probiotic : a treatment option in diarrhea and ibs

Probiotic : A treatment option

in diarrhea and IBS

DIARRHOEA

• Increase in FREQUENCY, LIQUIDITY, VOLUME of stools

• Stool weight more than/equal to 200 gm/day (western diet) or 450 gm/day (indian diet)

• Diarrhea - WHO defines as passage of loose or watery stools; 3 or more per day.

• Among children in the U.S., diarrhea accounts for more than 1.5 million outpatient visits, 200,000 hospitalizations, and ~300 deaths per year.

PSEUDO-DIARRHOEA

Increased frequency but with NORMAL VOLUME

Seen due to local inflammation of rectum (IBS, proctitis)• Patient passes small but frequent stools

TYPES OF DIARRHOEA• ACUTE: less than 2 weeks

• PERSISTENT: 2-4 weeks

• CHRONIC: more than 4 weeks

SYMPTOMS AND SIGNS

Bacterial bowel infection

COMPLICATIONS

Dehydration

Infections

• Leading cause of childhood morbidity & mortality in developing countries

• Important cause of malnutrition

• 80% of deaths due to diarrhoea occur in the first two years of life.

• Children <3 years of age in developing countries experience around three episodes of diarrhoea each year.

Morbidity

Epidemiologic features of Diarrhea

• 2 billion cases of diarrheal disease every year

– About 5000 deaths in children every day– Incidence and risk of mortality are highest in this age

group

• About 78% occur in the South-East Asian & African regions

ETIOLOGY OF ACUTE DIARRHOEA

Viral :

Rota Virus

Adenovirus

Norwalk Agent

Bacterial :

V. Cholera

ETEC, EIEC

Salmonella

Shigella

Campylobacter

Fungal :

Candida

Parasitic Infection

Giardia Lamblia

Cryptosporidium

Entamoeba Histolytica

Drugs

Laxatives

Sorbitol

Antacids

Lactulose

Theophylline

Antibiotics

Diet :

Food Poisoning

Food allergy

Treatment

• Elimination of the cause

• IV fluids and electrolytes

• Medications

Diarrheal Disease Current Management

Ofloxacin : Not recommended in childrenAmoebic infections are to the tune of 5% in children < 5yrs

Limitations of Prescribing antibiotic in Diarrhea / DysentryOfloxacin : Toxicity and risk of cartilage damageOfloxacin / Imidazoles : Bitter taste, Palatability, Nausea5-8 days of lengthy treatmentRecovery time is 4-5 days after treatmentNo effect on improvement of stool consistencyEmerging resistance, not recommened in < 8yrs of ageirrational combinations as H1/2 is different quinolones (12hrs) Metronidazole(8hrs)

Limitations

12

A functional gastrointestinal disorder

symptoms :

abdominal pain

bloating or distension and various

symptoms of disordered defecation.

Thompson et alThompson et al, , 19921992

IRRITABLE BOWEL SYNDROME (IBS)

Pathophysiology

14

Antidiarrheal medication is one of the approach for treating IBS

• Loperamide – effective when used prophylactically 2-16mg/d

• Cholestyramine

• Bismuth subsalicylate

NORMAL BACTERIAL FLORA OF THE GI TRACT

• Aerobic and anaerobic bacteria,

• yeast and fungi live into the GI tract 400 m2 of surface area.

• more than 2000 species of commensal bacterial organisms within our bodies

Therapeutical use of probiotic formulations in clinical practice. Clinical Nutrition 29 (2010) 701e725

Therapeutical use of probiotic formulations in clinical practice. Clinical Nutrition 29 (2010) 701e725

GI flora components

Therapeutical use of probiotic formulations in clinical practice. Clinical Nutrition 29 (2010) 701e725

Probiotics• Microbes found in the food supply that enhance human

health.

Criteria: • bacteria of human origin

• able to adhere to the intestinal mucosa

• have potential to colonize in the GI tract

• can produce antimicrobial substances,

• stable against bile, HCl, and other acids, enzymes, and oxygen, and determined to be safe and effective.

World Gastroenterology Organisation Practice Guideline Probiotics and prebiotics.www.worldgastroenterology.org/.../guidelines/19_probiotics_prebiotics

Benefits of probiotics….

Mechanism of Action• Suppression of growth or epithelial binding/invasion by pathogenic

bacteria

– 1. Decrease luminal pH

– 2. Secrete antimicrobial peptides

– 3. Inhibit bacterial invasion

– 4. Block bacterial adhesion to epithelial cells

Purported mechanisms of action of probiotics.

I.P. Kaur et al. / European Journal of Pharmaceutical Sciences 15 (2002) 1 –9

Altered Disease States

Probiotics have been thought to improve or ameliorate a plethora of states, the most commonly reported upon are:

• Various states of diarrhea

• Inflammatory Bowel Disease

• H. Pylori Ulcers

• Urinary Tract Infections

• Vaginal Candida Overgrowth

Diarrhea is the condition most beneficially treated by probiotic therapy.

This can include diarrhea associated with

• antibiotics,

• travel,

• gastroenteritis,

• lactose intolerance,

• and Inflammatory Bowel Disease.

Commercially used probiotic strains.

Therapeutical use of probiotic formulations in clinical practice. Clinical Nutrition 29 (2010) 701e725

Probiotics for Prevention and Treatment of Diarrhea Stefano Guandalini, MD

Use of different probiotics in children

ROLE OF SACCHAROMYCESBOULARDI

Saccharomyces boulardii

• Saccharomyces boulardii (S. boulardii)-yeast isolated from the skin of Lychees

• non-pathogenic

• thermotolerant yeast

• grows optimally at 370C.

• It is a live yeast that is available as a lyophilized preparation for adults as a 250 mg capsule.

Prajapati P, Patel M, Krishnamurthy R. Saccharomyces boulardii- a probiotic of choice. CIBTech Journal of Biotechnology. 2013 Vol. 2 (2) April-June, pp.1-6

Properties of S boulardii

• resistant to stomach acids and bile acids

• Although the optimal temperature for most strains of Saccharomyces range from 22-30 c, S. boulardii survives best at 37 c.

• S. boulardii is a safe and effective biotherapeutic agent for the treatment of gastrointestinal disease.

Prajapati P, Patel M, Krishnamurthy R. Saccharomyces boulardii- a probiotic of choice. CIBTech Journal of Biotechnology. 2013 Vol. 2 (2) April-June, pp.1-6

Pharmacokinetics

S. boulardii, when given orally -• steady-state concentrations – 3 days• clearance- 3-5 d after discontinuation

• half life -6 hours, • fecal steady state concentration (2 × 107/g) – 3 days

• some types of fiber (psyllium) increase S boulardii levels by 22%, while other type of fiber (pectin) shows no effect.

McFarland LV. Systematicv review and meta-analysis of Saccharomyces boulardii in adult patients. World J Gastroenterol 2010 May 14; 16 (18):2202-2222

Stability of S boulardii

• Probiotics may be available as lyophilized or heat-dried preparations.

• Lyophilized preparations -• stable over one year at room temperature, as long as it is

protected from moisture.

Prajapati P, Patel M, Krishnamurthy R. Saccharomyces boulardii- a probiotic of choice. CIBTech Journal of Biotechnology. 2013 Vol. 2 (2) April-June, pp.1-6

Mechanism of Action

McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adult patients. World J Gastroenterol 2010 May 14; 16 (18):2202-2222

Anti-Microbial Action – Direct Anti-Toxin Effect

• The anti-toxin action-mainly due to small peptides produced by the yeast.

• Able to inhibit enterotoxin and cytotoxic activities of C. difficile by degradation of toxin A and B

• Different types of mechanisms of action. • luminal action• trophic action• mucosal-anti-inflammatory signaling effects.

• S. boulardii may interfere with pathogenic toxins, • preserve cellular physiology, • interfere with pathogen attachment, • interact with normal microbiota

Prajapati P, Patel M, Krishnamurthy R. Saccharomyces boulardii- a probiotic of choice. CIBTech Journal of Biotechnology. 2013 Vol. 2 (2) April-June, pp.1-6

Inhibition of Growth and Invasion of Pathogen

• S boulardii directly inhibits the growth of several pathogens (Candida albicans, E. coli, Shigella, and cell invasion by Salmonella typhimurium.

• This mode of action important for the treatment of (chronic) inflammation of the digestive tract.

Prajapati P, Patel M, Krishnamurthy R. Saccharomyces boulardii- a probiotic of choice. CIBTech Journal of Biotechnology. 2013 Vol. 2 (2) April-June, pp.1-6

Theodoros Kelesidis and Charalabos Pothoulakis Ther Adv Gastroenterol (2012) 5(2) 111–125

Continue…

Theodoros Kelesidis and Charalabos Pothoulakis gastrointestinal disorders for the prevention and therapy of Saccharomyces boulardii Efficacy and safety of the probiotic

Research evidence for probiotic use in inflammatory bowel

syndrome (IBS)• .

• Multi-strain probiotics have been found to provide general relief of IBS symptoms such as abdominal pain, discomfort, and bloating.

• probiotics have a significant effect in altering the intestinal environment.

Journal of Gastroenterology and Hepatology

Probiotic for irritable bowel syndrome (IBS)

Bacillus coagulans(L.sporogenes)

• This has been found to provide significant improvement of bloating and abdominal pain in patients who are diagnosed with IBS.

Lactobacillus rhamnosus GG• Decreases the intensity and frequency of abdominal pain in

children with IBS

. Bifidobacterium bifidum• In a clinical trial done on this strain, 47% of people with IBS had

reported improved symptoms of IBS.

Bifidobacteria benefits on human health.

Therapeutical use of probiotic formulations in clinical practice. Clinical Nutrition 29 (2010) 701e725

Research to Support the Claims

#1 Effects of Saccharomyces boulardii in children with acute diarrhoea

• Aim:to evaluate the effect of S. boulardii in children with acute diarrhoea.

• Methods: randomise study• No. of childrens: 200• Dose: a daily dose of 250 mg (S. boulardii group) or placebo

(placebo group) for 5 days

• Conclusion: The placebo-controlled study suggested that S. boulardii significantly reduced the duration of acute diarrhoea and the duration of hospital stay.

Z. KURUGO¨ L & G. KOTUROG˘ LUEffects of Saccharomyces boulardii in children with acute diarrhoea. Acta Pædiatrica, 2005; 94: 44–47.

#2 Saccharomyces boulardii in the prevention of antibiotic-

associated diarrhoea in children

• Aim: To determine whether S. boulardii prevents antibiotic- associated diarrhoea in children

• Methods: • No. of children:269• Age:6 months to 14 years• with otitis media and/or respiratory tract infections

• Experimental group :Standard antibiotic treatment plus 250 mg of S. boulardii

• control group :Standard antibiotic treatment plus placebo

Conclusion-S.boulardii effectively reduces the risk of antibiotic-associated diarrhoea in children.

Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea in children: a randomized double-blind placebo-controlled trial M. KOTOWSKA, P. ALBRECHT & H. SZAJEWSKA. Aliment Pharmacol Ther 2005; 21: 583–590

Observations :

#3 Therapeutic effects of Saccharomyces boulardii on mild

residual symptoms in a stable phase of Crohn's disease

 •  Randomized, single-center, double-blind, placebo-controlled pilot study.

• 20 patients with established Crohn's disease suffering from diarrhea and moderate complaints

• Treatment : Saccharomyces boulardii (S.b.) in a dosage of 250 mg t.i.d., initially for two weeks in addition to the basic treatment.

•  • Results: reduction in the frequency of bowel movements (5.0 ±1.4 vs. 4.1 ±

2.3 evacuations/day, p < 0.01)•  

Plein K, Hotz J Department of Gastroenterology, General Hospital of Celle. Zeitschrift fur Gastroenterologie [1993, 31(2):129-134]

• After this initial phase, the patients were allocated in randomized order to the control group (n = 7) receiving placebo, or to the verum group (n = 10) receiving S.b.(250 mg t.i.d.) for 7 weeks, while the basic treatment was maintained.

• The group treated with S.b. showed a significant reduction in the frequency of bowel movements in the tenth week.No adverse drug events were observed.

#4 Lactobacillus rhamnosus GG in the prevention of antibiotic

associated diarrhea in children• Objective: efficacy of Lactobacillus rhamnosus (Lactobacillus GG) in

reducing the incidence of antibiotic-associated diarrhea.

• Study design: Two hundred two children between 6 months and 10 years of age were enrolled; LGG, 1 × 1010 – 2 × 1010 colony forming units per day, or comparable placebo was administered.

• Results:

• Twenty-five placebo-treated but only 7 LGG-treated patients had diarrhea.

• Lactobacillus GG overall significantly reduced stool frequency and increased stool consistency

• Conclusion: Lactobacillus GG reduces the incidence of antibiotic-associated diarrhea in children treated with oral antibiotics for common childhood infections.

Antonson, MD, Terri L. Hanner, RN, James V. Lupo, PhD, and Rosemary J. Young, RN, MS, THE JOURNAL OF PEDIATRICS VANDERHOOF ET AL VOLUME 135,NUMBER 5

Products in the market

Composition

Film Coated tablet contains : Probiotic Mixture• (L.sporogenes, Bifidobacterium lactis, Bifidobacterium bifidum &

L.rhamnosus GG) – 2 billion c.f.u

• Saccharomyces boulardii – 250/500 mg.

• Indications• Diarrheal Illnesses in Adults as well as in Children

• Affordable choice in children affected with Rotaviral Diarrhea.

• Indicated for Irritable Bowel Syndrome in the Adults. 

S.b. cells are resistant to gastric acidity, proteolytic degradation, and antimicrobial drugs.

Probiotic mixture is effective in alleviating irritable bowel syndrome symptoms.

Probiotic mixtures are beneficial for a range of health-related outcomes

Multi-strain probiotics appear to show greater efficacy than single strains.

Mixture using species with different effects against different pathogens have a broader spectrum of action that a single provided by a single strain.

Multi-strain supplements are formulated to target specific health conditions.·Response of Human and Rat Small Intestinal Mucosa to Oral Administration of Saccharomyces Boulardii JEAN-PAUL BUTS. PAU BERNASCONI,

MARIE-PAULE VAN CRAYNEST, PAUL MALDAGUE, AND ROGER DF MEYER, Vol. 20, No. 2, 1986

A probiotic mixture alleviates symptoms in irritable bowel syndrome patients: a controlled 6-month intervention K. KAJANDER*, , K. HATAKKA*, T. POUSSA, M. FA¨ RKKILA¨ § & R. KORPELA*, , – Aliment Pharmacol Ther 2005; 22: 387–394.

Benefits

*Note

Probiotics should not be taken by patients who have an impaired immune system. These are those who have HIV/AIDS, cancer, and undergoing chemotherapy.

Fungaemia is a rare complication of the administration of S. boulardii, and it is reported only in severely ill patients in intensive care units, mechanically ventilated, treated by broad-spectrum antibiotics with central venous catheter, or in immunocompromised adult patients. No fungaemia has been reported in otherwise healthy adults and children