Probiotics and Prebiotics: Medicine or Myth. Objectives 5/31/2013. Speaker s Disclosure Statement & Non Commercialism Agreement

Transcription

1 Probiotics and Prebiotics: Medicine or Myth Gregory Matsuura, Pharm.D., BCPS (AQ ID) Objectives Recall the differences between prebiotics and probiotics and their uses Identify the specific agents used in clinical trials and the results reported Recognize the commercially available products and their active components Discuss with patients the potential benefits, risks, and outcomes associated with these therapies Speaker s Disclosure Statement & Non Commercialism Agreement List of potential conflicts of interest: None List proprietary information or results of ongoing research that may be subject to different interpretations: None Presentation of this slide indicates my agreement to abide by the non commercialism guidelines provided on the CE Requirements page. 1

2 Good bacteria Stool = (1 trillion) bacteria per gram Beneficial role of intestinal microflora Disruption of flora risk Clostridium difficle Current in vitro tests are not adequate to predict in vivo outcomes Increasing good bacteria =?better outcomes? Prebiotics: feed the good bacteria Probiotics: supplement overall numbers Prebiotics Resist digestion in the upper GI tract Inulin Oligofructose Fructooligosaccharides (FOS) Stimulates growth of Bifidobacteria species Naturally occurring in many plants Root vegetables, leeks, onions, chicory North American diet 1 4g/day Other regions in the world 3 11g/day Kelly G Alternative medicine review 2008; 13 (4): Prebiotic Nomeclature Prebiotic Inulin Oligofructose FOS Process Hot water extracts without processing Partial hydrolysis of inulin and uses physical separation to remove long chain (DP 10) frutans Short chain, inulin type fructan mixes synthesized from sucrose 2

3 Inulin Commonly extracted from chicory root Long and short frutans Bifiogenic in infants and adults Inconsistent results on gut flora Individual patient flora variation Adult usual dose g/day Side effects: Bloating, abdominal pain, excessive flatulence Doses > 40g/day osmotic diarrhea Oligofructose Partial enzymatic hydrolyosis of inulin Long chain frutans removed Wide range of product purity Combination of fructans and free sugers Often used in combination artificial sweeteners Bacterial fermentation in proximal colon May have more GI side effects Shorter chains Adult usual dose 8 16g/day Fructooligosaccharides (FOS) Sucrose converted to FOS Fungal enzyme beta fructosidase Short chain, low molecular weight fructans More possible GI side effects Glucose and fructose also produced Bouhnik, et al N=40; 2.5g, 5g, 10g or 20g/day Bifidobacteria counts Greater in 10gm/day and 20gm/day Excess flatus in 20gm/day Bouhnik Y, et al. J Nutr Jan;129(1):

4 Prebiotics: Study outcomes Blood sugar regulation Colon cancer prevention Constipation IBS Lipid modification Inulin Oligofructose FOS No significant effects No significant effects stool frequency Improved symptoms No significant effects No significant effects NA stool frequency No significant effects No significant effects No significant effects NA stool frequency NA LDL in 12 obese patients Synbiotics Combination of prebiotics and probiotics Increases size and diversity of bifidobacteria Prebiotic content varies Unknown synergistic i dose Unknown if superior to probiotics alone Comparison trial NCT Completed: no results currently published De Vrese M and Schrezenmeir. Adv Biochem Engin/Biotechnol : Probiotics Eli Metchnikoff 1907 Selected bacteria associated with beneficial effects Commercial exploitation Most observations were anecdotal Substantial increase in research last 30 years Products which contain live microorganisms Provided in adequate doses in order to exert the desirable effects 4

5 Proposed Mechanisms of Action Enhancement of the epithelial barrier Inhibition of pathogen adhesion Competitive exclusion of pathogenic bacteria Modulation of the immune system Production of antimicrobial substances Streptococcus thermophilus Alpha hemolytic gram positive cocci AKA Lactococcus thermophilus Fermentation and production of dairy products Usually in combination products Probiotic Yogurts Bifidobacterium spp. Gram positive, anaerobic rod B. infantis, B. brevi, and B. longum Gastrointestinal density changes over time Predominate flora in infants Declines with age Production of lactic acid 5

6 Lactobacillus spp. Gram positive rod Vaginal and GI flora Lactobacillus rhamnosus (AKA GG) Sherwood Gorbach and Barry Goldin Lactobacillus Acidophilus Lactobacillus Casei Saccharomyces boulardii Isolated in 1923 from fruit Dietary supplement Lyophilized live yeast Inhibition of bacterial growth Antitoxin effects Inhibition of toxin receptor binding sites Direct proteolysis of the pathogenic toxins Stimulates intestinal mucosal activities Kelesidis T and Pothoulakis C. Ther Adv Gastroenterol 2012: 5(2) Concerns Marketed with taxonomically incorrect or fictious microbial names Lack of standards to define the number of viable organisms available No minimam manufacturing standards Some products are contaminated with unfriendly bacteria 6

7 Regularis = Regular Pharmacist Recommended* Probiotic Regulation Does not require FDA approval before being marketed Defined by the Dietary Supplement Health and Education Act (DSHEA) 1994 Manufacturers not required to provide FDA with evidence that substantiates the safety or purported benefits of their products, either before or after marketing 7

8 This product is not intended to diagnose, treat, cure, or prevent any disease Advertised indications Antibiotic associated diarrhea (AAD) Traveler's diarrhea Inflammatory bowel disease Urinary tract infections Nosocomial infections (Ventilator associated pneumonia) Helicobacter pylori Enterocolitis Constipation Allergy and atopic dermatitis Colic C. diff infection and prevention Hygiene hypothesis AKA micoflora hypothesis of allergic disease Low diversity of gut microbiota Less lactobacilli and bifidobacteria In infants associated with developing allergy later Allergy tolerance reconstituted with bifidobacteria Animal studies 8

9 Eczema Prevention: Limited evidence for benefit Combined pre and postnatal supplementation L. rhamnosus Treatment: Most studies are negative Effect not observed after 2 years of age World Allergy Organization Position Paper No clinically worthwhile benefit Colic Breastfed babies Controlled trials Positive outcomes Szajewska 2013 (n=80) 10 8 L. reuteri via dropper Day 28: Median difference 68 min crying Limited data on formula fed babes Puccio 2007 and Vlieger 2009: no improvement Prebiotic oligosaccharides May contribute to improve GI discomfort Szajewska H, et al. J Pediatr 2013;162: Mugambi MN, et al. Nutrition Journal 2012, 11:81 Necrotizing enterocolitis (NEC) Modulation of intestinal flora in preterm infants Time until target enteral feeding rate Some beneficial but others maybe harmful Pooled data trends towards favorable outcomes No product, dosage and method determined B. lactis and L. rhamnosus Not associated with reduced NEC or mortality Mihatsch WA. Et al. Clinical Nutrition 31 (2012)

10 Inflammatory bowel disease Crohn s disease Not effective in adult patients Ulcerative Colitis May help with ihinducing i remission i in mild mod d cases 28 patients with active UC Does not increase duration of remission Pouchitis Best results for chronic and recurrent pouchitis Urinary tract infections Beerepoot MA postmenopausal women: treated x 12 months Oral probiotic vs. TMP SMX 10 9 L. rhamnosus and L. reuteri twice daily At least 1 symptomatic UTI Lactobacilli 79.1% vs TMP SMX 69.3% TMP SMX participants: resistance developed 1 month: E. coli TMP SMX resistance by 20% Beerepoot MA, et al. Arch Intern Med May 14;172(9): Acute gastroenteritis Pediatrics Healthy infants and young children number of diarrheal stools Duration of the diarrhea 1 day. Viral gastroenteritis Not invasive bacterial infections dose dependent for doses > than Most data: L. rhamnosus Thomas DW, et al. Pediatrics 2010(6):

11 Helicobacter pylori Strains of Lactobacillus and Bifdobacterium In vitro bactericidal effects against H. pylori Release of bacteriocins Production of organic acids Inhibit adhesion to epithelial cells Added to standard therapy Moderately ( 10%) higher eradication rates Less diarrhea reported L. rhamnosus less/not effective Pediatric data inconclusive Vandenplans et al. Curr Infect Dis Rep 2013 Helicobacter pylori Shavakhi, et al Quadruple therapy + probiotic or placebo (n=180) Similar eradication rates (82.1 vs 84.8%, p=0.932) Low dosage of probiotic compound Combination of Lactobacillus; Bifidobacterium; streptococcus total viable count 200 million/day High frequency of upper GI adverse effects Diarrhea less frequent (2.2 vs 11%, p=0.016) Abdominal pain more frequent (10 vs 2.2,=0.029) Traveler s Diarrhea Travelers visiting developing countries 20% to over 50% of travelers Interfere with the colonization and invasion of bacteriainto into the intestinal wall Takahashi 2007 Meta analysis (n=3326) Not effective Takahashi O, et al. J Clin Gastroenterol Mar;41(3):

12 Antibiotic associated diarrhea (AAD) Adults: Hempel 2012 (meta analysis) Relative risk reduction of 0.58 (95% CI, 0.50 to 0.68) Most interventions were blends of probiotics Commonly included: L. rhamnosusorl or casei Predisposing antibiotic not described Pediatrics: Johnston 2011 (meta analysis) Relative risk reduction of 0.52 (95% CI, 0.38 to 0.78) high dose ( 5 billion CFUs/day) more effective Need more studies regarding strain specific probiotic Hempel S, et al. JAMA. 2012;307(18): Johnston BC, et al. Cochrane Database Syst Rev Nov 9;(11 Clostridium difficile Increasing national trend 2000 to 2009: Primary CDI cases more than tripled in US Avoidable health system cost $5,042 $7,179 per case $897 million to $1.3 billion annually Improving antimicrobial stewardship Antibiotic use increases CDI risk Seven to ten fold while taking antibiotic Three fold for subsequent 2 months MMWR March 2012,61: CDI: prevention (more is better?) Johnston et at Probiotics for the prevention of CDI Systematic review and Meta analysis 20 trials including 3818 patients Moderate quality evidence Probiotics reduced incidence by 66% Factors that favored probiotic Probiotic dosage >10 billion CFU/day Species: L. acidophilus + L. casei; S. boulardii Multiple strains Johnston BC, et al. Ann Intern Med Dec 18;157(12):

13 Johnston BC, et al. Ann Intern Med Dec 18;157(12): CDI: Treatment Surawicz et al (n=168) Patients with recurrent CDI Treated with vancomycin or metronidazole Then S. boulardii CFU/day x 4 wks or placebo Vancomycin 500 mg PO 4 times daily x 10 days Decrease in recurrences (16.7% vs. 50%; P =.05) Vancomycin 125mg PO 4 times daily x 10 days; metronidazole 250mg PO 4 times daily No difference in recurrence rate S. boulardii vs. placebo Surawicz CM, et al. Clin Infect Dis Oct;31(4): IDSA C. difficile 2010 guidelines Administration of currently available probiotics is not recommended to prevent primary CDI, as there are limited data to support this approach and there is a potential risk of bloodstream infection (C III). Cohen SH, et al. Infect Control Hosp Epidemiol 2010; 31(5):

14 American Journal of GASTROENTEROLOGY: C. difficile 2013 guidelines Although there is moderate evidence that two probiotics ( L. rhamnosus GG and S. boulardii ) decrease the incidence of antibiotic associated diarrhea, there is insufficient evidence that probiotics prevent C. difficile infection. (Strong recommendation, lowquality evidence) Surawicz CM, et al. Am J Gastroenterol Apr;108(4): American Journal of GASTROENTEROLOGY: 2013 guidelines There is limited evidence for the use of adjunct probiotics to decrease recurrences in patients with recurrent CDI. (Moderate recommendation, moderate quality evidence) Surawicz CM, et al. Am J Gastroenterol Apr;108(4): Ventilator associated pneumonia (VAP) Critical illness Creates a hostile environment in gut that Changes the normal intestinal microbiota Favors the growth of pathogens Selective gut decontamination Reduced mortality Increase bacterial resistance Probiotics administration less likely to develop VAP Theodorakopoulou M, et al. Int J Antimicrob Agents

15 Adverse reactions Mostly GI related Abdominal cramping, nausea, soft stools, flatulence Short term use not associated with severe ADRs Excludes immunocompromisedi Excludes severely debilitated Cases of systemic infection Bacteremia Fungemia Lactobacillius Bacteremia Involves L. rhamnosus 6 wk male: copious nonbloody diarrhea 7 10 day courses of broad spectrum antibiotics 17 yro male: ulcerative colitis Infliximab mesalamine and prednisone 67 yro male: self initiated treatment Mitral valve prolapse resulted in endocarditis Land MH, el at. Pediatrics Jan;115(1): Vahabnezhad, et al. J Clin Gastroenterol May Jun;47(5):437 9 Mackay, et al. Clin Microbiol Infect May;5(5): Saccharomyces fungemia 91 cases of documented S. boulardii fungemia 48% received S. boulardii probiotic 8% were near patients who had received S. boulardii Recent case yro with rheumatoid arthritis bowel resection including recurrent C. difficile 13 days of treatment with S boulardii Venugopalan V, et al. Emerg Infect Dis Nov;16(11): Thygesen JB, et al. BMJ Case Rep Mar 27;

16 Saccharomyces fungemia S. boulardii: IDSA/SHEA CDI guidelines Specifically recommend avoiding use Immunocompromised Critically ill Central IV line Environmental contamination Opening 500mg packet of S. baulardii Air contamination 1 meter distance Persisted up to 30 min after Hands persistently contaminated Even after hand washing Adults Pediatrics Eczema NA Weak data for prevention Colic NA Breastfeed babies Necrotizing enterocolitis NA Possible prevention Inflammatory bowel disease May help for acute disease NA Ui Urinary tract infections i May hl help for preventing NA recurrent UTIs in females Acute gastroenteritis NA May reduce symptoms Helicobacter pylori Modest in cure rate Modest in cure rate Traveler s Diarrhea Not likely effective NA AAD Beneficial Beneficial C. Diff May help with prevention NA Administration and duration Duration typically ranged 7 14 days At least for the duration of abx therapy Up to a week after completion of therapy Lactobacillus products at least 2 hours before or after antibiotics Hempel S, et al. JAMA. 2012;307(18):

17 Differences in choice Product Organisms Quantity VSL#3 Bifidobacterium breve, 900 billion Packets DS Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus Streptococcus thermophilus Nature s Lactobacillus Acidophilus 25 million blend Acidophilus Lactobacillin Florastor Saccharomyces Boulardii 250mg Question #1 Which of the following is less likely to cause GI symptoms due to a lower proportion of short frutans? A (orange): Fructooligosaccharides (FOS) B (yellow): Oligofructose C (pink): Lactose D (green): Inulin Question #2 The IDSA specifically warns against which probiotic in patients with central lines? ( ) S h hil A (orange): Streptococcus thermophilus B (yellow) :Saccharomyces boulardii C (pink): Bifidus Regularis D (green): Lactobacillus rhamnosus (GG) 17

18 Question #3 The evidence of probiotics is strongest for which indication? A (orange): Inflammatory bowel ldisease B (yellow) : Prevention of travelers diarrhea C (pink) : Antibiotic associated diarrhea D (green): Eczema Question #4 Which government body regulates the manufacture of probiotics? A (orange): Unregulated B (yellow): NIH C (pink): FDA D (green): National Center for Complementary and Alternative Medicine Question #5 Studies indicate the number of colony forming units (CFU) should be in what quantity for the prevention of CDI? A (orange): >10 7 B (yellow) : >10 8 C (pink) : >10 9 D (green): >