraco RJ, et al. Characteristics and antibiotic use associated with Short-Term risk of clostridium difficile infection among hospitalized patients. AJCP, 2015, 143(6):895-900.
43.	Stevens V, Dumyati G, Brown J, et al. Differential risk of clostridium difficile infection with proton pump inhibitor use by level of antibiotic exposure. Pharmacoepidem Dr S, 2011, 20(10):1035-1042.
44.	Lin YC, Huang YT, Lee TF, et al. Characteristics of patients with clostridium difficile infection in Taiwan. Epidemiol Infect, 2013, 141(10):2031-2038.
45.	Wang Y, Atreja A, Wu X, et al. Similar outcomes of IBD inpatients with clostridium difficile Infection detected by ELISA or PCR assay. Dig Dis Sci, 2013, 58(8):2308-2313.
46.	Brown KA, Fisman DN, Moineddin R, et al. The magnitude and duration of clostridium difficile infection risk associated with antibiotic therapy:a hospital cohort study. PLoS One, 2014, 9(8):e105454.
47.	Kaneko T, Matsuda R, Taguri M, et al. Clostridium difficile infection in patients with ulcerative colitis:Investigations of risk factors and efficacy of antibiotics for steroid refractory patients. Clin Res Hepatol Gastroenterol, 2011, 35(4):315-320.
48.	Ananthakrishnan AN, Cagan A, Gainer VS, et al. Higher plasma vitamin D is associated with reduced risk of clostridium difficile infection in patients with inflammatory bowel diseases. Aliment Pharmacol Ther, 2014, 39(10):1136-1142.
49.	Regnault H, Bourrier A, Lalande V, et al. Prevalence and risk factors of clostridium difficile infection in patients hospitalized for flare of inflammatory bowel disease:A retrospective assessment. Dig Liver Dis, 2014, 46(12):1086-1092.
50.	Ticinesi A, Nouvenne A, Folesani G, et al. Multimorbidity in elderly hospitalised patients and risk of clostridium difficile infection:a retrospective study with the Cumulative Illness Rating Scale (CIRS). BMJ, 2015, 5(10):9316-9322.
51.	Rodríguez Garzotto A, Mérida García A, Muñoz Unceta N, et al. Risk factors associated with clostridium difficile infection in adult oncology patients. Support Care Cancer, 2015, 23(6):1569-1577.
52.	Lee S. Ertapenem prophylaxis associated with an increased risk of clostridium difficile infection among surgical patients infect. Control Hos Epidemiol, 2015; 36(11):1351-1354.
53.	Leonard AD, Ho KM, Flexman J. Proton pump inhibitors and diarrhea related to clostridium difficile infection in hospitalised patients:a case-control study. Intern Med J, 2012, 42(5):591-594.
54.	George RH, Symonds JM, Dimock F, et al. Identification of clostridium difficile as a cause of pseudomembranous colitis. BMJ, 1978, 1(3):695-698.
55.	Williams C. Occurrence and significance of gastric colonization during acid-inhibitory therapy. Best Pract Res Clin Gastroenterol, 2001, 15(3):511-517.
56.	Kyne L, Warny M, Qamar A, et al. Asymptomatic carriage of clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med, 2000, 342(6):390-400.
57.	Drug Safety and Availability. FDA Drug Safety Communication:Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). Avaliable at:http://www.fda.gov/Drugs/DrugSafety/ucm²90510.htm.

1. Kelly CP, La Mont JT. Clostridium difficile-more difficult than eve. N Engl J Med, 2008, 359(18):1932-1940.
2. McDonald EG, Milligan J, Frenette C, et al. Contiunous proton pump inhibitor therapy and the associated risk of recurrent clostridium difficile infection. JAMA Intern Med, 2015, 175(5):784-791.
3. Zilberberg MD, Reske K, Olsen M, et al. Risk factors for recurrent clostridium difficile infection (CDI) hospitalization among hospitalized patients with an initial CDI episode:a retrospective cohort study. BMC Infect Dis, 2014(14):306-312.
4. Bauer MP, Notermans DW, van Benthem BH, et al. Clostridium difficile infection in Europe:a hospital-based survey. Lancet, 2011, 377(9759):63-73.
5. Wells GA, Shea B, O'Connell D, et al. Th e Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Available at:http://www.ohri.ca/programs/clinicalepidemiology/oxford.htm.
6. Yuhara H, Steinmaus C, Cohen SE, et al. Is diabetes mellitus an independent risk factor for colon cancer and rectal cancer? Am J Gastroenterol, 2011, 106(11):1911-1921.
7. Dial S. Risk of clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors:cohort and case-control studies. CMAJ, 2004, 171(1):33-38.
8. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial clostridium difficile infection. Arch Intern Med, 2010, 170(9):784-790.
9. Dalton BR, Lye-Maccannell T, Henderson EA, et al. Proton pump inhibitors increase significantly the risk of clostridium difficile infection in a low-endemicity, non-outbreak hospital setting. Aliment Pharmacol Ther, 2009, 29(6):626-634.
10. Shah S, Lewis A, Leopold D, et al. Gastric acid suppression does not promote clostridial diarrhoea in the elderly. QJM, 2000, 93(4):175-181.
11. Yip C, Loeb M, Salama S, et al. Quinolone use as a risk factor for nosocomial clostridium difficile-associated diarrhea. Infect Control Hosp Epidemiol, 2001, 22(3):572-575.
12. Cunningham R, Dale B, Undy B, et al. Proton pump inhibitors as a risk factor for clostridium difficile diarrhoea. J Hosp Infect, 2003, 54(3):243-245.
13. Dial S, Delaney JA, Barkun AN, et al. Use of gastric acid-suppressive agents and the risk of community-acquired clostridium difficile-associated disease. JAMA, 2005, 294(3):2989-2995.
14. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med, 2005, 353(8):2442-2449.
15. Modena S, Bearelly D, Swartz K, et al. Clostridium difficile among hospitalized patients receiving antibiotics:a case-control study. Infect Control Hosp Epidemiol, 2005, 26(3):685-690.
16. Muto CA, Pokrywka M, Shutt K, et al. A large outbreak of clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp Epidemiol, 2005, 26(3):273-280.
17. Kazakova SV, Ware K, Baughman B, et al. A hospital outbreak of diarrhea due to an emerging epidemic strain of clostridium difficile. Arch Intern Med, 2006, 166(7):2518-2524.
18. Lowe DO, Mamdani MM, Kopp A, et al. Proton pump inhibitors and hospitalization for clostridium difficile-associated disease:a population-based study. Clin Infect Dis, 2006, 43(4):1272-1276.
19. Yearsley KA, Gilby LJ, Ramadas AV, et al. Proton pump inhibitor therapy is a risk factor for clostridium difficile-associated diarrhea. Aliment Pharmacol Ther, 2006, 24(4):613-619.
20. Akhtar AJ, Shaheen M. Increasing incidence of clostridium difficile-associated diarrhea in African-American and Hispanic patients:association with the use of proton pump inhibitor therapy. J Natl Med Assoc, 2007, 99(4):500-504.
21. Cadle RM, Mansouri MD, Logan N, et al. Association of proton-pump inhibitors with outcomes in clostridium difficile colitis. Am J Health Syst Pharm, 2007, 64(22):2359-2363.
22. Dubberke ER, Reske KA, Yan Y, et al. Clostridium difficile——associated disease in a setting of endemicity:identification of novel risk factors. Clin Infect Dis, 2007, 45(12):1543-1549.
23. Jayatilaka S, Shakov R, Eddi R, et al. Clostridium difficile infection in an urban medical center:five-year analysis of infection rates among adult admissions and association with the use of proton pump inhibitors. Ann Clin Lab Sci, 2007, 37(6):241-247.
24. Mcfarland LV, Clarridge JE, Beneda HW, et al. Fluoroquinolone use and risk factors for clostridium difficile-associated disease within a Veterans Administration Health Care System. Clin Infect Dis, 2007, 45(9):1141-1151.
25. Aseeri M, Schroeder T, Kramer J, et al. Gastric acid suppression by proton pump inhibitors as a risk factor for clostridium difficile-associated diarrhea in hospitalized patients. Am J Gastroenterol, 2008, 103(9):2308-2313.
26. Baxter R, Ray GT, Fireman BH. Case-control study of antibiotic use and subsequent clostridium difficile-associated diarrhea in hospitalized patients. Infect Control Hosp Epidemiol, 2008, 29(7):44-50.
27. Kim JW. Proton pump inhibitors as a risk factor for recurrence of clostridium-difficile-associated diarrhea. World J Gastroenterol, 2010, 16(28):3573-3577.
28. Kim YG, Jang BI, Choi EJ, et al. Proton pump inhibitors with recurrent clostridium difficile associated disease:a case-control analysis matched by propensity score. J Clin Gastroenterology, 2012, 46(5):397-400.
29. Linsky A, Gupta K, Lawler EV, et al. Proton pump inhibitors and risk for recurrent clostridium difficile infection. Arch Intern Med, 2010, 170(9):772-778.
30. Linney S, Fernandes T, Einarson T, et al. Association between use of proton pump inhibitors and a clostridium difficile-associated disease outbreak:case-control study. Can J Hosp Pharm, 2010, 63(1):31-37.
31. Dial S. Proton pump inhibitor use and risk of community-acquired clostridium difficile-associated disease defined by prescription for oral vancomycin therapy. CMAJ, 2006, 175(7):745-748.
32. Kutty PK, Woods CW, Sena AC, et al. Risk factors for and estimated incidence of community-associated clostridium difficile infection, North Carolina, USA. Emerg Infect Dis, 2010, 16(2):197-204.
33. Marwick CA, Yu N, Lockhart MC, et al. Community-associated clostridium difficile infection among older people in Tayside, Scotland, is associated with antibiotic exposure and care home residence:cohort study with nested case-control. J Antimicrob Chemother, 2013, 68(12):2927-2933.
34. Novack L, Kogan S, Gimpelevich L, et al. Acid suppression therapy does not predispose to clostridium difficile infection:the case of the potential bias. PLoS One, 2014, 9(10):e110790.
35. Mori N, Aoki Y. Clinical characteristics and risk factors for community-acquired clostridium difficile infection:A retrospective, case-control study in a tertiary care hospital in Japan. J Infect Chemother, 2015, 21(12):864-867.
36. Barletta JF, El-Ibiary SY, Davis LE, et al. Proton pump inhibitors and the risk for hospital-acquired clostridium difficile infection. Mayo Clin Proc, 2013, 88(10):1085-1090.
37. Bishara J, Farah R, Mograbi J, et al. Obesity as a risk factor for clostridium difficile Infection. Clin Infect Dis, 2013, 57(4):489-493.
38. Pakyz AL, Jawahar R, Wang Q, et al. Medication risk factors associated with health care-associated clostridium difficile infection:a multilevel model case-control study among 64 US academic medical centres. J Antimicrob Chemother, 2014, 69(4):1127-1131.
39. Soes LM, Holt HM, Böttiger B, et al. Risk factors for clostridium difficile infection in the community:a case-control study in patients in general practice, Denmark, 2009-2011. Epidemiol Infect, 2014, 142(07):1437-1448.
40. Barletta JF, Sclar DA. Proton pump inhibitors increase the risk for hospital-acquired clostridium difficile infection in critically ill patients. Crit Care Med, 2014, 18(6):714-717.
41. Sahay T, Ananthakrishnan AN. Vitamin D deficiency is associated with community-acquired clostridium difficile infection:a case-control study. BMC Infect Dis, 2014, 14(2):661-666.
42. Aldrete SDM, Magee MJ, Friedman-Moraco RJ, et al. Characteristics and antibiotic use associated with Short-Term risk of clostridium difficile infection among hospitalized patients. AJCP, 2015, 143(6):895-900.
43. Stevens V, Dumyati G, Brown J, et al. Differential risk of clostridium difficile infection with proton pump inhibitor use by level of antibiotic exposure. Pharmacoepidem Dr S, 2011, 20(10):1035-1042.
44. Lin YC, Huang YT, Lee TF, et al. Characteristics of patients with clostridium difficile infection in Taiwan. Epidemiol Infect, 2013, 141(10):2031-2038.
45. Wang Y, Atreja A, Wu X, et al. Similar outcomes of IBD inpatients with clostridium difficile Infection detected by ELISA or PCR assay. Dig Dis Sci, 2013, 58(8):2308-2313.
46. Brown KA, Fisman DN, Moineddin R, et al. The magnitude and duration of clostridium difficile infection risk associated with antibiotic therapy:a hospital cohort study. PLoS One, 2014, 9(8):e105454.
47. Kaneko T, Matsuda R, Taguri M, et al. Clostridium difficile infection in patients with ulcerative colitis:Investigations of risk factors and efficacy of antibiotics for steroid refractory patients. Clin Res Hepatol Gastroenterol, 2011, 35(4):315-320.
48. Ananthakrishnan AN, Cagan A, Gainer VS, et al. Higher plasma vitamin D is associated with reduced risk of clostridium difficile infection in patients with inflammatory bowel diseases. Aliment Pharmacol Ther, 2014, 39(10):1136-1142.
49. Regnault H, Bourrier A, Lalande V, et al. Prevalence and risk factors of clostridium difficile infection in patients hospitalized for flare of inflammatory bowel disease:A retrospective assessment. Dig Liver Dis, 2014, 46(12):1086-1092.
50. Ticinesi A, Nouvenne A, Folesani G, et al. Multimorbidity in elderly hospitalised patients and risk of clostridium difficile infection:a retrospective study with the Cumulative Illness Rating Scale (CIRS). BMJ, 2015, 5(10):9316-9322.
51. Rodríguez Garzotto A, Mérida García A, Muñoz Unceta N, et al. Risk factors associated with clostridium difficile infection in adult oncology patients. Support Care Cancer, 2015, 23(6):1569-1577.
52. Lee S. Ertapenem prophylaxis associated with an increased risk of clostridium difficile infection among surgical patients infect. Control Hos Epidemiol, 2015; 36(11):1351-1354.
53. Leonard AD, Ho KM, Flexman J. Proton pump inhibitors and diarrhea related to clostridium difficile infection in hospitalised patients:a case-control study. Intern Med J, 2012, 42(5):591-594.
54. George RH, Symonds JM, Dimock F, et al. Identification of clostridium difficile as a cause of pseudomembranous colitis. BMJ, 1978, 1(3):695-698.
55. Williams C. Occurrence and significance of gastric colonization during acid-inhibitory therapy. Best Pract Res Clin Gastroenterol, 2001, 15(3):511-517.
56. Kyne L, Warny M, Qamar A, et al. Asymptomatic carriage of clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med, 2000, 342(6):390-400.
57. Drug Safety and Availability. FDA Drug Safety Communication:Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). Avaliable at:http://www.fda.gov/Drugs/DrugSafety/ucm²90510.htm.

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