Presentation on theme: "Wake Forest University School of Medicine"— Presentation transcript:
1 Wake Forest University School of Medicine ProbioticsKathi J Kemper, MD, MPHWake Forest University School of Medicine“You’ve been fooling around with alternative medicine, haven’t you?”
2 DisclaimerI have the following financial relationships with the manufacturer of a commercial product and/or provider of commercial services discussed in this CME activity: American Academy of Pediatrics, “Mental Health, Naturally "Author. Royalties anticipated.The presentation will include no description of any proprietary items for screening, diagnosis, or treatments.I do not intend to discuss an unapproved or investigative use of a commercial product in my presentation.
3 Objectives By the end of this session, participants will be able to: Define and give two examples of probiotics and prebiotics and foods that contain themSummarize studies about the effectiveness and safety of using probiotics to prevent/treatDiarrhea, constipation, NEC, and colicEczemaIdentify one potential side effect and one contraindication to using probiotics
4 Prebiotics (functional food) First identified in 1995Non-digestible food ingredients that stimulate the growth and/or activity of probioticsTypically oligosaccharides: galactooligosaccharides (GOS), fructo-OS (FOS), xylo-OS (XOS), InulinFound in: Breastmilk, Jerusalem artichoke, chicory root, raw dandelion greens, leeks, onions, garlic, asparagus, whole grains, beans, bananaAdding Prebiotics to Probiotics increases production of gut Short-Chain Fatty Acids (SCFA)
5 Probiotics: definition World Health Organization:“live microorganisms which when administered in adequate amounts confer a health benefit on the host”They:Survive stomach acid and bileEstablish residence in the intestinesImpart health benefits
7 Probiotic examples Lactobacillus sp. reuteri casei ramnosus AcidophilusStreptococcus sp.Bifidobacterium sp.Infantis (breastmilk)lactislongumbrevebifidumSacharomyces boulardiiEnterococcus spMixturesFormulations: drops, chewable tablets, lozenges, capsules, straws, bottle capsBrands most often recommended on CHIM listserv include BioGaia, Culturelle, Florastor
8 Initial Intentional Probiotic Use Eli Metchnikoff - early 20th century (Russian Nobel laureate, professor at Pasteur Institute in Paris)ObservedBulgarians who drank milk fermented by lactic-acid producing bacteria had long livesLactic acid lowers gut pH and inhibits the growth of some pathogenic bacteria.Metchnikoff began drinking fermented milk and soon Parisian physicians did likewise.Henry Tissier at Pasteur Institute identified bacteria common in breastfed infant stool: BifidobacterLactobacillus acidophilus breaks down lactose and allows lactose intolerant individuals to drink milk
9 Probiotics- normal source? Colonization at birth with maternal speciesSpecific organisms vary by age in first yearBecome established by 1 yearDiet – maternal milk, fermented milk, pickles, fermented soy (tempeh), etc.“Successful” probiotic treatment leads to temporary colonization
10 Primary Pediatric Uses of Probiotics Manage lactose intolerance (L acidophilus)Antibiotic-associated diarrhea and infectious diarrheaDecrease constipationDecrease risk of NEC and all cause mortality in premature infantsDecrease dental cariesTreatment of H pylorii infections, UTIDecrease colicDecrease risk of developing eczemaDecrease upper respiratory tract infections
11 Antibiotic-associated Diarrhea Systematic review of 9 placebo-controlled studies (2 in children) using various products: 60% reduction in incidence and duration of antibiotic associated diarrhea compared with placebo (P<0.01) 20029/10 pediatric trials (different products) favored probiotics (RR 0.49; 95% CI 0.32 to 0.74). None of the 5 trials monitoring adverse events (n = 647) reported a serious adverse event.Johnston BC. Cochrane Database Syst Rev, 2007D’Souza et al. BMJ, 2002What I do: recommend 2-4 weeks of probiotics for all kids who receive an antibiotic prescription.
12 Probiotics: infectious diarrhea Treatment:Systematic review > 9 studies in 1-36 month old children; significant reduction in diarrhea days (0.7, 95% CI: ) and fewer stools with L GG (95% CI: ); Dose response curve with higher L GG dose . Also S. boulardii and L reuteriiVan Niel et al. Pediatrics, 2002Allen et al. Cochrane Database Syst Rev, 2004Prevention:2006 systematic review of 5 RCTs in day care and hospital settings: modest, but significant benefit for rotavirus or C. Diff. L GG, L reuteri > B lactisGuandalini. J Clin Gastroenterol, 2008
13 *Chemotherapy-associated diarrhea Benefits for pediatric oncology patients with diarrhea (incl C diff). Benchimol EI. J Pediatric Hematology/Oncology, 2004Breast cancer and colorectal cancer patients receiving chemotherapy had markedly less diarrhea with probiotics El-Atti S.Journal of Parenteral & Enteral Nutrition, 2009; Osterlund P. Br J Cancer, 2007Radiation induced diarrhea attenuated with probiotics. Delia P.Tumori, 2007; Fuccio L. J Clin Gastroenterol, 2009; Giralt J. Intl J Rad Onc Bio Physics, 2008
14 * Decreased risks in adults Recurrent colon and bladder cancer with probiotics/synbiotics; implications for pediatrics?Perioperative infections in abdominal surgery with probiotics in adults.Implications for pediatrics
15 Probiotics: constipation Meta-analysis of 5 RCTs (3 adults n = 266; ) 2 children, n = 111). In adults, data suggest favorable effects of several probiotics. In children, L. casei rhamnosus Lcr35, but not L. rhamnosus GG, showed a beneficial effect.Chmielewska A. World J Gastroenterol, 2010Anecdotally, I’ve had good success. More research needed on effectiveness for constipation!
16 Probiotics: NEC prevention Meta-analysis of 9 trials randomizing 1,425 premature infants (<37 weeks or < 2500 gms) to prophylactic probiotics, vs. placebo or TAU; probiotics significantly reduced severe NEC by RR 0.32 and mortality by 0.43 (P<0.05); no impact on nosocomial sepsis or length of TPN.Safety: no observed cases of systemic infection with the probiotic agents.More research needed in ELBW infants.Alfaleh K. Neonatology, 2010
17 * Probiotics reduce all-cause mortality and NEC “A systematic review, …of 11 randomized, controlled trials (RCTs) in 2176 infants of <34 weeks' gestation revealed that oral probiotics reduced all-cause mortality and necrotizing enterocolitis (NEC) by more than half (P < ).” How?“Probiotics upregulate local and system immunity, increase anti-inflammatory cytokines and gut impermeability to bacteria and toxins, and suppress pathogens associated with NEC.”Tarnow-Mordi, et al. Pediatrics, 2010 (editorial)Soll RF. Pediatrics, 2010 (editorial)Deshpande G, et al Pediatrics, 2010 (meta-analysis)
20 *Probiotics for Premature Infants: widespread implementation? What about < 1000 gram infants?11 studies used 10 different probioticsWhich strains? Combinations?What dose?Should strain and dose depend on type of milk feeding?Contraindications? (case report toxicity)Routine vs. informed consent?Soll RF. Pediatrics, 2010 (editorial)
21 Probiotics: colicRCT of L reuteri vs. simethicone for 28 days in 83 breast-fed infantsDaily median crying timeDay 7 P:159 minutes vs S: 177 minutesDay 28 P: 51 minutes vs S: 145 minutes (P<0.01)Percent responders by 28 days: 95% of Probiotic vs. 7% of simethicone (P<0.01)No adverse effects reportedSavino F. Pediatrics, 2007
22 Probiotics: eczemaProbiotic supplements for Finnish pregnant moms with 1st degree fam hx atopy: L GG 10 bill cfu’s daily for 2-4 weeks before delivery, followed by infants daily for 6 months. At 2 years old, eczema prevalence reduced from 46% to 23% (RR 0.51, CI: ); at 4 years, relative risk reduction for atopic eczema of 0.57 (95% CI: ); at 7 years, RR reduction: 0.58 (95% CI, ; P = .027).Kalliomaki et al. Lancet 2001; Lancet, 2003; J Allergy Clin Immunol, 2007Dutch RdbPCT (B. bifidum, B. lactis, and L. lactis) was given to pregnant women and to babies for first 12 months. Decreased risk of eczema with active treatment at 3 months, 6/50 vs 15/52 (P = 0.035) and at 12 months 23/50 vs 31/48.Niers L. Allergy, 2009
23 Probiotics and infections High risk of allergy 1,018 pregnant mothers RCT mix (L rhamnosus GG and LC705, B breve Bb99, P freudenreichii) vs. placebo for 4 weeks before delivery; infants received same with or without GOS for 6 months.Two year follow-up – no difference in neonatal morbidity, colic, or serious adverse effects; significantly fewer antibiotics prescribed to synbiotic group and fewer respiratory infectionsKukkonen K. Pediatrics, 2008
24 Probiotics: Respiratory Illness Weizman, et al. 12 weeks of B lactis or L reuteri vs. TAU controlsSignificant reductions, all favoring L reuteri inDays with fever (0.17 vs. 0.8, P<0.001)Episodes of fever (0.1 vs. 0.4, P<0.001)Antibiotic prescriptions (0.06 vs. 0.19, P<0.05)Weizman, Pediatrics, 2005
25 *Nosocomial infections L GG to prevent nosocomial GI and Respiratory infectionsRdbpCT, N=742 hospitalized childrenDose L GG 109 daily in 100 ml fermented milkRRisk of GI infections 0.4 for LGG vs. placebo; NNT 15; (vomiting RR 0.3; diarrhea RR 0.24)RRisk of Respiratory infections 0.38 for LGG v placebo, NNT 30Hojsak I. , et alPediatrics, 2010 (May)
26 Probiotics: prescribing Which organism to use?S boulardii, Lactobacillus, and E faecium have prevented antibiotic-associated diarrheaL GG and L reuterii reduced infectious diarrheaL GG for eczemaL reuteri for colicWhich product? What dose? How long?Side effects? Cost?
27 Probiotics: recommending Lactobacillus rhamnosus GG, reuterii, best studied to dateCombination products not well studied, but may work as wellTypical effective “dose”: 10 billion organisms/dMost require refrigerationCan give in cool food/drink
28 *Probiotics: product variability 2004 Can Fam Physician (Huff BA) found 0/10 brands tested matched microbiologic specifications on label; typically, 0-10% of label quantities, often not including any of stated bacteria1996 BMJ (Hamilton-Miller JM) only 2/13 study of 13 British brands contained quantity of cfu listed on label
29 Probiotics: product variability ConsumerLab.com tested 25 probiotic products19 for general population, 3 for children, 3 yogurts8 claimed a specific number of organisms per serving13 claimed only a number of organisms at time of manufacture8/25 contained less than 1 percent of the claimed number of live bacteria or of the expected minimum of 1 billion.7 of the 8 that gave expected numbers per serving met those countsNone contaminated with bacteria, mold, or fungusAll enteric-coated capsules passed testing
30 Probiotics: common products FlorastorNature’s Way enteric coated 35CulturelleOrganismsSaccharomyces boulardiiL rhamnosus, casei, plantarum, acidophilus, lactis, diacetylactis, bulgaricus, salivarius, helveticus,B longum, breve, infantisS thermophilusL. GGQuantity per “dose”10 billion35 billion10 billion (reliability?)Some products are available as dairy free preparations. Sedona labs, Klaire labs, Kirkman labs, Pharmax – all recommended by various members of CHIM listserv
31 Probiotics: what’s in yogurt? ProductActiviaBreyers 99% Fat Free Fruit on the Bottom…DanActiveStonyfield Farm French Vanilla Nonfat YogurtYoPlusTypeB regularis (animalis, DN )L acidophilus? othersL casei Immunitatis (casei, DN )BifidusL acidophilus, casei, bulgaricus, reuteriB. Lactis Bb-12 + inulin
32 Probiotic safetyCase reports of bacteremia, fungemia, endocarditis, meningitis in immunocompromised children on ventilators2% bloating, gas, diarrheaIncreased allergic sensitization?Food is safer than pills!
33 Take home points… Good evidence for: Infectious diarrhea, tx Antibx-assoc diarrheaNEC; premature mortalityPromising evidence for:Preventiong atopic conditionsConstipationIn the future we may be using probiotics as we use antibiotics today: with specific strains used for certain clinical situations guided by controlled studiesPrescribingLactobacillus GG best studied to dateCombination products not well studied, but may work as well10 billion organisms/dKeep refrigerated (except Culturelle and BioGaia)Give in cool food/drink2% risk bloating/gas
34 Suggested Practice Changes Recommend L. acidophilus for patients with lactose intoleranceFor the next 30 days, recommend probiotics for outpatients who receive a prescription for antibiotics; monitor rate of diarrhea as a side effectTry different probiotic products yourself and monitor your own gut reactionRecommend probiotics (L GG) for patients with infectious diarrhea.Talk with your local neonatologist about using probiotics to help reduce risk of NEC.In the next week, talk with one mother of an infant about probiotics to help with colic.Ask your hospital library to subscribe to ConsumerLab.com. Prepare a handout comparing different probiotic products for your patients.Join the AAP SOCIM:
36 Probiotics: proposed mechanisms Adherence and subsequent stimulation of gut immune systemUp-regulation of mucin geneEnhance secretory IgAMaintain normal macrophage functionCompetition for essential nutrientsProduction of antimicrobial factorsProvide favorable environment for growth of other beneficial bacteriaProduction of short-chain fatty acids with anti-inflammatory properties