1. Probiotics to Prevent Antibiotic Associated Diarrhea By Jens Langsjoen

2. Outline Background of probiotics and AAD Efficacy of probiotics to prevent AAD Safety of probiotics UNMH inpatient probiotics Recommendations

3. Background on Probiotics “Live microorganisms, which when adminstered in adequate amounts, confer a health benefit on the host” -FAO/WHO Can be Bacteria or Fungi Common OTC supplement Have been studied in AAD, IBD, IBS, C diff, Cancer, allergies

4. Origins “Bacterium Lactis” 1 st Bacteria ever discovered… in souring milk o Joseph Lister 1857

5. Causes of AAD Killing Anaerobic bacteria o They normally digest carbohydrates o This causes an Osmotic diarrhea Altering gut flora  overgrowth of pathogens o Like C diff!!! o More alteration of gut flora = more diarrhea Pro-motility o erythromycin 1. Doron SI, Hibberd PL, Gorbach SL. Probiotics for prevention of antibiotic- associated diarrhea, J Clin Gastroenterol 2008;42 Suppl 2:S58-63.

6. Frequency of AAD Frequency range: 5-34%, Can occur between initiation of abx and 2 months  Hospitalized patients  Sicker patients, old and young.  Broad spectrum antibiotics.  B-Lactams, cephalosporins, clindamycin.  Longer Antibiotic Duration  History of AAD

7. AAD Frequency Clinical Trials PopulationAgeCountry# ptsFrequency Inpatient>50 yrsUK5633.9% Inpatient>18yrsUSA13429.9% InpatientChildrenJapan45522.6 Outpatient>1yrsUK12014% In/out<14yrsPoland12723% 2. Wistrom J, Norrby SR, Myhre EB, Eriksson S, Granstrom G, Lagergren L, Englund G, Nord CE, Svenungsson B. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study, J Antimicrob Chemother 2001;47:43-50.

8. AAD Frequency Population Studies PopulationAgeCountry# ptsFrequency Inpatient>12yrsSweden24624.9% Outpatient<15yrsFrance65011% Outpatient<14.5yrsThailand2256.2% AmbulatoryAdultsUSA358,3890.0012%

9. Clostridium Difficile 10-25% of AAD are C diff infections 6 Extended LOS: between 3-7days Increased subsequent infections: 20-65% 6. Al-Eidan FA, McElnay JC, Scott MG, Kearney MP. Clostridium difficile-associated diarrhoea in hospitalised patients, J Clin Pharm Ther 2000;25:101-109.

10. Probiotic MOA We only have theories… Suppression of pathogenic bacterial growth Improving intestinal barrier function o inducing protective cytokines Immune system modulation o Suppressing pro-inflammatory cytokines

11. Metanalyses of Probiotics for AAD All Probiotics o Avadhani 8 RCTs o Johnston 9 RCTs o Cremonini 9 RCTs o D’Souza 22 RCTs o McFarland 25 RCTs o Videlock 34 RCTs ALL SHOW PROBIOTICS TO BE EFFECTIVE S. Boulardii o McFarland 10 RCTs o Szajewska 6 RCTs Lactobacillus o Kale-Pradham 10 RCTs o Sazawal 19 RCTs

12. Meta-analysis: McFarland 2006 American Journal of Gastroenterology 31 RCTs on AAD prevention and C diff tx. 25 RCTs on AAD: 2810 patients, all settings, all ages 6 RCTs on C diff diarrhea tx and prevension. 4. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease, Am J Gastroenterol 2006;101:812- 822.

13. RR 0.43 CI (0.31-0.58)

14. Meta-analysis: McFarland 13 of 25 trials (52%) showed  AAD Prevention of AAD: RR 0.43 (0.31-0.58) NNT~8 High heterogeneity  Multiple subgroup analyses done to assess.  No difference in adults vs peds.  Most (90%) of studies were underpowered  Likely 2/2 differences in population (age) and intervention (dose, strains)

15. Metanalysis: Videlock April 2012-Alimentary Pharmacology & Therapeutics 34 double-blind RCTs, 4138 pts: o All ages, all settings, pts on abx given probiotics for AAD prevention o Includes 20/25 studies from McFarland. Thorough search strategy (Cochrane methodology) 5. Videlock EJ, Cremonini F. Meta-analysis: probiotics in antibiotic-associated diarrhoea, Aliment Pharmacol Ther 2012.

17. Results: Videlock Pooled data for AAD prevention  RR 0.53 (0.44 to 0.63)  NNT: 8 (using pooled raw data) o diffucult to interpret given heterogeniety Significant heterogeneity  multiple subgroup analyses and metaregressions performed

18. Subgroup Analyses: Videlock All 34 trials: Pooled data RR 0.53 (0.44 to 0.63) 24 adult trials: RR 0.53 (0.43-0.66) 10 pediatric: RR 0.48 (0.35 to 0.65) 13 Adult inpatient: RR 0.52 (0.38 to 0.72)

19. Subgroup Analyses- Risk of Bias 14 Low risk : RR 0.48 (0.35-0.68) 10 Unclear risk: RR 0.48 (0.37-0.63) 10 High risk: RR 0.62 (0.46-0.84)

20. How to Explain the Heterogeniety? Efficacy by Dose Efficacy by treatment duration Efficacy by Probiotic strain Efficacy for inpatient adults

21. Efficacy by Dose Gao et al. 7  RCT with 235 pts, using L. Acidophilus + L Casei  placebo vs 50 billion vs 100 billion CFUs  Assessed AAD and C diff recurrence. 7. Gao XW, Mubasher M, Fang CY, Reifer C, Miller LE. Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic- associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients, Am J Gastroenterol 2010;105:1636-1641.

22. Dose Response: Gao AAD 50 Billion CFUs 100 Billion CFUs

23. Dose Response: Gao C diff 50 Billion CFUs 100 Billion CFUs

24. Efficacy by Dose Johnston et al. 8  Subgroup analysis 5b CFUs/day  for >5b: RR 0.53 ( 0.29-0.55 )  for <5b: RR 0.80 ( 0.53-1.21 ) Interaction p=0.01 McFarland  >10 billion CFU dose more effective  8/12 (67%) high dose trials Efficacious vs 2/12 (17%) non-efficacious 8. Johnston BC, Goldenberg JZ, Vandvik PO, Sun X, Guyatt GH. Probiotics for the prevention of pediatric antibiotic-associated diarrhea, Cochrane Database Syst Rev 2011;(11):CD004827.

25. Efficacy by treatment duration McFarland  Tx duration range 5d-8wks  NS difference Videlock  16 trials- Equal to abx duration: RR 0.49 (0.38-0.63)  12 trials- 7d longer than abx: RR 0.53 (0.38-0.75)

26. Efficacy by Probiotic Strain McFarland-  Only L. Rhamnosus GG, S. Boulardii and probiotic mixtures were effective Johnston  Only LGG, L Coagulans, and S. Boulardii effective Videlock-  Similar RR across all probiotic strains o L. GG 8 trials 847 pts: RR 0.40 (0.20-0.81) o S. Boulardii 7 trials 1007 pts: RR 0.46 (0.30-0.70) o Any lactobacilli 24 trials 2817 pts : RR 0.56 (0.45-0.69) o Bifidobacteria 10 trials 602 pts: RR 0.55 (0.37-0.82)

27. Lactobacilli Efficacy Videlock  Any lactobacilli 24 trials 2817 pts RR 0.56 (0.45-0.69) Kale-Pradhan- Lactobacilli meta-analysis 9  10 RCTs, 1862 pts  doses of 2-40 billion CFUs  in Adults- RR 0.24 (0.08-0.75) 9. Kale-Pradhan PB, Jassal HK, Wilhelm SM. Role of Lactobacillus in the prevention of antibiotic- associated diarrhea: a meta-analysis, Pharmacotherapy 2010;30:119-126.

28. Saccharomyces Boulardii Efficacy Szajewska, 2005 Meta-analysis  5 RCTs, 1076 pts  RR= 0.43 (0.23-0.78)  NNT of 10 McFarland, 2010 Meta-analysis 10  10 RCTs, pooled RR: 0.47 (0.35-0.63) Videlock 2012- S. Boulardii Subgroup 11  7 RCTs 1007 pts: RR 0.46 (0.30-0.70) 10. McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adult patients, World J Gastroenterol 2010;16:2202-2222. 11. Szajewska H, Mrukowicz J. Meta-analysis: non-pathogenic yeast Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea, Aliment Pharmacol Ther 2005;22:365-372.

29. S. Boulardii- McFarland 2010 RR: 0.47 (0.35-0.63)

30. Efficacy in Hospitalized Adult Patients Avadhani: meta-analysis of Inpatient adults. 8 RCTs  AAD 1220 pts RR 0.56 (0.44–0.71)  C diff 471 pts RR 0.29 (0.18–0.46) Videlock : subgroup- 13 adult inpatient trials  AAD 1693 pts: RR 0.52 (0.38 to 0.72) 6 more inpatient trials currently ongoing

31. What do the experts think? American College of Gastroenterology formed “Yale Workshop on Probiotics” 12  2011 update, Probiotics for AAD: level A recommendation for S. boulardii, LGG, and combo of L. casei, L. bulgaricus, World Gastrenterology Association 2008  “In AAD, there is strong evidence of efficacy for S. boulardii or L. rhamnosus GG in adults” 12. Floch MH, Walker WA, Madsen K, Sanders ME, Macfarlane GT, Flint HJ, Dieleman LA, Ringel Y, Guandalini S, Kelly CP, Brandt LJ. Recommendations for probiotic use-2011 update, J Clin Gastroenterol 2011;45 Suppl:S168-71.

32. Safety: Population Studies Salminen et al. 13  Finland, 1990: L. Rhamnosus introduced into dairy  3 Trillion CFUs/person/year  11 cases of Lactobacillus bacteremia from 1990-2000  No increased incidence Saxelin et al. 14  4 year study in South Finland.  No relation between Lacto. Bcx strains and those used buy food industry 13. Salminen MK, Lactobacillus bacteremia during a rapid increase in probiotic use of Lactobacillus rhamnosus GG in Finland, Clin Infect Dis 2002;35:1155-1160. 14. Saxelin M, Chuang NH, Chassy B, Rautelin H, Makela PH, Salminen S, Gorbach SL. Lactobacilli and bacteremia in southern Finland, 1989-1992, Clin Infect Dis 1996;22:564-566.

33. Safety: Clinical Trials From 61-98’ 143 probiotic trials, 7,526 pts  no adverse effects.  no fungemia or bacteremia Videlock 2012 Meta-analysis  4138 pts no adverse events Wolf et al. Blinded safety RCT on 39 HIV pts 15  no adverse events. 15. Wolf BW, Wheeler KB, Ataya DG, Garleb KA. Safety and tolerance of Lactobacillus reuteri supplementation to a population infected with the human immunodeficiency virus, Food Chem Toxicol 1998;36:1085-1094.

34. Safety: Case Reports Bacteremia: 6 cases  4 in children with short gut syndrome Fungemia: 29 cases to date.  24 in ICUs, had CVCs, or immunosuppressed.  1 report of 2 neighbors being infected by fungus. 16. Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr 2006;83:1256-64; quiz 1446-7.

35. Summary Efficacy: Works for AAD prevention. NNT 5-10 Dose: in the billions, more (>5-50 billion) is better Duration: for duration of Abx therapy Strains: Best evidence for S. Boulardii, LGG, and Mixed strains. Safety: potentially fungemia- S. Boulardii in ICU pts, pts with central lines, and the immunosuppressed.

36. Products Available Inpatient UNMH Lactinex (L. Acidophilus and L. Bulgaricus) Florastor (S. Boulardii) Yoplait (commercial yogurt)

37. Lactinex L. Acidophilus and L Bulgaricus 1 tab: 1 million CFUs 1 pack granules: 100 million CFUs, 100 tabs= 1 granule pack. Cost of granules: $13 per 5 days, $0.86 per packet 2 trials on Lactinex for AAD prevention  Gotz (1979): 79 inpatient Adults. NS  Tankanow (1990): 38 outpatient peds. NS

38. Florastor Saccharomyces Boulardii 5 Billion CFUs per 250mg capsule Cost: $8 per 5 days, $0.79 per pill Restricted to pediatric use only. Great efficacy data

39. Yoplait Comercial Yogurt One serving contains around 280 million CFUs of L. Acidophilus and S. Thermophilus 17 Cost: at 3 a day; $15 per 5 days…? 2 RCTs on comercial Yogurt: 1 positive, 1 negative 17. Dunlap BS, Yu H, Elitsur Y. The probiotic content of commercial yogurts in west virginia, Clin Pediatr (Phila) 2009;48:522-527.

40. Saving the Hospital Money Hickson et al. 18  Cost to prevent 1 AAD: $100  Cost to prevent 1 C diff: $120 Kyne et al. 3  Cost per pt to treat C diff: $3,669  Cost of C diff in 2008: $3.2 billion 3. Kyne L, Hamel MB, Polavaram R, Kelly CP. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile, Clin Infect Dis 2002;34:346-353. 18. Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, Bulpitt CJ. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial, BMJ 2007;335:80.

41. Recommendations Get S. Boulardii approved for adults. Once approved, use in all patients on antibiotics except those with central lines, the immunosuppressed, and ICU patients. In the meantime, use Lactinex granules 2 packets TID mixed with Yogurt TID  ~1.5 billion CFUs/day

42. Pro-bios or Anti-bios?

43. 1. Doron SI, Hibberd PL, Gorbach SL. Probiotics for prevention of antibiotic-associated diarrhea, J Clin Gastroenterol 2008;42 Suppl 2:S58-63. 2. Wistrom J, Norrby SR, Myhre EB, Eriksson S, Granstrom G, Lagergren L, Englund G, Nord CE, Svenungsson B. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study, J Antimicrob Chemother 2001;47:43-50. 3. Kyne L, Hamel MB, Polavaram R, Kelly CP. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile, Clin Infect Dis 2002;34:346-353. 4. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease, Am J Gastroenterol 2006;101:812-822. 5. Videlock EJ, Cremonini F. Meta-analysis: probiotics in antibiotic-associated diarrhoea, Aliment Pharmacol Ther 2012. 6. Al-Eidan FA, McElnay JC, Scott MG, Kearney MP. Clostridium difficile-associated diarrhoea in hospitalised patients, J Clin Pharm Ther 2000;25:101-109. 7. Gao XW, Mubasher M, Fang CY, Reifer C, Miller LE. Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients, Am J Gastroenterol 2010;105:1636-1641. 8. Johnston BC, Goldenberg JZ, Vandvik PO, Sun X, Guyatt GH. Probiotics for the prevention of pediatric antibiotic-associated diarrhea, Cochrane Database Syst Rev 2011;(11):CD004827. 9. Kale-Pradhan PB, Jassal HK, Wilhelm SM. Role of Lactobacillus in the prevention of antibiotic-associated diarrhea: a meta- analysis, Pharmacotherapy 2010;30:119-126. 10. McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adult patients, World J Gastroenterol 2010;16:2202-2222. 11. Szajewska H, Mrukowicz J. Meta-analysis: non-pathogenic yeast Saccharomyces boulardii in the prevention of antibiotic- associated diarrhoea, Aliment Pharmacol Ther 2005;22:365-372. 12. Floch MH, Walker WA, Madsen K, Sanders ME, Macfarlane GT, Flint HJ, Dieleman LA, Ringel Y, Guandalini S, Kelly CP, Brandt LJ. Recommendations for probiotic use-2011 update, J Clin Gastroenterol 2011;45 Suppl:S168-71. 13. Salminen MK, Tynkkynen S, Rautelin H, Saxelin M, Vaara M, Ruutu P, Sarna S, Valtonen V, Jarvinen A. Lactobacillus bacteremia during a rapid increase in probiotic use of Lactobacillus rhamnosus GG in Finland, Clin Infect Dis 2002;35:1155-1160. 14. Saxelin M, Chuang NH, Chassy B, Rautelin H, Makela PH, Salminen S, Gorbach SL. Lactobacilli and bacteremia in southern Finland, 1989-1992, Clin Infect Dis 1996;22:564-566. 15. Wolf BW, Wheeler KB, Ataya DG, Garleb KA. Safety and tolerance of Lactobacillus reuteri supplementation to a population infected with the human immunodeficiency virus, Food Chem Toxicol 1998;36:1085-1094. 16. Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr 2006;83:1256-64; quiz 1446-7. 17. Dunlap BS, Yu H, Elitsur Y. The probiotic content of commercial yogurts in west virginia, Clin Pediatr (Phila) 2009;48:522-527. 18. Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, Bulpitt CJ. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial, BMJ 2007;335:80.