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Con/Probiotics: The Utility of Probiotics in Infectious Gastrointestinal Illness

Con/Probiotics: The Utility of Probiotics in Infectious Gastrointestinal Illness. John R. Stevens, MD Swedish Family Medicine May 9, 2014. Objectives. Define probiotics Delineate challenges in probiotic data Discuss the data for probiotic use in: Treatment of acute diarrheal illnesss

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Con/Probiotics: The Utility of Probiotics in Infectious Gastrointestinal Illness

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  1. Con/Probiotics: The Utility of Probiotics in Infectious Gastrointestinal Illness John R. Stevens, MD Swedish Family Medicine May 9, 2014

  2. Objectives • Define probiotics • Delineate challenges in probiotic data • Discuss the data for probiotic use in: • Treatment of acute diarrheal illnesss • Prevention of antibiotic associated diarrhea (AAD) • Prevention of C. Difficile associated diarrhea (CDD) • Treatment of H. Pylori Infection • Prevention of traveler’s diarrhea

  3. What’s Out There? • Probiotics – Microbial cell preparations or components of microbial cells with beneficial effect on the host • Lactobacillus – several strains • Saccharomyces boulardii • Bifedobacteria • And Many More! • Prebiotics • Inulin • Trans-galactooligosaccharide

  4. http://www.culturelle.com/purchase

  5. Yogurts and foods • May contain pre- or probiotics • Not all species are made equal • Purity of strains has been questioned • Components of yogurt can actually complicate symptoms

  6. It’s a long journey… • Cultures need to survive: • Preparation, packaging • Shelf time • Transit through GI tract • Temperature variance • Osmolar variance • And still be able to function… • Culligan EP, Hill C, Sleator RD. Probiotics and gastrointestinal disease: successes, problems and future prospects. Gut Pathog. 2009 Nov 23;1(1):19.

  7. Put this bacteria in your mouth… • Proposed action • Binding to enterocytes • Competition with pathogenic strains • Production of lactic acid and bacteriocins • Colonization may vary • Elimination varies • No medication interactions known • Culligan EP, Hill C, Sleator RD. Probiotics and gastrointestinal disease: successes, problems and future prospects. Gut Pathog. 2009 Nov 23;1(1):19.

  8. The trouble with options • Majority of studies are small • Multitude of probiotic strains • Dosing regimens in studies vary widely • Lack of pressure to validate claims • Variance within microbiome • Variance in exposure to etiologies of infection

  9. Acute diarrhea • In children <5: • Accounts for >1.5 millions visits annually • Approximately 300 deaths • Approximately 200,000 hospitalizations • Estimated $250 million directly, $1 billion indirect • In elderly – higher risk of mortality • Worldwide • 1.78 million deaths annually in low and middle income countries

  10. Use in infectious diarrhea • 2010 Cochrane Review • 63 studies including 8014 patients • Mean duration decrease nearly 25 hours • Stool frequency (Day 2) reduced by 0.8 • Diarrhea at or beyond 4 days decreased by 59% • No adverse events noted • Differences in studies are wide

  11. Use in pediatric infectious diarrhea • Van Niel2002– Lactobacillus meta-analysis • Decreased duration by 0.7 days • Decreased frequency by 1.6 at day 2, • Dosing regimens varied, apparent linear response

  12. Use in pediatric infectious diarrhea • Chen et. al. RCT, n=304 • Strains included Bacilllusmesentericus, Enterococcus Faecalis and Clostridium butyricum • TID x 7 days vs placebo • Decrease in mean duration from 86.3 to 60.1 hours • Overall hospital stay shorter

  13. Lactobacillus strains • Szajewska et. al. 2007 – 8 RCT, n=998 • Reduction of diarrhea by 1.1 days • Decreased by 2.1 days in rotavirus • No change in stool volume • Szajewska et. al. 2013 -15 RCT n=2963 • Decreased duration similar • Appeared to be more effective with >1010 CFU • No statistical significant difference in non-EU countries http://www.giantmicrobes.com/us/products/acidophilus.html

  14. Saccharomyces • Szajewska et. al. 2007, 5 RCT n=619 • Duration decreased by 1 day • All studies demonstrated decreased frequency of stools • Dosing range varied – 250-600mg qday • No adverse effects noted • Updated analysis 2009 • 4 additional studies • Only 1 study did not demonstrate decreased duration

  15. Acute infectious diarrhea • Duration of stools decreased by 1 day • Decreased frequency of stools is minimal • No adverse events noted • Specific probiotics appear to have efficacy: • Lactobacillus >1010 CFU total daily • Saccharomyces Boulardii at least 250mg once a day • Increased benefit in Rotavirus • May not be as effective in US population compared to EU population

  16. Persistent diarrhea in children • 1/3 of diarrheal related deaths in developing countries • 2013 Cochrane Review • Limited quality studies • Significant decrease in duration of diarrhea-4 days • Reduced Frequency of stools • No mortality in studies

  17. Antibiotic associated diarrhea • Studies are limited • Varied end points, methodology widely varied • McFarland -2006, 25 RCTs • Decreased in incidence by 57% • Hempel – 2012, 63 RCTs • Relative risk 0.58 • NNT 13 • Lenoir-Wijnkoop model study • Probiotics started within 48 hours of abx, continued 1 week post • Estimated savings £339 per patient

  18. Clostridium difficile prevention • McFarland -2006, 6 RCTs • Only Saccharomyces effectively decreased CDD • Johnston 2012- 20 RCTs • Incidence of CDD decreased by 66% • Hickson et. al. 2007 – Probiotic Drink • 135 Inpatients. 0% developed CDD, vs 17% in control • NNT = 6

  19. PLACIDE trial • Large Multi-center, double blinded RCT, n=2941 • Inpatients receiving antibiotics • MultistrainBifidobacteria or Lactobacillus vs placebo qday x21 days • Outcomes: AAD within 8 wks, C. Diff within 12 wks • No difference in AAD • C Difficile with low incidence (0.99%), insignificant difference

  20. Antibiotic associated diarrhea and C. difficile associated diarrhea • Moderate evidence to support probiotic use for prevention of antibiotic associated diarrhea • SOR B • Data is insufficient to suggest routine use of probiotics for prevention of C. Diff associated diarrhea.

  21. H. pylori treatment • Cindoruk2007 • Saccharomyces in association with triple therapy • Decreased associated SE • Diarrhea 15% vs31% • Epigastric discomfort 13% vs44% • Diffuse pain, gas, taste disturbanve, urticaria, nauesa w/o difference • Non-statistically significant higher eradication rate in probiotic arm 71% vs60%

  22. H. pylori • Kim 2008 • Yogurt containing several strains • Non-statistically significant increase in eradication rates • Increased frequency of adverse events in yogurt arm • 41% vs26% • Metallic taste was only statistically significant difference

  23. Prevention of traveler's diarrhea • Estimated incidence 5-50% • Limited prevention regimens • McFarland 2007, meta-analysis of blinded RCT • 12 studies • 6 found significant reduction in incidence • 6 did not. • Pooled data confers RR 0.85,

  24. Other Proposed Uses • Prevention of BV, UTI • Celiac • Constipation • IBS • Lactose intolerance

  25. Cautions • Probiotics regulation limited • Strains may not be pure • Variety of products available to patients • Long-term studies do not exist • Caution in critically ill, significantly immunocompromised

  26. Take home points • Little to no harm in probiotic use in immunocompetent persons • Some demonstrated benefit in decreased duration of diarrheal symptoms and decreased stool frequency in acute diarrhea • Data to support in use in prevention of AAD is moderate • Mixed data to support use in H. Pylori eradication. • Insufficient data to strongly support use in prevention of traveler's diarrhea. • Questionable benefit in elderly • Daily dosing for prevention in healthy adults without strong support

  27. Questions • Special Thanks • Maureen Brown, MD • Carroll Haymon, MD • Anna McDonald, MD • Swedish CME Staff • Wifey-Poo • Baby Nugget

  28. Resources • Culligan EP, Hill C, Sleator RD. Probiotics and gastrointestinal disease: successes, problems and future prospects. Gut Pathog. 2009 Nov 23;1(1):19. • Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray, CJL. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367 (9524):1747–5 • Churgay, C., Aftab, Z. Gastroenteritis in Children: Part II Prevention and Management. Am Family Physician. 2012 85(11):1066-1070. • Tucker AW, Haddix AC, Bresee JS, Holman RC, Parashar UD, Glass RI. Cost-effectiveness analysis of a rotavirus immunization program for the United States. JAMA. 1998 May 6;279(17):1371-6. • Glass RI, Lew JF, Gangarosa RE, LeBaron CW, Ho MS. Estimates of morbidity and mortality rates for diarrheal diseases in American children. J Pediatr. 1991 Apr;118(4 Pt 2):S27-33. • Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev. 2010 Nov 10;(11):CD003048. • Van Niel CW, Feudtner C, Garrison MM, Christakis DA. Lactobacillus therapy for acute infectious diarrhea in children: a meta-analysis. Pediatrics. 2002 Apr;109(4):678-84.\ • Chen CC, Kong MS, et. al. Probiotics have clinical, microbiologic, and immunologic efficacy in acute infectious diarrhea. Pediatr Infect Dis J. 2010 Feb;29(2):135-8.

  29. Resources cont’d • Szajewska H, Skórka A, Ruszczyński M, Gieruszczak-Białek D. Meta-analysis: Lactobacillus GG for treating acute diarrhoea in children. Aliment PharmacolTher. 2007 Apr 15;25(8):871-81. • Szajewska H, Skórka A, Ruszczyński M, Gieruszczak-Białek D. Meta-analysis: Lactobacillus GG for treating acute gastroenteritis in children--updated analysis of randomised controlled trials. Aliment PharmacolTher. 2013 Sep;38(5):467-76. • Szajewska H, Skórka A, Dylag M. Aliment PharmacolTher. Meta-analysis: Saccharomyces boulardii for treating acute diarrhoea in children. 2007 Feb 1;25(3):257-64. • Szajewska H, Skórka A.. Saccharomyces boulardii for treating acute gastroenteritis in children: updated meta-analysis of randomized controlled trials. Aliment PharmacolTher. 2009 Nov 1;30(9):960-1 • Bernaola Aponte G, BadaMancilla CA, Carreazo NY, Rojas Galarza RA. Probiotics for treating persistent diarrhoea in children. Cochrane Database Syst Rev. 2013 Aug 20;8:CD007401. • Hempel S, Newberry SJ, et. al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA. 2012, 307(18):1959-69. • McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. 2006 Apr;101(4):812-22.

  30. Resources Cont’d • Lenoir-Wijnkoop I, Nuijten MJ, Craig J, Butler CC, Nutrition economic evaluation of a probiotic in the prevention of antibiotic-associated diarrhea. Front Pharmacol. 2014 Feb 17;5:13. • Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, BulpittCJ..Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007 Jul 14;335(7610):80. • Johnston BC, Ma SS, Goldenberg JZ, Thorlund K, Vandvik PO, Loeb M, GuyattGH..Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012 Dec 18;157(12):878-88 • Allen SJ1, Wareham K, Wang D, et. al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficilediarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2013 Oct 12;382(9900):1249-57 • McFarland LV. Meta-analysis of probiotics for the prevention of traveler's diarrhea. Travel Med Infect Dis. 2007 Mar;5(2):97-105. • Cindoruk M, Erkan G, Karakan T, Dursun A, Unal S. Efficacy and safety of Saccharomyces boulardii in the 14-day triple anti-Helicobacter pylori therapy: a prospective randomized placebo-controlled double-blind study. Helicobacter. 2007 Aug;12(4):309-16. • Kim MN, Kim N, Lee SH, Park YS, Hwang JH, Kim JW, Jeong SH, Lee DH, Kim JS, Jung HC, Song ISThe effects of probiotics on PPI-triple therapy for Helicobacter pylori eradication.. Helicobacter. 2008 Aug;13(4):261-8.

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