Skip to main content

Advertisement

SpringerLink
Log in

Magnitude and direction of the association between Clostridium difficile infection and proton pump inhibitors in adults and pediatric patients: a systematic review and meta-analysis

  • Original Article—Alimentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

A Correction to this article was published on 30 January 2020

This article has been updated

Abstract

Background

Clostridium difficile infection (CDI) is a cause of increased morbidity and health care costs among hospitalized patients. Proton pump inhibitors (PPIs) are mainly used for the treatment of acid-related upper gastrointestinal diseases. The aim of the study was to assess the risks associated with initial and recurrent CDI in adult and pediatric patients treated with PPIs.

Methods

A systematic search was performed using PubMed (Medline), Embase, and Web of Science with the following search terms: (“proton pump inhibitor,” “PPI,” or “acid suppression”) AND (“infection,” “diarrhea,” “diarrhoea,” “colitis,” or “disease”) AND (“Clostridium difficile”). Meta-analysis was performed using Revman5.3 software. Pooled odds ratios (ORs) presented as standard plots with 95% confidence intervals (CIs) were determined.

Results

Sixty-seven eligible studies were selected. PPI use was significantly associated with risk of CDI (OR 2.34, 95% CI 1.94–2.82; P < 0.00001). Pooled data from twelve studies demonstrated a significant association between PPI use and recurrent CDI (OR 1.73, 95% CI 1.39–2.15; P = 0.02). Subgroup analysis revealed significant associations between PPI use and an increased incidence of CDI among adult (OR 2.30, 95% CI 1.89–2.80; P < 0.00001) and pediatric (OR 3.00, 95% CI 1.44–6.23; P < 0.00001) patients.

Conclusions

PPI use was associated with CDI in adult and pediatric patients, and with recurrent CDI. Although many risk factors are associated with the occurrence and recurrence of CDI, consideration should be given to not administering PPIs at any age if they are unnecessary.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Change history

  • 30 January 2020

    In the original publication of the article, Table 1 and Figs. 2a, 2b, 3a were published with errors.

  • 30 January 2020

    In the original publication of the article, Table 1 and Figs. 2a, 2b, 3a were published with errors.

References

  1. Kim KH, Fekety R, Batts DH, et al. Isolation of Clostridium difficile from the environment and contacts of patients with antibiotic-associated colitis. J Infect Dis. 1981;143:42–50.

    Article  CAS  PubMed  Google Scholar 

  2. Kyne L, Hamel MB, Polavaram R, et al. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis. 2002;34:346–53.

  3. Cunningham R. Proton pump inhibitors and the risk of Clostridium difficile-associated disease: further evidence from the community. CMAJ. 2006;175:757.

  4. Brown E, Talbot GH, Axelrod P, et al. Risk factors for Clostridium difficile toxin-associated diarrhea. Infect Control Hosp Epidemiol. 1990;11:283–90.

    Article  CAS  PubMed  Google Scholar 

  5. Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med. 2011;365:1693–703.

    Article  CAS  PubMed  Google Scholar 

  6. Yachimski PS, Farrell EA, Hunt DP, et al. Proton pump inhibitors for prophylaxis of nosocomial upper gastrointestinal tract bleeding: effect of standardized guidelines on prescribing practice. Arch Intern Med. 2010;170:779–83.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Rodriguez-Pardo D, Almirante B, Bartolome RM, et al. Epidemiology of Clostridium difficile infection and risk factors for unfavorable clinical outcomes: results of a hospital-based study in Barcelona, Spain. J Clin Microbiol. 2013;51:1465–73.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hebert C, Du H, Peterson LR, et al. Electronic health record-based detection of risk factors for Clostridium difficile infection relapse. Infect Control Hosp Epidemiol. 2013;34:407–14.

    Article  PubMed  Google Scholar 

  9. Almeida R, Gerbaba T, Petrof EO. Recurrent Clostridium difficile infection and the microbiome. J Gastroenterol. 2016;51:1–10.

    Article  CAS  PubMed  Google Scholar 

  10. Tleyjeh IM, Bin Abdulhak AA, Riaz M, et al. Association between proton pump inhibitor therapy and Clostridium difficile infection: a contemporary systematic review and meta-analysis. PLoS One. 2012;7:e50836.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Janarthanan S, Ditah I, Adler DG, et al. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol. 2012;107:1001–10.

    Article  CAS  PubMed  Google Scholar 

  12. Deshpande A, Pasupuleti V, Thota P, et al. Risk factors for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2015;36:452–60.

    Article  PubMed  Google Scholar 

  13. 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;177:784–91.

    Article  PubMed  Google Scholar 

  14. 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;37:1408–17.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 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:e110790.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Brown KE, Knoderer CA, Nichols KR, et al. Acid-suppressing agents and risk for Clostridium difficile infection in pediatric patients. Clin Pediatr (Phila). 2015;54:1102–6.

    Article  Google Scholar 

  17. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med. 2001;135:982–9.

    Article  CAS  PubMed  Google Scholar 

  18. Li S, Zeng XT, Ruan XL, et al. Holmium laser enucleation versus transurethral resection in patients with benign prostate hyperplasia: an updated systematic review with meta-analysis and trial sequential analysis. PLoS One. 2014;9:e101615.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bavishi C, Dupont HL. Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment Pharmacol Ther. 2011;34:1269–81.

    Article  CAS  PubMed  Google Scholar 

  21. Kwok CS, Arthur AK, Anibueze CI, et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol. 2012;107:1011–9.

    Article  CAS  PubMed  Google Scholar 

  22. Faleck DM, Salmasian H, Furuya EY, et al. Proton pump inhibitors do not increase risk for Clostridium difficile infection in the intensive care unit. Am J Gastroenterol. 2016;111:1641–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. George RH, Symonds JM, Dimock F, et al. Identification of Clostridium difficile as a cause of pseudomembranous colitis. Br Med J. 1978;1:695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jump RL, Pultz MJ, Donskey CJ. Vegetative Clostridium difficile survives in room air on moist surfaces and in gastric contents with reduced acidity: a potential mechanism to explain the association between proton pump inhibitors and C. difficile-associated diarrhea? Antimicrob Agents Chemother. 2007;51:2883–7.

  25. Wilson KH, Sheagren JN, Freter R. Population dynamics of ingested Clostridium difficile in the gastrointestinal tract of the Syrian hamster. J Infect Dis. 1985;151:355–61.

    Article  CAS  PubMed  Google Scholar 

  26. Sanaka M, Yamamoto T, Kuyama Y. Effects of proton pump inhibitors on gastric emptying: a systematic review. Dig Dis Sci. 2010;55:2431–40.

    Article  CAS  PubMed  Google Scholar 

  27. Thorens J, Froehlich F, Schwizer W, et al. Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. Gut. 1996;39:54–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kaur S, Vaishnavi C, Prasad KK, et al. Comparative role of antibiotic and proton pump inhibitor in experimental Clostridium difficile infection in mice. Microbiol Immunol. 2007;51:1209–14.

    Article  CAS  PubMed  Google Scholar 

  29. Hegarty JP, Sangster W, Harris LR 3rd, et al. Proton pump inhibitors induce changes in colonocyte gene expression that may affect Clostridium difficile infection. Surgery. 2014;156:972–8.

    Article  PubMed  Google Scholar 

  30. Stewart DB, Hegarty JP. Correlation between virulence gene expression and proton pump inhibitors and ambient pH in Clostridium difficile: results of an in vitro study. J Med Microbiol. 2013;62:1517–23.

    Article  CAS  PubMed  Google Scholar 

  31. Garey KW, Sethi S, Yadav Y, et al. Meta-analysis to assess risk factors for recurrent Clostridium difficile infection. J Hosp Infect. 2008;70:298–304.

    Article  CAS  PubMed  Google Scholar 

  32. Abou Chakra CN, Pepin J, Sirard S, et al. Risk factors for recurrence, complications and mortality in Clostridium difficile infection: a systematic review. PLoS One. 2014;9:e98400.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Willing BP, Russell SL, Finlay BB. Shifting the balance: antibiotic effects on host–microbiota mutualism. Nat Rev Microbiol. 2011;9:233–43.

  34. Koenig JE, Spor A, Scalfone N, et al. Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci USA. 2011;108(Suppl 1):4578–85.

    Article  CAS  PubMed  Google Scholar 

  35. 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;353:2442–9.

    Article  CAS  PubMed  Google Scholar 

  36. Yearsley KA, Gilby LJ, Ramadas AV, et al. Proton pump inhibitor therapy is a risk factor for Clostridium difficile-associated diarrhoea. Aliment Pharmacol Ther. 2006;24:613–9.

  37. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med. 2010;170:784–90.

    Article  PubMed  Google Scholar 

  38. Vesteinsdottir I, Gudlaugsdottir S, Einarsdottir R, et al. Risk factors for Clostridium difficile toxin-positive diarrhea: a population-based prospective case-control study. Eur J Clin Microbiol Infect Dis. 2012;31:2601–10.

    Article  CAS  PubMed  Google Scholar 

  39. Wang X, Cai L, Yu R, et al. ICU-onset Clostridium difficile infection in a university hospital in China: a prospective cohort study. PLoS One. 2014;9:e111735.

  40. Shah S, Lewis A, Leopold D, et al. Gastric acid suppression does not promote clostridial diarrhoea in the elderly. QJM. 2000;93:175–81.

    Article  CAS  PubMed  Google Scholar 

  41. Cunningham R, Dale B, Undy B, et al. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea. J Hosp Infect. 2003;54:243–5.

    Article  CAS  PubMed  Google Scholar 

  42. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171:33–8

    Article  PubMed  PubMed Central  Google Scholar 

  43. 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;294:2989–95

    Article  CAS  PubMed  Google Scholar 

  44. Modena S, Bearelly D, Swartz K, et al. Clostridium difficile among hospitalized patients receiving antibiotics: a case-control study. Infect Control Hosp Epidemiol. 2005;26:685–90.

    Article  PubMed  Google Scholar 

  45. Al-Tureihi FI, Hassoun A, Wolf-Klein G, et al. Albumin, length of stay, and proton pump inhibitors: key factors in Clostridium difficile-associated disease in nursing home patients. J Am Med Dir Assoc. 2005;6:105–8.

    Article  PubMed  Google Scholar 

  46. 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;26:273–80.

    Article  PubMed  Google Scholar 

  47. 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;166:2518–24.

    Article  PubMed  Google Scholar 

  48. 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;43:1272–6.

    Article  CAS  PubMed  Google Scholar 

  49. Dial S, Delaney JA, Schneider V, et al. Proton pump inhibitor use and risk of community-acquired Clostridium difficile-associated disease defined by prescription for oral vancomycin therapy. CMAJ. 2006;175:745–8.

    Article  PubMed  PubMed Central  Google Scholar 

  50. 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;99:500–4.

    PubMed  PubMed Central  Google Scholar 

  51. 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; 37:241–7

    PubMed  Google Scholar 

  52. 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; 45:1543–9

    Article  PubMed  Google Scholar 

  53. 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;64:2359–63.

    Article  CAS  PubMed  Google Scholar 

  54. 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;45:1141–51.

    Article  PubMed  Google Scholar 

  55. 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; 103:2308–13

    Article  PubMed  Google Scholar 

  56. 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;29:44–50.

    Article  PubMed  Google Scholar 

  57. Debast SB, Vaessen N, Choudry A, et al. Successful combat of an outbreak due to Clostridium difficile PCR ribotype 027 and recognition of specific risk factors. Clin Microbiol Infect. 2009;15:427–34.

    Article  CAS  PubMed  Google Scholar 

  58. 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;29:626–34.

    Article  CAS  PubMed  Google Scholar 

  59. Kim JW, Lee KL, Jeong JB, et al. Proton pump inhibitors as a risk factor for recurrence of Clostridium difficile-associated diarrhea. World J Gastroenterol. 2010;16:3573–7.

  60. Linsky A, Gupta K, Lawler EV, et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med. 2010;170:772–8.

    Article  PubMed  Google Scholar 

  61. Turco R, Martinelli M, Miele E, et al. Proton pump inhibitors as a risk factor for paediatric Clostridium difficile infection. Aliment Pharmacol Ther. 2010;31:754–9.

    Article  CAS  PubMed  Google Scholar 

  62. Bajaj JS, Ananthakrishnan AN, Hafeezullah M, et al. Clostridium difficile is associated with poor outcomes in patients with cirrhosis: a national and tertiary center perspective. Am J Gastroenterol. 2010;105:106–13.

  63. 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;63:31–7.

    PubMed  PubMed Central  Google Scholar 

  64. Manges AR, Labbe A, Loo VG, et al. Comparative metagenomic study of alterations to the intestinal microbiota and risk of nosocomial Clostridum difficile-associated disease. J Infect Dis. 2010;202:1877–84.

    Article  PubMed  Google Scholar 

  65. Jenkins PJ, Teoh K, Simpson PM, et al. Clostridium difficile in patients undergoing primary hip and knee replacement. J Bone Jt Surg Br. 2010;92:994–8.

    Article  CAS  Google Scholar 

  66. Stevens V, Dumyati G, Brown J, et al. Differential risk of Clostridium difficile infection with proton pump inhibitor use by level of antibiotic exposure. Pharmacoepidemiol Drug Saf. 2011;20:1035–42.

    Article  CAS  PubMed  Google Scholar 

  67. Naggie S, Miller BA, Zuzak KB, et al. A case-control study of community-associated Clostridium difficile infection: no role for proton pump inhibitors. Am J Med. 2011;124(276):e1–7.

    Google Scholar 

  68. Hensgens MP, Goorhuis A, van Kinschot CM, et al. Clostridium difficile infection in an endemic setting in the Netherlands. Eur J Clin Microbiol Infect Dis. 2011;30:587–93.

  69. Kim YG, Graham DY, Jang BI. Proton pump inhibitor use and recurrent Clostridium difficile-associated disease: a case-control analysis matched by propensity score. J Clin Gastroenterol. 2012;46:397–400.

    Article  CAS  PubMed  Google Scholar 

  70. Leonard AD, Ho KM, Flexman J. Proton pump inhibitors and diarrhoea related to Clostridium difficile infection in hospitalised patients: a case-control study. Intern Med J. 2012;42:591–4.

    Article  CAS  PubMed  Google Scholar 

  71. Lupse M, Flonta M, Cioara A, et al. Predictors of first recurrence in Clostridium difficile-associated disease. A study of 306 patients hospitalized in a Romanian tertiary referral center. J Gastrointest Liver Dis. 2013;22:397–403.

    Google Scholar 

  72. Samie AA, Traub M, Bachmann K, et al. Risk factors for recurrence of Clostridium difficile-associated diarrhoea. Hepatogastroenterology. 2013;60:1351–4.

    PubMed  Google Scholar 

  73. Mizui T, Teramachi H, Tachi T, et al. Risk factors for Clostridium difficile-associated diarrhea and the effectiveness of prophylactic probiotic therapy. Pharmazie. 2013;68:706–10.

    CAS  PubMed  Google Scholar 

  74. Freedberg DE, Salmasian H, Friedman C, et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection among inpatients. Am J Gastroenterol. 2013;108:1794–801.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Campbell KA, Phillips MS, Stachel A, et al. Incidence and risk factors for hospital-acquired Clostridium difficile infection among inpatients in an orthopaedic tertiary care hospital. J Hosp Infect. 2013;83:146–9.

    Article  CAS  PubMed  Google Scholar 

  76. 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;88:1085–90.

    Article  CAS  PubMed  Google Scholar 

  77. Pakyz AL, Jawahar R, Wang Q, et al. Medication risk factors associated with healthcare-associated Clostridium difficile infection: a multilevel model case-control study among 64 US academic medical centres. J Antimicrob Chemother. 2014;69:1127–31.

    Article  CAS  PubMed  Google Scholar 

  78. Barletta JF, Sclar DA. Proton pump inhibitors increase the risk for hospital-acquired Clostridium difficile infection in critically ill patients. Crit Care. 2014;18:714.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Samady W, Bush R, Pong A, et al. Predictors of Clostridium difficile infections in hospitalized children. J Hosp Med. 2014;9:94–8.

    Article  PubMed  Google Scholar 

  80. Zhu Y, Wang L, Feng S, et al. Risk factors for Clostridium difficile-associated diarrhea among cancer patients. Zhonghua Zhong Liu Za Zhi. 2014;36:773–7.

  81. Sathyendran V, McAuliffe GN, Swager T, et al. Clostridium difficile as a cause of healthcare-associated diarrhoea among children in Auckland, New Zealand: clinical and molecular epidemiology. Eur J Clin Microbiol Infect Dis. 2014;33:1741–7.

    Article  CAS  PubMed  Google Scholar 

  82. Freedberg DE, Lamouse-Smith ES, Lightdale JR, et al. Use of acid suppression medication is associated with risk for C. difficile infection in infants and children: a population-based study. Clin Infect Dis. 2015;61:912–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Abdelfatah M, Nayfe R, Nijim A, et al. Factors predicting recurrence of Clostridium difficile infection (CDI) in hospitalized patients: retrospective study of more than 2000 patients. J Investig Med. 2015;63:747–51.

    Article  PubMed  Google Scholar 

  84. McDonald EG, Milligan J, Frenette C, et al. Continuous proton pump inhibitor therapy and the associated risk of recurrent Clostridium difficile infection. JAMA Intern Med. 2015;175:784–91.

    Article  PubMed  Google Scholar 

  85. Jimenez J, Drees M, Loveridge-Lenza B, et al. Exposure to gastric acid-suppression therapy is associated with health care- and community-associated Clostridium difficile infection in children. J Pediatr Gastroenterol Nutr. 2015; 61:208–11

    Article  CAS  PubMed  Google Scholar 

  86. 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 Open. 2015;5:e009316.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Hikone M, Ainoda Y, Tago S, et al. Risk factors for recurrent hospital-acquired Clostridium difficile infection in a Japanese university hospital. Clin Exp Gastroenterol. 2015; 8:191–6

    PubMed  PubMed Central  Google Scholar 

  88. Ramos-Martinez A, Ortiz-Balbuena J, Asensio-Vegas A, et al. Characteristics of Clostridium difficile infection in patients with discordant diagnostic test results. Revista Espanola De Enfermedades Digestivas. 2016; 108:304–8

    PubMed  Google Scholar 

  89. Depoorter L, Verhaegen J, Joosten E. Use of proton pump inhibitors and risk of nosocomial Clostridium difficile infection in hospitalized elderly adults. J Am Geriatr Soc. 2016;64:667–9.

    Article  PubMed  Google Scholar 

  90. Gordon D, Young LR, Reddy S, et al. Incidence of Clostridium difficile infection in patients receiving high-risk antibiotics with or without a proton pump inhibitor. J Hosp Infect. 2016;92:173–7.

    Article  CAS  PubMed  Google Scholar 

  91. Imlay H, Kaul D, Rao K. Risk factors for Clostridium difficile infection in HIV-infected patients. SAGE Open Med. 2016;4:2050312116684295.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Lewis PO, Litchfield JM, Tharp JL, et al. Risk and severity of hospital-acquired Clostridium difficile infection in patients taking proton pump inhibitors. Pharmacotherapy. 2016;36:986–93.

    Article  CAS  PubMed  Google Scholar 

  93. Ramos A, Ortiz J, Asensio A, et al. Risk factors for Clostridium difficile diarrhea in patients with solid organ transplantation. Prog Transpl. 2016;26:231–7.

    Article  Google Scholar 

  94. Ro Y, Eun CS, Kim HS, et al. Risk of Clostridium difficile infection with the use of a proton pump inhibitor for stress ulcer prophylaxis in critically ill patients. Gut Liver. 2016;10:581–6.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Rogala BG, Malat GE, Lee DH, et al. Identification of risk factors associated with Clostridium difficile infection in liver transplantation recipients: a single-center analysis. Transpl Proc. 2016;48:2763–8.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Ms. Mayumi Yamada and Ms. Chiyomi Ito for excellent technical assistance.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

    Tadayuki Oshima, Liping Wu, Min Li, Hirokazu Fukui, Jiro Watari & Hiroto Miwa

  2. Department of Gastroenterology, The Third People’s Hospital of Chengdu, Chengdu, China

    Liping Wu & Min Li

Authors
  1. Tadayuki Oshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liping Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Min Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hirokazu Fukui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiro Watari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroto Miwa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tadayuki Oshima.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oshima, T., Wu, L., Li, M. et al. Magnitude and direction of the association between Clostridium difficile infection and proton pump inhibitors in adults and pediatric patients: a systematic review and meta-analysis. J Gastroenterol 53, 84–94 (2018). https://doi.org/10.1007/s00535-017-1369-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-017-1369-3

Keywords

Search

Navigation