Probiotics Integrative Medicine SIG APA Meetings May 1

Probiotics Integrative Medicine SIG APA Meetings May 1, 2006 David K. Becker, MD, MPH UCSF Department of Pediatrics “You’ve been fooling around with alternative medicine, haven’t you? ”

Outline n What are probiotics and how do they work n Current proposed uses and a look at some of the evidence n Issues in prescribing their use

Probiotics: definitions n World Health Organization: n “live microorganisms which when administered in adequate amounts confer a health benefit on the host” n A bacterial strain that: n n Survives the stomach acid and bile Adheres to intestinal lining Grows and establishes temporary residence in the intestines Imparts health benefits R Fuller. Probiotics: The Scientific Basis. London: Chapman and Halls. 1992

Probiotics n Lactobacillus sp. reuteri n casei n ramnosus n acidophilus Streptococcus sp. Bifidobacterium sp. n infantis n lactis n longum n breve n bifidum Sacharomyces boulardii (nonhuman) VSL no. 3 n n n

Probiotics n Colonization at birth n Similar to maternal species n Specific organisms vary by age in first year n Become established by 1 year n In children and adults, “Successful” treatment with probiotics leads to temporary colonization only

Probiotics: proposed mechanisms n Adherence and subsequent stimulation of gut immune system n n n Up-regulation of mucin gene Enhance secretory Ig. A Maintain normal macrophage function n Competition for essential nutrients n Production of antimicrobial factors n Provide favorable environment for growth of other beneficial bacteria n Production of short-chain fatty acids with antiinflammatory properties

Probiotics: Proposed uses n n n n Infectious diarrhea Antibiotic-associated diarrhea IBD, IBS, and pouchitis Necrotizing Enterocolitis Bacterial vaginosis Recurrent UTI’s Atopic diseases Immune system enhancement H pylori infections Dental caries Radiation induced diarrhea Cardiovascular risk reduction Constipation Rheumatoid arthritis

Probiotics: Proposed uses Ratings: A: strong Rating the Evidence B: good C: fair Floch et al (2006) Natural Standard (2006) Infectious diarrhea A B Antibiotic-associated diarrhea A C Diarrhea prevention B B IBS C B B? B/C Atopic dermatitis/Allergy Floch, et al. Recommendations for Probiotic Use. J Clin Gastro. 40(3). 2006 www. naturalstandard. com

Probiotics: Proposed uses Ratings: A: strong Rating the Evidence B: good C: fair Floch et al (2006) Ulcerative colitis C Crohn’s disease C H pylori infection C Natural Standard (2006) NEC Bacterial vaginosis B A C C UTI’s Floch, et al. Recommendations for Probiotic Use. J Clin Gastro. 40(3). 2006 www. naturalstandard. com C C

Probiotics: the evidence n Antibiotic-associated diarrhea: n D’Souza et al (BMJ 2002) n n Systematic review of 9 placebo-controlled studies (2 in children) Various probiotics (4 uses S Bouladarii) 60% reduction in antibiotic associated diarrhea compared with placebo (OR 0. 37, 95% CI 0. 26 -0. 53) Vanderhoof et al (J Pediatr 1999) n n n 202 children, 6 mo - 10 yr, otitis/pharyngitis, amox/amox-clav Oral antibiotics in an outpatient setting for 10 days Lactobacillus GG, 10 (<12 kg) or 20 (>12 kg) billion cfu’s for 10 d Rated stool consistency and frequency 26% of controls and 8% of L GG had diarrhea Of those with diarrhea, 5. 9 days in placebo, 4. 7 days in L GG

Probiotics: the evidence n Infectious diarrhea: n Van Niel et al (Peds 2002) n n n Systematic review of 9 studies (all outside US, 1 -36 months) Various probiotics (4 used L GG) Mean reduction in diarrhea of 0. 7 days (95% CI: 0. 3 -1. 2) 1. 6 fewer stools in L GG groups (95% CI: 0. 7 -2. 6) Dose response curve with higher L GG dose Two other meta-analyses also showed benefits, particularly with L GG n n Allen et al. Cochrane Database Syst Rev, 2004 Szajewska et al. J Pediatr Gastroenterol Nutr, 2001

Probiotics: the evidence n Prevention of infections in day care: n Weizman et al (Peds 2005) n n n Double-blind, placebo-controlled RCT 14 day care centers in Israel, 4 -10 months of age Formula with B lactis, L reuteri, or no probiotics (no breastfeeding) Mean intake: 1 billion orgs Intervention and follow-up totaled 12 weeks Both probiotic groups had: § Fewer febrile episodes § Fewer diarrhea episodes § Shorter diarrhea episodes n n No difference in rate or duration of respirator illnesses L reuteri group did significantly better than B lactis group

Probiotics: the evidence n Atopic disease: n Kalliomaki et al (Lancet 2001) n n n L GG, 10 bill cfu’s, given to mother’s with a family hx of a first degree relative with an atopic condition (asthma, eczema, allergic rhinitis). Mothers for 2 -4 weeks before delivery, then infants or lactating mothers for the first 6 months. Outcome: atopic disease at 2 yrs. Frequency of eczema reduced from 46% to 23% (RR 0. 51, CI: 0. 32 -0. 84) Kalliomaki et al (Lancet 2003) n n 4 yr follow up study (54 of 68 controls, 53 of 64 intervention) Relative risk reduction for atopic eczema of 0. 57 (95% CI: 0. 330. 97)

Probiotics: prescribing n Which organism to use? n Which product? n For what conditions? n What dose? n For How long? n Any side effects to be aware of? n How much does it cost?

Probiotics: prescribing Lactobacillus GG best studied to date n Combination products not well studied, but may work as well n 10 billion organisms/d n Keep in fridge n Give in cool food/drink n 2% risk bloating/gas n

Probiotics: prescribing n Consumer. Lab. com tested 25 probiotic products n 19 for general population, 3 for children, 3 yogurts n 8 claimed a specific number of organisms per serving n 13 claimed only a number of organisms at time of manufacture n 8/25 contained less than 1 percent of the claimed number of live bacteria or of the expected minimum of 1 billion. n 7 of the 8 that gave expected numbers per serving met those counts n None contaminated with bacteria, mold, or fungus n All enteric-coated capsules passed testing

Probiotics: prescribing ABC Dophilus Jarro-Dophilus EPS Baby’s Jarro. Dophilus Culturelle Organisms B bifidum S thermophilus B infantis L rhamnosus L casei L plantarum L acidophilus B longum B breve P adidilactici L diacetylactis B breve B lactis Blongum B bifidum L casei L rhamnosus Lactobacillus GG Quantity per “dose” 1 bill total orgs 4. 4 bill total orgs 3 bill total orgs 10 billion orgs (Consumer Labs) Cost per dose for 9 -10 bill orgs/dose $4. 00 $0. 57 $0. 69 $0. 67

Probiotics: prescribing Nature’s Way Primidophilus for children Nature’s Way Primidophilus for kids chewable Nature’s Way Primidophilus junior Organisms L acidophilus L rhamnosus B longum B infantis L acidophilus L rhamnosus B longum L acidophilus L rhamnosus B breve B longum B infantis L acidophilus L rhamnosus Quantity per “dose” 2. 9 bill total orgs 1. 5 bill orgs 1 bill total orgs $1. 33 (3 doses/cont) $1. 50 (9 doses/cont) (Consumer Labs) Cost per dose for 9 -10 bill orgs/dose $0. 50 (30 -60 doses/cont) $1. 88 (8 doses/cont)

Probiotics: prescribing Nature Made acidophilus Breyers 99% Fat Free Fruit on the Bottom… Stonyfield Farm French Vanilla Nonfat Yogurt UAS Labs DDS Junior Organisms L acidophilus ? others Bifidus ? L acidophilus L casei L bulgaricus L reuteri B infantis L acidophilus FOS Quantity per “dose” 500 million 1 billion org ? ? (8 oz cont. ) 1 bill total orgs ? ? (8 oz cont. ) 2 (? 5) bill total orgs (Consumer Labs) $5. 00 (2 doses/cont. ) ? $$$ $1. 00 (14 doses/cont) Cost per dose for 9 -10 bill orgs/dose

Take home points… n Good evidence for: n n Infectious diarrhea Antibx-assoc diarrhea n Promising evidence for: n n n Prevention of infectious diarrhea Prevention of atopic conditions other uses? n Prescribing n n n n In the future we may be using probiotics as we use antibiotics today: with specific strains used for certain clinical situations guided by controlled studies Lactobacillus GG best studied to date Combination products not well studied, but may work as well 10 billion organisms/d Keep in fridge Give in cool food/drink 2% risk bloating/gas

Studies at UCSF n Probiotics to prevent antibiotic-associated diarrhea in hospitalized children (Andi Shane, MD) 2 mo - 12 yrs n L GG, 10 billion cfu’s, given throughout antibiotic course n

Studies at UCSF n Trial of Infant Probiotic Supplementation to Prevent Asthma (TIPS) (Michael Cabana, MD) L GG, 10 billion cfu’s, given within 2 weeks for 6 months n Follow development of asthma over 3 years n Beginning recruitment n