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The Uses and Dangers of ProbioticsMegan Koyle, Pharm.D.

Anthony Nelson, Pharm.D.

PGY1 residents

Boise VAMC

Objectives Describe and define probiotics List common products on the market Review possible mechanisms of action

that may be beneficial Identify common uses and briefly discuss

current evidence Identify less common uses and briefly

discuss current evidence (or lack there of) Recognize potential dangers of probiotic

use

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PRO-BIO-TIC1 Pro: derived from Greek, meaning

promoting or for

Bio: life

tic: pertaining to

QUIZ TIME! 2 Who was the FATHER of probiotics?

A. Louis Pasteur

B. Al Gore

C. Elie Metchnikoff

D. Hippocrates

E. William Proctor

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The FATHER of Probiotics2 A Russian scientist

Proposed theory that toxic bacteria in the gut were a cause of aging

Drank rotten milk (lactic acid) to kill

these harmful bacteria

Wrote a book, that led to the future

development of probiotics

PRO-BIO-TIC4 AKA

Normal flora

Good bacteria

Helpful bacteria

Friendly bacteria

Individual bacteria identified by: Genus

Species

Strand (number)

(http://www.dfwchild.com/Fort-Worth/features/1014/Keeping-Kids-Healthy-With-Probiotics)

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Your Normal Flora4 Contains around 400 strains of bacteria, fungi,

and parasites TRILLIONS of bacteria live in our digestive tracts Common bacteria found in supplements:

Lactobacillus species

Bifidobacteria species

Saccaromyces boulardii

Products available4 Over 100 products are commercially

available

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Examples: Florajen

Proviva

Culturelle

Align

Bacid

Activia

Florastor

There is NOT generic equivalence with probiotic strains/products due to variability

Products have different: Manufacturing methods

Storage requirements

Species related differences

(http://www.mc.vanderbilt.edu/root/vumc.php?site=preceptorprogram&doc=42329)

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Try to stick with specific products that have shown benefit in CLINICAL STUDIES

(http://www.mc.vanderbilt.edu/root/vumc.php?site=preceptorprogram&doc=42329)

Possible Mechanisms

(http://ncp.sagepub.com/content/24/1/10/F1.large.jpg)

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Common Uses1 Irritable Bowel Syndrome

Infectious Diarrhea

Antibiotic-Related Diarrhea

Travelers Diarrhea

Less Common Uses Allergies

Immunity

Dental health

Cancer prevention

Genitourinary health

Antihyperlipidemia

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Rumor Has It

Rumor vs TruthProbiotics can lower your cholesterol

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Conflicting5 Studies have shown modest reductions in Total

cholesterol and LDL while other have shown no effect Meta- analysis found overall decreases of total

(-6.40 mg/dL) and LDL cholesterol (-4.90 mg/dL)

Inhibit intestinal cholesterol absorption Occurs through binding of and incorporation of

cholesterol in bacterial cells

Suppress reabsorption of bile acids Synthesized by cholesterol

Rumor vs TruthProbiotics are effective in newborns with intestinal infections

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YES! But6 This has only been studied in

preterm infants

There has been some evidence showing the use of probiotics in infant prevents necrotizing enterocolitis NEC may be due to abnormal

bacterial colonization Dicloflor Culturelle Florastor Infloran Bifidobacterium

A number of commercial product infant mild formulas contain probiotics

Rumor vs TruthProbiotics are recommended for antibiotic-associated diarrhea

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*TRUTH7 Several meta-analysis have showed reductions in

risk for development of antibiotic associated diarrhea (AAD) Results: Relative risk reduction of 32% Number needed to treat: 13 Consistent across subgroup analysis

Other sources say approximately 60-65% reduction in AAD incidence (cite source)-see refere

Most commonly studied species included: Lactobacillus, Saccaromyces boulardii, and bifidobacterium

RECENT NEWS PLACIDE study

Conducted in Wales and northeastern England

Involved 5 hospitals, 68 different medical and surgical units, and more than 17,000 patients aged 65 years or older.

Showed no benefit, with increased risk for flatulence and bloating

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How much, how long???6 Lactobacillus or Bifidobacterium spp:

Most studies conducted with 3-5 billion CFU/day BID

Saccaromyces boulardii:

500 mg BID if standardized to (30 billion/G)

Should try to use formulations/species that were used in clinical trials

Rumor vs TruthProbiotics reduce your risk of cancer

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Maybe -glucuronidase : Produced by pathogenic

bacteria in the GI tract

levels increase tumor growth

production of blood vessels that feed the tumor

Convert certain molecules into procarcinogens Colon cancer

Bladder cancer

Breast cancer

Rumor vs TruthProbiotics can prevent travelers-diarrhea

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Possibly8,9 Mixed results

Meta-analysis in 2007 showed a 15% relative risk reduction for travelers diarrhea

Saccaromyces boulardii and mixture of lactobacillus and bifidobacterium showed most benefit

Rumor vs TruthProbiotics can help decrease risk of developing allergies

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Its Promising!18 Ureaplasma urealyticum

Colonize the human genital tract

women taking probiotics during pregnancy in the incidence of

childhood eczema in infants

May show some positive evidence for ashtma

L. rhamnosus GG

Rumor vs TruthProbiotics can be used to prevent Lung infections

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YES! Several clinical trials have evaluated

probiotics for preventing respiratory tract infections Common cold

Sinusitis

Pharyngitis

Acute otitis media

Rumor vs TruthProbiotics can be used to treat and prevent irritable bowel syndrome

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Perhaps yes, perhaps not10 Conflicting evidence

May decrease symptoms of Irritable Bowel Syndrome-Constipation abdominal discomfort

bloating

difficult bowel movements

Primarily evidence for Bifidobacterium

Rumor vs TruthProbiotic promote female reproductive and bladder health

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Yes and No May be helpful in bacterial vaginosis

Lactobacilli produce hydrogen peroxide and lactic acid which lower vaginal pH and may help prevent the

overgrowth of other bacteria

A number of studies have failed to demonstrate protection UTIs Yeast infections

Does not seem to reduce the risk of vaginal candidiasis infection following use of antibiotics

Rumor vs TruthProbiotics prevent tooth decay

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YES! But11,12 Systemic review of 23 randomized clinical

trials assesing use of probiotics on oral health In two-thirds of the selected papers,

probiotics demonstrated a capacity to reduce S. Mutans counts in saliva and/or plaque .

But to date, RCTs on this topic are insufficient to provide scientific clinical evidence.

Probiotics and oral protection11,12 Has been shown to prevent

Dental caries

Periodontitis

Oral fungal infections

Halitosis

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Probiotics and Teeth11,12 Probiotics may inhibit bacteria S. Mutans

from forming biofilms in our mouths

Preventing adhesion of bacteria

Competing for nutrients

Enhance immune responses

Rumor vs TruthProbiotics can treat and prevent infectious-diarrhea

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TRUTH! May duration of

infectious diarrhea by 30.5 hours Primarily due to

Rotovirus

Theoretical Dangers of Probiotics15,16 Ability to cause infection

Transfer of antibiotic resistance to the GI flora

Toxic effects to the GI tract

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Dangers of Probiotics15,16 Risk of bacteremia & fungemia

Bifidobacterium

Endocarditis

Lactobacilli Species Sepsis endocarditis

Saccharomyces boulardii

Fungemia

Proposed Risk Factors for Probiotic Bacteremia/Fungemia15,16

Major risk factors

1) Immune compromise, including a debilitated state or malignancy

2) Premature infants

Minor risk factors

1) Central venous catheters

2) Impaired intestinal epithelial barrier, eg, diarrheal illness, intestinal inflammation

3) Administration of probiotic by jejunostomy

4) Concomitant administration of broad spectrum antibiotics to which probiotic is resistant

5) Probiotics with properties of high mucosal adhesion or known pathogenicity

6) Cardiac valvular disease (Lactobacillus probiotics only)

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Dangers of Probiotics Lactobacillus species

Contain plasmids for antibiotic resistance

Tetracyclines Erythromycin Chloramphenicol

Transfer to other bacteria is rare

Dangers of Probiotics15,16 Potential risk of GI toxicity

GI tract breaking down lactic acid bacteria Lactic acidosis

Probiotics prevent deconjugation of bile salts Malabsorption

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When Choosing a probiotic17 Check the label

Beware of the internet

Pick certified probiotics

Storage

Finally

Scientific evidence supporting specific uses is still lacking

The FDA has not approved any health claims

Probiotics do not replace any proven treatments

Monitor closely if any serious underlying health problems

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Summary Probiotics have many potential uses

There are vast amounts of information about probiotics and much of this information is conflicting

It is important is to weigh the potential risks and benefits based on individual patient factors

References1. Pharmacist letter. Online Training Course Probiotics. Accessed August 10, 2014.

http://pharmacistsletter.therapeuticresearch.com/ce/ceCourse.aspx?rn=2&cs=student&s=PL&pc=13-103&pm=0&quiz=1#references

2. Wikipedia. lie Metchnikoff. http://en.wikipedia.org/wiki/%C3%89lie_Metchnikoff .Accessed August 10, 2014

3. http://patients.gi.org/topics/probiotics-for-the-treatment-of-adult-gastrointestinal-disorders/

4. Saljoughian, M. Probiotics: a Closer Look. Accessed August 10, 2014. http://www.uspharmacist.com/content/c/9786/?t=men's_health,gastroenterology

5. Guo Zhuang et al. Research advances with regards to clinical outcome and potential mechanisms of cholesterol-lowering effects of probiotics. Clinical Lipidology. 2012;501-507.

6. NCCAM. Oral Probiotics: An Introduction. Accessed August 10, 2014. http://nccam.nih.gov/health/probiotics/introduction.htm

7. Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA. 2012 May 9;307(18):1959-69. doi: 10.1001/jama.2012.3507.

8. D'Souza AL, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in prevention of antibiotic associated diarrhea: meta-analysis. BMJ 2002;324:1361

9. Allen SJ, Okoko B, Martinez E, Gregorio G, Dans LF. Probiotics for treating infectious diarrhoea. Cochrane Database Syst Rev. 2004;(2):CD003048. Review. Update in: Cochrane Database SystRev. 2010;(11)

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References

10. Goldin BR et.al.Clinical Indications for Probiotics: An Overview. Clin Infect Dis. (2008) 46 (Supplement 2): S96-S100.

11. Cagetti MG, Mastroberardino S, Milia E, Cocco F, Lingstrm P, Campus G. The use of probiotic strains in caries prevention: a systematic review. Nutrients. 2013 Jul 5;5(7):2530-50.

12. Bizzini B, Pizzo G, Scapagnini G, Nuzzo D, Vasto S. Probiotics and oral health. Curr Pharm Des. 2012;18(34):5522-31.

13. Whorwell PJ, Altringer L, Morel J, Bond Y, Charbonneau D, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol. 2006;101:15811590.

14. McFarland LV. Meta-analysis of probiotics for the prevention of traveler's diarrhea. Travel Med Infect Dis. 2007 Mar;5(2):97-105.

15. Snydman DR. The safety of probiotics. Clin Infect Dis. 2008 Feb 1;46 Suppl 2:S104-11; discussion S144-51.16. Boyle RJ, et. al.Probiotic use in clinical practice: What are the risks? Am J Clin Nutr June 2006 vol. 83

no. 6 1256-1264

17. Probiotics: What they are and what they can do for you. American Gastroenterological Association. Accessed July 20, 2014. http://www.gastro.org/patient-center/diet-medications/probiotics

18. Goldin BR et.al.Clinical Indications for Probiotics: An Overview. Clin Infect Dis. (2008) 46 (Supplement 2): S96-S100.