In short Article

Resistance to antibiotics due to gastric acid suppressants?

Gastric acid-suppressive agents such as proton pump inhibitors (PPIs), histamine 2(H2) antagonists or antacids effectively reduce gastro-oesophageal and gastro-duodenal symptoms and prevent the development of ulcers due to NSAIDs. There is, however, abundant scientific literature showing that prolonged use of gastric acid suppressants is not without its risks. For instance, PPIs are associated with intestinal infections and diarrhoea caused by Clostridioides difficile, vitamin B12 and magnesium deficiencies, as well as interstitial nephritis. In addition, attempts to discontinue this medication often fail due to rebound effects. A recently published meta-analysis adds another risk to this list: intestinal colonisation by antibiotic-resistant bacteria. In view of the growing worldwide problems of resistance, this emphasizes the importance of carefully considering whether to start or end treatment with gastric acid suppressants.

  • A meta-analysis of observational studies found that the use of gastric acid-suppressive agents, particularly proton pump inhibitors, is associated with an increased risk of intestinal colonisation by  highly resistant micro-organisms. 
  • The presence of resistant bacteria in the intestines increases the risk of infections by these bacteria at other sites in the body, and turns the patient into a source of infection for others.
  • An increased risk of infecting others also increases the risk of antibiotic resistance spreading through the population.
  • Assessing the options for gradually discontinuing the use of gastric acid suppressants may help reduce unnecessary prolonged use of these drugs.

  1. Scally B, Emberson JR, Spata E, et al. Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials. Lancet Gastroenterol Hepatol. 2018;3(4):231-241. doi:10.1016/S2468-1253(18)30037-2
  2. Lanas A, Scheiman J. Low-dose aspirin and upper gastrointestinal damage: epidemiology, prevention and treatment. Curr Med Res Opin. 2007;23(1):163-173. doi:10.1185/030079907X162656
  3. de Groot NL, Hagenaars MP, Smeets HM, Steyerberg EW, Siersema PD, van Oijen MG. Primary non-variceal upper gastrointestinal bleeding in NSAID and low-dose aspirin users: development and validation of risk scores for either medication in two large Dutch cohorts. J Gastroenterol. 2014;49(2):245-253. doi:10.1007/s00535-013-0817-y
  4. Hedberg J, Sundström J, Thuresson M, Aarskog P, Oldgren J, Bodegard J. Low-dose acetylsalicylic acid and gastrointestinal ulcers or bleeding--a cohort study of the effects of proton pump inhibitor use patterns. J Intern Med. 2013;274(4):371-380. doi:10.1111/joim.12103
  5. Willems RPJ, van Dijk K, Ket JCF, Vandenbroucke-Grauls CMJE. Evaluation of the Association Between Gastric Acid Suppression and Risk of Intestinal Colonization With Multidrug-Resistant Microorganisms: A Systematic Review and Meta-analysis [published online ahead of print, 2020 Feb 24]. JAMA Intern Med. 2020;180(4):561-571. doi:10.1001/jamainternmed.2020.0009
  6. Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol. 2007;102(9):2047-2057. doi:10.1111/j.1572-0241.2007.01275.x
  7. Wei L, Ratnayake L, Phillips G, et al. Acid-suppression medications and bacterial gastroenteritis: a population-based cohort study. Br J Clin Pharmacol. 2017;83(6):1298-1308. doi:10.1111/bcp.13205
  8. Hafiz RA, Wong C, Paynter S, David M, Peeters G. The Risk of Community-Acquired Enteric Infection in Proton Pump Inhibitor Therapy: Systematic Review and Meta-analysis. Ann Pharmacother. 2018;52(7):613-622. doi:10.1177/1060028018760569
  9. Bavishi C, Dupont HL. Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment Pharmacol Ther. 2011;34(11-12):1269-1281. doi:10.1111/j.1365-2036.2011.04874.x
  10. Kerst AJ. Langdurig gebruik van maagzuurremmers. Hoe kan de huisarts hiermee omgaan? Gebu. 2001;35(9):105-106.
  11. Van Wetten NI. Gebu. 2013;47(10):112.
  12. Bijl D. Protonpompremmers en het risico van heupfactuur Gebu. 2007;41(6): 68.
  13. Van der Linden MW. Behandeling van gastro-oesofageale reflux en dyspepsie met H2-receptorblokkerende geneesmiddelen en protonpompremmers. Gebu. 2009;43(4);37-43.
  14. Kerst AJ. Protonpompremmers zijn geen 'beschermers', het zijn geneesmiddelen. Gebu. 2016;5(11):126-127.
  15. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310(22):2435-2442. doi:10.1001/jama.2013.280490
  16. Tran-Duy A, Connell NJ, Vanmolkot FH, et al. Use of proton pump inhibitors and risk of iron deficiency: a population-based case-control study. J Intern Med. 2019;285(2):205-214. doi:10.1111/joim.12826
  17. Heidelbaugh JJ. Proton pump inhibitors and risk of vitamin and mineral deficiency: evidence and clinical implications. Ther Adv Drug Saf. 2013;4(3):125-133. doi:10.1177/2042098613482484
  18. Jung SB, Nagaraja V, Kapur A, Eslick GD. Association between vitamin B12 deficiency and long-term use of acid-lowering agents: a systematic review and meta-analysis. Intern Med J. 2015;45(4):409-416. doi:10.1111/imj.12697
  19. Van den Berg S, Scheer ML, Homan ND. Ernstige hypomagnesiëmie door protonpompremmers. Ned Tijdschr Geneeskd. 2018;162:D2702.
  20. De Waal YR, Ixkes MC, Steenbergen E, et al. Medicamenteuze tubulo-interstitiële nefritis. Ned Tijdschr Geneeskd. 2011;155:A3665
  21. 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(9):765-771. doi:10.1001/archinternmed.2010.94
  22. Zhou B, Huang Y, Li H, Sun W, Liu J. Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporos Int. 2016;27(1):339-347. doi:10.1007/s00198-015-3365-x
  23. De Vries TW, Janssens HJ. 2018. Protonpompremmers bij zuigelingen. Gebu. 2018;52(7-8):62-63.
  24. Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171(1):33-38. doi:10.1503/cmaj.1040876
  25. Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA. 2005;294(23):2989-2995. doi:10.1001/jama.294.23.2989
  26. Aseeri M, Schroeder T, Kramer J, Zackula R. 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. doi:10.1111/j.1572-0241.2008.01975.x
  27. 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. doi:10.1001/archinternmed.2010.89
  28. Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA. Proton pump inhibitors and risk for recurrent Clostridium difficile infection [published correction appears in Arch Intern Med. 2010 Jul 12;170(13):1100]. Arch Intern Med. 2010;170(9):772-778. doi:10.1001/archinternmed.2010.73 
  29. Hassing RJ, Verbon A, de Visser H, Hofman A, Stricker BH. Proton pump inhibitors and gastroenteritis. Eur J Epidemiol. 2016;31(10):1057-1063. doi:10.1007/s10654-016-0136-8
  30. Stichting Farmaceutische Kengetallen. Maagbeschermer omeprazol meeste gebruikers in 2019. Pharm Weekbl. 2020;155(5):8.
  31. Giannella RA, Broitman SA, Zamcheck N. Gastric acid barrier to ingested microorganisms in man: studies in vivo and in vitro. Gut. 1972;13(4):251-256. doi:10.1136/gut.13.4.251
  32. Imhann F, Bonder MJ, Vich Vila A, et al. Proton pump inhibitors affect the gut microbiome. Gut. 2016;65(5):740-748. doi:10.1136/gutjnl-2015-310376
  33. Jackson MA, Goodrich JK, Maxan ME, et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut. 2016;65(5):749-756. doi:10.1136/gutjnl-2015-310861
  34. Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;555(7698):623-628. doi:10.1038/nature25979
  35. Buffie CG, Pamer EG. Microbiota-mediated colonization resistance against intestinal pathogens. Nat Rev Immunol. 2013;13(11):790-801. doi:10.1038/nri3535
  36. Chanderraj R, Millar JA, Patel TS, et al. Vancomycin-Resistant Enterococcus Acquisition in a Tertiary Care Hospital: Testing the Roles of Antibiotic Use, Proton Pump Inhibitor Use, and Colonization Pressure. Open Forum Infect Dis. 2019;6(4):ofz139. Published 2019 Mar 15. doi:10.1093/ofid/ofz139
  37. Falk PS, Winnike J, Woodmansee C, Desai M, Mayhall CG. Outbreak of vancomycin-resistant enterococci in a burn unit. Infect Control Hosp Epidemiol. 2000;21(9):575-582. doi:10.1086/501806
  38. Dekkers OM. Bewijskracht: gerandomiseerd of observationeel onderzoek? Gebu. 2020;54(1):1-8.
  39. Wet medisch-wetenschappelijk onderzoek met mensen. 1 Januari 2020. Via: Geraadpleegd op 27 april 2020
  40. De Greeff SC, Schoffelen AF, Verduin SM. NethMap 2020 - Consumption of antimicrobial agents and antimicrobial resistance among medically important bacteria in the Netherlands in 2019. SWAB, the Dutch Foundation of the Working Party on Antibiotic Policy & the Centre for Infectious disease control (CIb) of the RIVM. Juni 2020.
  41. Leenstra T, Carbapenemase-producerende enterobacteriën in Nederland. Ned Tijdschr Geneeskd. 2017;161(47):D1585
  42. Katz  MH. Failing the Acid Test - Benefits of Proton Pump Inhibitors May Not Justify the Risks for Many Users. Arch Intern Med. 2010;170(9):747-748. doi:10.1001/archinternmed.2010.64
  43. Wang Y, Ye Z, Ge L, et al. Efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: systematic review and network meta-analysis. BMJ. 2020;368:l6744. Published 2020 Jan 6. doi:10.1136/bmj.l6744
  44. Heidelbaugh JJ, Goldberg KL, Inadomi JM. Overutilization of proton pump inhibitors: a review of cost-effectiveness and risk [corrected] [published correction appears in Am J Gastroenterol. 2009 Apr;104(4):1072] [published correction appears in Am J Gastroenterol. 2009 Mar;104(2 Suppl):S39]. Am J Gastroenterol. 2009;104 Suppl 2:S27-S32. doi:10.1038/ajg.2009.49
  45. Heidelbaugh JJ, Goldberg KL, Inadomi JM. Magnitude and economic effect of overuse of antisecretory therapy in the ambulatory care setting. Am J Manag Care. 2010;16(9):e228-e234.
  46. Lanas A. We Are Using Too Many PPIs, and We Need to Stop: A European Perspective. Am J Gastroenterol. 2016;111(8):1085-1086. doi:10.1038/ajg.2016.166
  47. Lee TC, McDonald EG. Deprescribing Proton Pump Inhibitors: Overcoming Resistance [published online ahead of print, 2020 Feb 24]. JAMA Intern Med. 2020;10.1001/jamainternmed.2020.0040. doi:10.1001/jamainternmed.2020.0040
  48. Numans ME, De Wit NJ, Dirven JA, et al. NHG-Standaard Maagklachten 2013. Via: Geraadpleegd op 15 juli 2020.
  49. Informatorium Medicamentorum. Hoofdstuk ‘Middelen bij peptische aandoeningen’. Via: KNMP Kennisbank. Geraadpleegd op 27 april 2020.
  50. Martin RM, Cao J, Brisse S, et al. Molecular Epidemiology of Colonizing and Infecting Isolates of Klebsiella pneumoniae. mSphere. 2016;1(5):e00261-16. Published 2016 Oct 19. doi:10.1128/mSphere.00261-16
  51. Carlet J. The gut is the epicentre of antibiotic resistance. Antimicrob Resist Infect Control. 2012;1(1):39. Published 2012 Nov 27. doi:10.1186/2047-2994-1-39
  52. Donskey CJ. The role of the intestinal tract as a reservoir and source for transmission of nosocomial pathogens. Clin Infect Dis. 2004;39(2):219-226. doi:10.1086/422002
  53. Tosh PK, McDonald LC. Infection control in the multidrug-resistant era: tending the human microbiome. Clin Infect Dis. 2012;54(5):707-713. doi:10.1093/cid/cir899


  • Sander van den Bogert, dr, pharmacist