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PROBIOTICS IN PEDIATRIC PRACTICE


               Dr Sarath Gopalan
•   Senior Consultant in Pediatric Gastroenterology,
    Hepatology and Clinical Nutrition, PSRI Hospital, New
    Delhi.
•   Visiting Consultant in Pediatric Gastroenterology and
    Hepatology, Indraprastha Apollo Hospital, New Delhi.
•   Executive Director, Centre for Research on Nutrition
    Support Systems, New Delhi.
•   Deputy Director, Nutrition Foundation of India, New
    Delhi.
Functions of gut flora
Fermentation of dietary waste and
  endogenous mucins
Energy recovery through the generation of
  short-chain fatty acids
Protection against colonization and invasion
  by pathogens (barrier effect)
Development, stimulation and modulation of
  the immune system
Gut flora
By the age of two years, the flora
 established is practically definitive
Every individual tends to have a relatively
 stable flora
Negative modification by antibiotics
Positive modification by probiotics
Probiotics
Probiotics are living microorganisms that
are consumed in order to obtain a beneficial
effect regardless of their intrinsic nutritional
value
Probiotics - criteria
Application in the living state
Resistance to gastric acid and bile
Ability to adhere to colonocytes
Ability to colonize the gut
Clinically proved favourable health-effect
Safety
Probiotics - effects
Involvement in production of essential nutrients
  of the colonic mucosa
Beneficial effect on intestinal immunity
Recovery of the disturbed gut mucosal barrier
  and prevention of microbial translocation
Elimination of toxins and eradication of
  microbial pathogens
Probiotics - effects

Competitive inhibitor of bacterial
 adhesion
Synthesis of compounds that inhibit or
 destroy pathogens
Competitive consumption of nutrients
 required for growth of pathogens
Probiotics and clinical usage
Benefits are of varying degree
 dependent on :
 Number of agents
 The dose
 Dosing patterns
 The characteristics of the host
 Underlying luminal microbial
 environment of the host
Probiotics - uses
Traveler’s diarrhoea
Antibiotic-associated diarrhoea
Relapsing Clostridium difficile colitis
Infantile diarrhoea
Rotavirus enteritis
Inflammatory bowel disease
Irritable bowel syndrome
Colon cancer
Probiotics - uses

Peritonitis

Acute pancreatitis

Diarrhoea associated with HIV infection
Probiotic agents with clinical data
 Lactobacillus GG
 Lactobacillus acidophilus
 Lactobacillus plantarum 299V
 Lactobacillus casei Shirota
 Bifidobacterium bifidum
 Bifidobacterium longam
 Streptococus thermophilus
 Enterococcus faecium SF68
 Saccharomyces boulardii
 Bacillus clausii
Lactobacillus
Lactobacillus is part of lactic acid
  bacteria - non pathogenic gram
  positive bacteria that produce lactic
  acid as a primary metabolic end
  product
Vary greatly from one species to
  another in genetic make up,
  colonization and adherence patterns
Term “lactobacillus” is meaningless
Lactobacillus casei –
         documented benefit
• Recurrence of superficial bladder cancer
  (Urol Int 1992; 49:125-129, Urol Int
  2002;68:273-280)

• Significant improvement in sodium
  absorption in short bowel syndrome
  (JPGN April 2001;32:506-508)
L. Casei Shirota - Constipation

IMPROVED FREQUENCY AND < GI SYMPTOMS


• Koebnick et al, Can J Gastroenterol 2003, Vol 17:11

• Bioscience Microflora 2006; 25 (2):39 – 48

• Chimielewska et al, World J Gastroenterol 2010; 16 (1) :
  69 – 75
• Krammer HJ, Coloproctology 2011; 33:109-113
Bacillus clausii


•ACUTE DIARRHEA

•ANTIBIOTIC – ASSOCIATED DIARRHEA

•TRAVELLER’S DIARRHEA


EXAMPLE OF SINGLE STRAIN CONCEPT TO
JUSTIFY STRAIN SPECIFICITY
Saccharomyces boularidii (Sb)

Non pathogenic thermophyilic yeast
Reaches high levels in stools in 3 – 5
 days
Undetectable by 2 - 6 days after
 discontinuation
Sb - anti toxin effects
Prevention of cytotoxicity of toxins A and
B of C. difficile
Reduces toxins A receptor binding
Neutralisation of cholera toxin
Neutralisation of heat stable enterotoxin
of E. coli
Sb and C. difficile enteropathy
Prevention of recurrence
                           Surawicz
Prevention of recurrence in those who
failed to respond to vancomycin and
metronidazole
                           McFarland
Sb and antibiotic associated
      diarrhoea (AAD)
Prophylactic use of Sb with beta
 lactam resulted in reduction of AAD
                     McFarland
Sb reduces the incidence of AAD in
 hospitalized patients
                      Surawicz
Efficiency in preventing AAD 56%
                     McFarland
Sb - clinical uses

Nasogastric alimentation associated
diarrhoea
  decrease in number of diarrhoeal
  days
HIV associated diarrhoea
   decrease in stool frequency
Sb - clinical uses
Crohn’s disease
  decreased frequency of bowel
  movements
Traveler’s diarrhoea
  reduction in the incidence of
  diarrhoea
Single probiotic or cocktail??!!
Rationale for using a probiotic “cocktail”- the
 beneficial effects of different probiotic
 agents may be additive – but is it really so?
Advantage of using a single strain – easy to
 study the desired therapeutic effect and
 interpret it as responsible for the observed
 benefit.
Probiotic Supplementation in
   Developing Countries of South Asia
• Issues Raised
2. Lack of sufficient evidence from South Asian countries
   regarding possible benefit of probiotic supplementation in
   humans.
3. It is likely that microbial colonization of the gut in
   individuals from countries like India who are exposed to a
   microbiologically hostile environment is considerably
   different from those in the developed countries of the
   West.
4. The possible benefit from a probiotic preparation is
   dependent on specificity of the strain as well as host
                                                                23
   response and these may differ in the two settings.
SUMMARY OF TRIALS(RCT)
S.   CLINICAL SETTING            PROBIOTIC STRAIN(S)            PURPOSE      RESULT
NO
1.   Acute watery diarrhea       L. acidophilus                 Treatment    No benefit

2.   Acute watery diarrhea       L. rhamnosus GG                Treatment    No benefit

3.   Persistent diarrhea         L.rhamnosus GG                 Treatment    Benefit

4.   Acute diarrhea              L .casei DN-11400, L.          Treatment
                                 bulgaricus, S. thermophilus,
                                 Lactococcus lactis,               +
                                 Lactococcus lactis cremoris,
                                 Leuconosta                                  Benefit
                                 mesenteroides cremoris         Prevention
5.   Morbidity                   B. Lactis(DR-10)               Prevention   Benefit

6.   Neonatal sepsis             L. plantarum                   Treatment    Benefit

7.   Ulcerative Colitis          VSL#3                          Treatment    Benefit

8.   Pediatric Irritable Bowel   VSL#3                          Treatment    Benefit
     Syndrome
9.   Acute diarrhea              L. casei Shirota               Prevention   Benefit

                                                                                          24
Guidelines for the treatment of gastroenteritis by ESPGHAN
Guarino & al. JPGN 2008;46:619-21



    “Probiotics may be an effective adjunct to the management of diarrhea.
      However, because there is no evidence of efficacy for many preparations, we
      suggest the use of Probiotic strains with proven efficacy and in appropriate
      doses for the management of children with AGE as an adjunct to rehydration
      therapy (II, B). The following Probiotics showed benefit in meta-analyses of
      clinical trials: Lactobacillus GG (I, A) and S.boulardii (I, A).
    Evidence of lack of risk of antibiotic resistance transfer is required for
      Probiotics proposed for clinical use (Vb, D).”



                 S. Boulardii is acknowledged
                 as an evidence-based probiotic
              and recommended by the ESPGHAN
LASPGHAN Guidelines
(Latin American Society of Pediatric Gastroenterology ,Hepatology and Nutrition)




                                    Only S.boulardii & L.GG
                                    has been give 1A
                                    grade level of evidence
PEDIATRIC CASE STUDIES – L. casei Shirota


                          N 3 YRS F
  RECURRENT LOOSE STOOLS - FOR 18 MONTHS
  Given antibiotics for 3 – 5 days on most occasions, loose
  stools subsided, but frequent recurrence.
  L. casei Shirota consumed once daily ( 65 ML) for 5
  months ( irrespective of occurrence of loose stools) –
  parents observed decreased frequency of episodes of loose
  stools.
PEDIATRIC CASE STUDIES – (L.casei Shirota)- contd..


                      S    6 YRS        M
PASSAGE OF HARD STOOLS WITH DIFFICULTY - 2 YRS
IRREGULAR STOOL FREQUENCY               - 2 YRS

Had received lactulose and cremaffin intermittently – no significant benefit.

Then, received continuous medical treatment for 6 months as follows:-
•    LACTULOSE 15 ML TWICE DAILY ( AFTER LUNCH & DINNER), MON – SAT, 6 DAYS /
     WEEK.
•    POLYETHLENE GLYCOL ½ PACKET ONCE WEEKLY (EVERY SUNDAY) DISSOLVED IN
     TOTAL 1000 ML (600 ML BISLERI WATER + 400 ML MANGO FROOTI JUICE) OVER 3 HRS
     FOR 2 MONTHS, THEN STOPPED.
•    L. casei Shirota FOR 6 MONTHS AND STILL CONTINUING.
•    DISTINCT CLINICAL IMPROVEMENT - REGULAR STOOL PASSAGE ( 1 -2 / DAY), EASY.
Thank You

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Probiotics in Pediatric Practice

  • 1. PROBIOTICS IN PEDIATRIC PRACTICE Dr Sarath Gopalan • Senior Consultant in Pediatric Gastroenterology, Hepatology and Clinical Nutrition, PSRI Hospital, New Delhi. • Visiting Consultant in Pediatric Gastroenterology and Hepatology, Indraprastha Apollo Hospital, New Delhi. • Executive Director, Centre for Research on Nutrition Support Systems, New Delhi. • Deputy Director, Nutrition Foundation of India, New Delhi.
  • 2. Functions of gut flora Fermentation of dietary waste and endogenous mucins Energy recovery through the generation of short-chain fatty acids Protection against colonization and invasion by pathogens (barrier effect) Development, stimulation and modulation of the immune system
  • 3. Gut flora By the age of two years, the flora established is practically definitive Every individual tends to have a relatively stable flora Negative modification by antibiotics Positive modification by probiotics
  • 4. Probiotics Probiotics are living microorganisms that are consumed in order to obtain a beneficial effect regardless of their intrinsic nutritional value
  • 5. Probiotics - criteria Application in the living state Resistance to gastric acid and bile Ability to adhere to colonocytes Ability to colonize the gut Clinically proved favourable health-effect Safety
  • 6. Probiotics - effects Involvement in production of essential nutrients of the colonic mucosa Beneficial effect on intestinal immunity Recovery of the disturbed gut mucosal barrier and prevention of microbial translocation Elimination of toxins and eradication of microbial pathogens
  • 7. Probiotics - effects Competitive inhibitor of bacterial adhesion Synthesis of compounds that inhibit or destroy pathogens Competitive consumption of nutrients required for growth of pathogens
  • 8. Probiotics and clinical usage Benefits are of varying degree dependent on : Number of agents The dose Dosing patterns The characteristics of the host Underlying luminal microbial environment of the host
  • 9. Probiotics - uses Traveler’s diarrhoea Antibiotic-associated diarrhoea Relapsing Clostridium difficile colitis Infantile diarrhoea Rotavirus enteritis Inflammatory bowel disease Irritable bowel syndrome Colon cancer
  • 10. Probiotics - uses Peritonitis Acute pancreatitis Diarrhoea associated with HIV infection
  • 11. Probiotic agents with clinical data Lactobacillus GG Lactobacillus acidophilus Lactobacillus plantarum 299V Lactobacillus casei Shirota Bifidobacterium bifidum Bifidobacterium longam Streptococus thermophilus Enterococcus faecium SF68 Saccharomyces boulardii Bacillus clausii
  • 12. Lactobacillus Lactobacillus is part of lactic acid bacteria - non pathogenic gram positive bacteria that produce lactic acid as a primary metabolic end product Vary greatly from one species to another in genetic make up, colonization and adherence patterns Term “lactobacillus” is meaningless
  • 13. Lactobacillus casei – documented benefit • Recurrence of superficial bladder cancer (Urol Int 1992; 49:125-129, Urol Int 2002;68:273-280) • Significant improvement in sodium absorption in short bowel syndrome (JPGN April 2001;32:506-508)
  • 14. L. Casei Shirota - Constipation IMPROVED FREQUENCY AND < GI SYMPTOMS • Koebnick et al, Can J Gastroenterol 2003, Vol 17:11 • Bioscience Microflora 2006; 25 (2):39 – 48 • Chimielewska et al, World J Gastroenterol 2010; 16 (1) : 69 – 75 • Krammer HJ, Coloproctology 2011; 33:109-113
  • 15. Bacillus clausii •ACUTE DIARRHEA •ANTIBIOTIC – ASSOCIATED DIARRHEA •TRAVELLER’S DIARRHEA EXAMPLE OF SINGLE STRAIN CONCEPT TO JUSTIFY STRAIN SPECIFICITY
  • 16. Saccharomyces boularidii (Sb) Non pathogenic thermophyilic yeast Reaches high levels in stools in 3 – 5 days Undetectable by 2 - 6 days after discontinuation
  • 17. Sb - anti toxin effects Prevention of cytotoxicity of toxins A and B of C. difficile Reduces toxins A receptor binding Neutralisation of cholera toxin Neutralisation of heat stable enterotoxin of E. coli
  • 18. Sb and C. difficile enteropathy Prevention of recurrence Surawicz Prevention of recurrence in those who failed to respond to vancomycin and metronidazole McFarland
  • 19. Sb and antibiotic associated diarrhoea (AAD) Prophylactic use of Sb with beta lactam resulted in reduction of AAD McFarland Sb reduces the incidence of AAD in hospitalized patients Surawicz Efficiency in preventing AAD 56% McFarland
  • 20. Sb - clinical uses Nasogastric alimentation associated diarrhoea decrease in number of diarrhoeal days HIV associated diarrhoea decrease in stool frequency
  • 21. Sb - clinical uses Crohn’s disease decreased frequency of bowel movements Traveler’s diarrhoea reduction in the incidence of diarrhoea
  • 22. Single probiotic or cocktail??!! Rationale for using a probiotic “cocktail”- the beneficial effects of different probiotic agents may be additive – but is it really so? Advantage of using a single strain – easy to study the desired therapeutic effect and interpret it as responsible for the observed benefit.
  • 23. Probiotic Supplementation in Developing Countries of South Asia • Issues Raised 2. Lack of sufficient evidence from South Asian countries regarding possible benefit of probiotic supplementation in humans. 3. It is likely that microbial colonization of the gut in individuals from countries like India who are exposed to a microbiologically hostile environment is considerably different from those in the developed countries of the West. 4. The possible benefit from a probiotic preparation is dependent on specificity of the strain as well as host 23 response and these may differ in the two settings.
  • 24. SUMMARY OF TRIALS(RCT) S. CLINICAL SETTING PROBIOTIC STRAIN(S) PURPOSE RESULT NO 1. Acute watery diarrhea L. acidophilus Treatment No benefit 2. Acute watery diarrhea L. rhamnosus GG Treatment No benefit 3. Persistent diarrhea L.rhamnosus GG Treatment Benefit 4. Acute diarrhea L .casei DN-11400, L. Treatment bulgaricus, S. thermophilus, Lactococcus lactis, + Lactococcus lactis cremoris, Leuconosta Benefit mesenteroides cremoris Prevention 5. Morbidity B. Lactis(DR-10) Prevention Benefit 6. Neonatal sepsis L. plantarum Treatment Benefit 7. Ulcerative Colitis VSL#3 Treatment Benefit 8. Pediatric Irritable Bowel VSL#3 Treatment Benefit Syndrome 9. Acute diarrhea L. casei Shirota Prevention Benefit 24
  • 25. Guidelines for the treatment of gastroenteritis by ESPGHAN Guarino & al. JPGN 2008;46:619-21  “Probiotics may be an effective adjunct to the management of diarrhea. However, because there is no evidence of efficacy for many preparations, we suggest the use of Probiotic strains with proven efficacy and in appropriate doses for the management of children with AGE as an adjunct to rehydration therapy (II, B). The following Probiotics showed benefit in meta-analyses of clinical trials: Lactobacillus GG (I, A) and S.boulardii (I, A).  Evidence of lack of risk of antibiotic resistance transfer is required for Probiotics proposed for clinical use (Vb, D).” S. Boulardii is acknowledged as an evidence-based probiotic and recommended by the ESPGHAN
  • 26. LASPGHAN Guidelines (Latin American Society of Pediatric Gastroenterology ,Hepatology and Nutrition) Only S.boulardii & L.GG has been give 1A grade level of evidence
  • 27. PEDIATRIC CASE STUDIES – L. casei Shirota N 3 YRS F RECURRENT LOOSE STOOLS - FOR 18 MONTHS Given antibiotics for 3 – 5 days on most occasions, loose stools subsided, but frequent recurrence. L. casei Shirota consumed once daily ( 65 ML) for 5 months ( irrespective of occurrence of loose stools) – parents observed decreased frequency of episodes of loose stools.
  • 28. PEDIATRIC CASE STUDIES – (L.casei Shirota)- contd.. S 6 YRS M PASSAGE OF HARD STOOLS WITH DIFFICULTY - 2 YRS IRREGULAR STOOL FREQUENCY - 2 YRS Had received lactulose and cremaffin intermittently – no significant benefit. Then, received continuous medical treatment for 6 months as follows:- • LACTULOSE 15 ML TWICE DAILY ( AFTER LUNCH & DINNER), MON – SAT, 6 DAYS / WEEK. • POLYETHLENE GLYCOL ½ PACKET ONCE WEEKLY (EVERY SUNDAY) DISSOLVED IN TOTAL 1000 ML (600 ML BISLERI WATER + 400 ML MANGO FROOTI JUICE) OVER 3 HRS FOR 2 MONTHS, THEN STOPPED. • L. casei Shirota FOR 6 MONTHS AND STILL CONTINUING. • DISTINCT CLINICAL IMPROVEMENT - REGULAR STOOL PASSAGE ( 1 -2 / DAY), EASY.