Probiotics Terms: Probiotic – Probiotics are live microorganisms (bacteria or yeasts) which, when administered in adequate amounts, confer a health benefit on the host Prebiotic - nutritional supplement taken to increase the amounts of beneficial bacterial in the gut or vagina. Example “FOS” (fructose oligosaccharides) Biotherapeutic agent - microorganism used for specific therapeutic activity in humans Nutriceutical - food products with beneficial effects in preventing or treating diseases

Predominant Flora: Stomach Stomach (0-103 cfu/ml): Gram+ aerobes, Lactobacillus & Streptococcus

Predominant Flora: Vagina Vagina: diverse aerobes & anaerobes including Lactobacillus jensenii, Lactobacillus acidophilus, Lactobacillus casei.

Predominant Flora: Urinary Tract Kidneys: sterile Bladder: sterile Urethra: 101-102 E. coli

Predominant Flora: Intestines Small intestine: Proximal ileum (103-104 cfu/ml) aerobic Gram+ Distal ileum (1011-1012 cfu/ml) Gram- anaerobes Colon (1011-1012 cfu/ml): Bacteroides, Eubacteria, Peptostreptococci, E. coli, Bifidobacterium, Fusobacteria

Functions of Normal Flora Digestion Production of vitamins Mucosal maturation Stimulate Immune System Attachment Intestinal transit Colonization resistance

Use of Probiotics in Larger Controlled Trials in Humans Prevention of Diarrhea antibiotic associated diarrhea infantile diarrhea traveler’s diarrhea Treatment of Diarrhea Clostridium difficile disease acute diarrhea - pediatric and adult

Saccharomyces boulardii and Antibiotic Associated Diarrhea in Hospitalized Patients N=180; site: University of Washington, Harborview Hospital Start Antibiotic Stop Antibiotic Stop Study Yeast continued for 14d Start Yeast (within 48h)

Surawicz et al., Gastroenterol. 1989;96:981

Saccharomyces boulardii and Beta lactam Antibiotic Associated Diarrhea in Hospitalized Patients N=193; site: University of Washington, University of Kentucky Start Antibiotic Stop Antibiotic Stop Study yeast or placebo continued for 3d Start yeast or placebo

McFarland et al. Am J Gastroenterol 1995;90:439-448

Lactobacillus GG & Prevention of Infantile Nosocomial Diarrhea [Methods] DBPC in Poland 81 hospitalized children (1-36 months old) No diarrhea on admission Randomized during stay: – LGG (12 x 109 CFU/d) – Placebo Szajewska H. J Pediatr 2001;138:361-5.

Lactobacillus GG & Prevention of Infantile Nosocomial Diarrhea [Results] 33.3 *p<0.05 16.7 6.7* 2.2* Placebo (n=36) L. GG (n=45) Szajewska H. J Pediatr 2001;138:361-5.

D’Souza et al., BMJ 2002;324:1361

Lactobacilli and Pediatric Diarrhea Treatment (L. rhamnosus and L Lactobacilli and Pediatric Diarrhea Treatment (L. rhamnosus and L. reuteri in hospital setting) N=69 Rosenfeldt et al., Pediatr Infec Dis 2002;21:411

Huang, et al. , Digestive Diseases and Sciences, Vol. 47, No Huang, et al., Digestive Diseases and Sciences, Vol.47, No. 11 (Nov 2002)

McFarland et al., JAMA; 271, 1913-1918, (1994).

S. boulardii & High Dose Vancomycin for C. difficile Disease 50% *p=0.05 16.7%* Placebo (n=14) S. boulardii (n=18) Surawicz CM. Clin Infect Dis 2000;31:1012-7.

Rates of Clostridium difficile per 100 000 Patients in the United Kingdom General Practice Research Database Dial, S. et al. JAMA 2005;294:2989-2995. Copyright restrictions may apply.

Comparison of Community-Acquired Matched Cases and Controls--Medication Variables Dial, S. et al. JAMA 2005;294:2989-2995. Copyright restrictions may apply.

Clostridium difficile Disease C. difficle makes 2 toxins. Recent strains are more toxinogenic severity ranges from simple antibiotic associated diarrhea to mild colitis to pseudomembranous colitis to toxic megacolon to death Relapses following treatment are common Risk factors are antimicrobial exposure; recently gastric acid suppressive therapy has also been found to be a significant risk All antibiotics have some (undefined) risk but those impacting the anaerobic intestinal microflora may have a higher risk (beta lactams, clindamycin, tetracyclines, etc) Treatment is metronidazole 250mg QID as a first try. If treatment failure or relapse, use vancomycin PO 125mg QID. If failure, 500mg QID. Use Saccharomyces boulardii probiotic to prevent relapses. Dose is 500mg BID for 4-6weeks.

Other Uses for Probiotics –Limited Data Crohn’s Disease Ulcerative Colitis Pouchitis Allergy/Exema Irritable Bowel Syndrome Dental caries High Cholesterol Urinary Tract Infections Helicobacter pylori Lactose Intolerance Candida vaginal infections Bacterial Vaginosis

Potential Advantages and Disadvantages of Probiotics Multiple Mechanisms of Action Resistance is Infrequent Use May Reduce Exposure to Antibiotics Delivery of Microbial Enzymes Well Tolerated Benefit to Risk Ration is Favorable Few Controlled Trials Persistence Possible Translocation Possible Transfer of Resistance Plasmids? Infection Possible Quality Control Issues Regulatory Issues in USA

Lactobacillus rhamnosus GG Dietary Supplement: Culturelle

Saccharomyces boulardii Dietary Supplement: Florastor

Evidence supporting commercially available (USA) probiotics* condition L. acidophilus L. reueri LGG Sb AAD Uneven Good Acute Adult ? Acute pediatric Traveler diarrhea Fair C. dif Limited BV Good** Good*** L. acidophilus=Lactinex; L. reueri=Probiotica; LGG=Culturelle; Sb=Florastor; ** strains tested not yet available in USA

Probiotics Summary Living microorganisms with multiple mechanisms of action Good safety profile Some applications to prevent and treat infectious diseases An alternative to antibiotics in some situations May have other applications, e.g. allergy, cancer, colitis, IBS Product selection is very important