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: StomachPredominant Flora: Stomach

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

Predominant Flora: VaginaPredominant Flora: Vagina

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

Predominant Flora: Urinary Predominant Flora: Urinary TractTract

Kidneys: sterile

Bladder: sterile

Urethra: 101-102 E. coli

Predominant Flora: IntestinesPredominant 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 FloraFunctions of Normal Flora

DigestionDigestion Production of vitaminsProduction of vitamins Mucosal maturationMucosal maturation Stimulate Immune SystemStimulate Immune System AttachmentAttachment Intestinal transitIntestinal transit Colonization resistanceColonization 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

Stop Antibiotic

Start Antibiotic

Start Yeast (within 48h)

Stop Study

Yeast continued for 14d

Saccharomyces boulardii and Antibiotic Associated Diarrhea in Hospitalized PatientsN=180; site: University of Washington, Harborview Hospital

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

Stop Antibiotic

Start Antibiotic

Start yeast or placebo

Stop Study

yeast or placebo continued for 3d

Saccharomyces boulardii and Beta lactam Antibiotic Associated Diarrhea in Hospitalized PatientsN=193; site: University of Washington, University of Kentucky

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

LactobacillusLactobacillus GG & Prevention of GG & Prevention of Infantile Nosocomial Diarrhea Infantile Nosocomial Diarrhea

[Methods][Methods] DBPC in PolandDBPC in Poland 81 hospitalized children (1-36 months old)81 hospitalized children (1-36 months old) No diarrhea on admissionNo diarrhea on admission Randomized during stay:Randomized during stay:

–– LGG (12 x 10 LGG (12 x 109 9 CFU/d)CFU/d) –– Placebo Placebo

Szajewska H. J Pediatr 2001;138:361-5.

Lactobacillus Lactobacillus GG & Prevention of GG & Prevention of Infantile Nosocomial Diarrhea Infantile Nosocomial Diarrhea [Results][Results]

0

5

10

15

20

25

30

35

%

NDRotaviral

6.7*2.2*

33.3

16.7

*p<0.05

L. GG (n=45) Placebo (n=36)

Szajewska H. J Pediatr 2001;138:361-5.

D’Souza et al., BMJ 2002;324:1361

Lactobacilli and Pediatric Diarrhea Treatment Lactobacilli and Pediatric Diarrhea Treatment (L. rhamnosus and L. reuteri in hospital (L. rhamnosus and L. reuteri in hospital

setting)setting)

05

1015

202530

3540

4550

dur (h) d5 dia (%) d5 rota(%) hosp days

treatedcontrol

N=69 Rosenfeldt et al., Pediatr Infec Dis 2002;21:411

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

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

S. boulardiiS. boulardii & High Dose & High Dose Vancomycin for Vancomycin for C. difficileC. difficile Disease Disease

0

10

20

30

40

50

60

% C

DD

rec

urre

nces

50%

16.7%*

Surawicz CM. Clin Infect Dis 2000;31:1012-7.

S. boulardii (n=18)

Placebo(n=14)

*p=0.05

Copyright restrictions may apply.

Dial, S. et al. JAMA 2005;294:2989-2995.

Rates of Clostridium difficile per 100 000 Patients in the United Kingdom General Practice Research Database

Copyright restrictions may apply.

Dial, S. et al. JAMA 2005;294:2989-2995.

Comparison of Community-Acquired Matched Cases and Controls--Medication Variables

Clostridium difficile DiseaseClostridium 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 DataOther 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

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

Advantages Disadvantages

Potential Advantages and Disadvantages of Probiotics

Lactobacillus rhamnosus GG Dietary Supplement: Culturelle

Saccharomyces boulardii Dietary Supplement: Florastor

Evidence supporting commercially available (USA) Evidence supporting commercially available (USA) probiotics*probiotics*

AADAAD UnevenUneven GoodGood GoodGood GoodGood

Acute Acute AdultAdult

?? ?? GoodGood GoodGood

Acute Acute pediatricpediatric

?? ?? GoodGood GoodGood

Traveler Traveler diarrheadiarrhea

?? ?? FairFair FairFair

C. difC. dif ?? ?? LimitedLimited GoodGood

BVBV Good**Good** Good***Good*** ?? ??

condition L. acidophilus L. reueri LGG Sb

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