Drugs Used in Acute Diarrhea Wandee Varavithya

1. Drugs Used in Acute Diarrhea
Wandee Varavithya
Pediatric Department,
Ramathibodi Hospital,
Mahidol University

2. Diarrhea definition
3 loose or watery stools in a day-WHO
(1 large watery or one mucous bloody
stool)
Children-stool weight >10 mL/kg/day
Adult stool weight >200 gm/day

3. Bulletin of WHO 2008; 86: 710-7.
Estimating child mortality due to diarrhea
in developing countries
Thailand 2010 :49 death
2001 -0.35/100,000
2012- 0.10/100,000
Total pop. 64.7 million
Children 3.5 million

4. Burden of disease:Age distribution of diarrhea
cases/1000, 12% admission, (S.Sutra,2010)
Age (yrs) 1(ad 63) 2(54.) 3 (26) 4(17) 5(12)
A04 3,614 4,014 2,345 1,555 1,162
A05 5,724 10,477 7,474 5,801 4,693
A08 23,564 23,155 11,393 7,5 40 4,921
A09 195,595 212,671 110,082 71,198 49,574
OPD 228,497 250,317 131,294 86,094 60,35
A04 other bacterial, A05 Food poisoning ,A08 Viral,
A09 gastroenteritis presume-infection

5. Bacteria
Shigella
Samonella (non-
typhi)
Campylobacter
jejuni
Vibrio cholerae
E.coli
Common pathogens in childhood
diarrhea
Virus
Rotavirus
Adenovirus
Astrovirus
Norwalk
Parasite
E.histolytica
Giardia
lamblia

6. Pathogenesis of acute
diarrhea

7. CFTR
1-
2-
Enkep
halin
3-ENS
block

8. Mouth 2000
Saliva 1500
Gastric 2500
Liver, bile 500
Pancreas 1500
Small bowel 1000
Total intake
~ 9000 mL
Upper small intestine
Middle small bowel
5600
Lower small intestine 2000
Large bowel 1300
Total absorption
~ 8900 mL
Stool output 100 ml.
Normal gut balance

9. Concurrent loss in different type of diarrhea
Shigella/Salmonella 30-60
Rotavirus 30-90
E.coli 30-90
V.cholerae 120-240
mL./kg/day

10. Electrolytes composition of in diarrheal
stool
Stool electrolytes (mmol/L)
Pathogen Na+ K + Cl- HCO3
-
V.cholerae 101 27 92 32
Rotavirus 37 38 22 6
ETEC 53 37 24 18
Others 56 25 55 14
Mahalanabis, et al 1970, Molla, et al. 1981.

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Acute diarrhea is self-limitted disease, from:
1. Fluid and electrolyte loss
Dehydration
Hypovolemic shock
2. Nutrition consequences
Decrease in dietary intake and
intestinal absorption
Nutrition deficit
Infection; pneumonia, UTI, sepsis

12. Causes of death in diarrhea
 Acute diarrhea;Dehydration- shock
 Persistent diarrhea: Malnutrition
 Complication;Infection-pneumonia
UTI, sepsis

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What happen during diarrhea
Gut
dysbiosis

14. Physiopathology of diarrhea
Malabsorption Hypersecretion Enterocyte damage

15. The objectives of treatment are to:
 Prevent dehydration, if there are no signs of
dehydration;
 Treat dehydration, when it is present;
 Prevent nutritional damage, by feeding during
and after diarrhoea; and
 Reduce the duration and severity of diarrhoea,
and the occurrence of future episodes, by
giving supplemental zinc.

16. Luminal side
Mucosal cell
Intestinal wall
VILLUS CELLS
A
B
C
D
A
T
CRYPT CELLS
AT
A
T
Cl-
Cl- Na+
Na+
Na+
Pase
Pase
PaseNa+
Na+
Na+
Na+
Cl-
Glucose
CFTRORS failure
Bacteria 9%
Rotavirus 11%
Cystic fibrosis transmembrane reductance receptor

17. WHO 4 Rules
 Rule 1: Give the child more fluids than usual,
to prevent dehydration
 Rule 2: Give supplemental zinc (10 - 20 mg) to
the child, every day for 10 to 14 days
 Rule 3: Continue to feed the child, to prevent
malnutrition
 Rule 4: Take the child to a health worker if
there are signs of dehydration or other
problems
 oral rehydration therapy for children with some

18. WHO standard ORS vs R-ORS
R-ORTORS-WHO formular

19. Composition of original and reduced-
osmolarity WHO ORS
Original ORS RO ORS (mmol/L)
Sodium 90 75
Chloride 80 65
Potassium 20 20
Citrate 30 10
Glucose 111 75
Total osmolarity 331 245(mOsm/L)
Development:ORS + rice , ORS + Zinc, ORS+ Liposome

20. Original oral rehydration solution
 Effective for treatment of 90% of diarrhoea
cases
Reduced osmolarity oral rehydration solution
 Same effectiveness as original oral rehydration
solution
 Improved safety
 20% decrease in stool output
 30% reduction in vomiting
 40% reduction in the need for unscheduled
intravenous treatment
Santosham et al. Lancet 2010; 376: 63-7.
Strategies for management of acute
diarrhoea in developing countries

21. Epithelial restoration
 Food for enterocytes
 Zinc for epithelial repair
 Probiotics for recovery of damage cells
 Cholystyramine for removal of insults
 Growth hormone
 Interleukin 2

22. ORS+Zinc deficiency
Essential mineral (micronutrients)
Zn deficiency
- Impaired water and electrolyte absorption
- Decreased brush border enzymes
- Impaired cellular and hummoral immunity

23. Clinical Dx;8 month old infant has had fever,
vomiting, nasal discharge
and passed 8 liquid stools.

24. 12 old boy passed 2 large watery stools then
developed cold hands, feet and fainting.

25. 2 months old female infant has body temp 38.5o C and
passes 6 greenish mucous bloody stools.

26. A 2 years old boy developed T 40.5o C, convulsion and passed 2
greenish liquid foul smell stools followed by frequent small
mucous bloody stools 2-3/hour. He has loose sphincter tone.

28.  ORS - ORT
 Early Feeding
 Antibiotics for Shigellosis++
Cholerae -
Salmonellosis +
 Absorbents -
 Anticholinergic -
 Antimotility -
 Probiotics ++
Concept of diarrhea treatment

29. Antibiotics may do harm
 EHEC -bacteria die release toxin
increase risk to HUS.
 Salmonella -prolong carrier.
 Rotavirus -prolong recovery.
 V. cholerae -drug resistance
How to select case to give antibiotics

30. Current therapeutic options for diarrhea
Diarrhoea
Therapy Options
Anti-
infectives
▪ Ciprofloxacin
▪ Rifaximin
▪ Nifuroxazide
▪ Ofloxacin
▪ Azithromyci
▪ Doxycyclin
Adsorben
ts
▪ Diosmectite
▪ Bismuth
Probiotics
▪ S.boulardii
▪ L.rhamnosusGG
▪ L. reuteri
Others
▪ Racecadotril
Vaccines
▪ Rotarix®
▪ RotaTeq®
Motility
inhibitors
▪ Loperamide
• Diphenoxylate
▪ Atropine

31. Formation UL réservée à l'usage interne. Reproduction pour communication externe interdite _ 4. UL/Mode d'action/Mars 2010_short_ 31
Certaines études ne sont peut-être pas incluses dans votre RCP (Résumé des Caractéristiques du Produit)
กลุ่มยารักษาท้องเสีย การแนะนาให้ใช้ ข้อมูลสนับสนุน
Probiotics
(L. rhamnosus GG and S.
boulardii)
recommended
แนะนาให้ใช้
(I, A) (strong
recommendation, moderate
quality evidence).
Racecadotril Considered
ต้องพิจารณาอย่างถ้วนถี่ก่อนจะใช้
(II, B) (weak
recommendation,
moderate quality evidence).
Smectite (ตัวดูดซับ) Considered
ต้องพิจารณาอย่างถ้วนถี่ก่อนจะใช้
(II, B) (weak
recommendation,
low quality evidence).
ถ่าน (activated charcoal)
สารดูดซับอื่นๆ (kaolin-pectin)
Not recommended
ไม่แนะนา
(III, C) (weak
recommendation,
very low quality evidence).
ยาลดการเคลื่อนไหวของลาไส้ (Loperamide) Not recommended
ไม่แนะนา
(II, B) (strong
recommendation,
very low quality evidence).
Bismuth subsalicylate
ยาเคลือบป้องกันติดเชื้อ
Not recommended
ไม่แนะนา
(III, C) (strong
recommendation,
low quality evidence).
Zinc (Children older than 6
months in developing countries,
may be benefit
อาจจะได้ประโยชน์บ้าง
(I, A) (strong
recommendation, moderate
Recommendation of EPSGAN
เอกสารใช้อบรมบุคคลากรทางการแพทย์เท่านั้นห้ามเผยแพร่ โดยไม่ได้รับอนุญาต

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• Natural probiotics
• fermented milk products : yogurt, kefir, buttermilk, lassi
• sauerkraut, kimchi
• Commercialised fermented milk
• ~ natural probiotic but industrial preparation
• milk as vehicle
• Commercialised probiotic food supplements
• ~ natural probiotic but industrial preparation
• in “health care shops”, etc.
• capsule as vehicle (“medication-like”)
• Probiotic drug
• Clinical trials
• Marketing authorization
• Manufactoring process GMP (Good manufactoring process)
Probiotic :Live microorganisms that confer a health benefit on the host
when administered in adequate amounts

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Bacterial probiotics
Nonbacterial probiotics
Vandenplas Y, et al. SA J Child Health. 2007;1(3):116-119.
Sb is the unique YEAST
PROBIOTIC
3
3
Probiotics
Probiotics: “not all are created equal”

34. Probiotics
Bacterial Probiotics
- Lactobacillus rhamnosus GG
- Bifidobacterium in combination
- Streptococcus thermophilus
- Enterococcus faecium
Yeast Probiotics
- Saccharomyces boulardii
World gastroenterology practice guideline.
Probiotics and Prebiotics. 2008.

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แบคทีเรีย ยีสต์
ข้อดี
อัตราการอาศัยในร่างกาย
99 %
< 1 % ไม่ตั้งรกรากในร่างกาย
ขนาด 1 ไมครอน 10 ไมครอน ใหญ่กว่า 10 เท่า เพิ่มประสิทธิภาพการจับเชื้อ
ก่อโรค
ถูกฆ่าด้วยยาปฏิชีวนะ ไม่ถูกฆ่าด้วยยาปฏิชีวะนะ ใช้ร่วมกับ ยาปฏิชีวนะได้
ไม่ส่งต่อยีนส์ดื้อยา
ไม่ทนกรด ทนกรด สามารถอยู่รอด ผ่านกระเพาะและมาทางานที่
ลาไส้ได้
ความแตกต่างของยีสต์โปรไบโอติก กับ แบคทีเรียโปรไบโอติก

37. 37
Saccharomyces boulardii
CNCM I-745
Elimination of Bacterial
Toxins
Toxin producing bacteria
1 - Moré, Margret I., Alexander Swidsinski. "Saccharomyces boulardii CNCM I-745 supports regeneration of the intestinal
microbiota after diarrheic dysbiosis–a reviewClinical and Experimental Gastroenterology 11 (2015): 237
Klena J et al. J Bacteriol. 2005;187(5):1710-1715.
Liu C. Robbins and Cotran pathologic basis of disease. 7th ed; 2005:797-876.
Todd WT, et al. Davidson's principles and practice of medicine. 20th ed.; 2006:283-376.
http://www.cdiff-support.co.uk/about.htm
Voth DE, et al. Clin Microbiol Rev. 2005;18(2):247-263.
ADP, Adenosine Diphosphate; AMP,
Adenosine Monophosphate; G, G Protein;
LPS, Lipopolysaccharide; LT, Labile toxin; ST,
Stable toxin;
“S. boulardii produces factors that
neutralize bacterial toxins and modulate
host cell signaling pathways implicated in
proinflammatory response during bacterial
infection”1

38. 38 4-5-2019
Recommendation Quality
evidence
Probiotics “some” probiotics + ORS  duration acute
GE
Strong Weak
L. rhamn GG Can be considered Strong Weak
L. reuteri DSM17938 Can be considered Weak Weak
L. rhamn 573L/1,
573L/2, 573L/3
Insufficient evidence Weak Moderate
L. acidophilus Insufficient evidence Weak Weak
L. paracasei ST11 Insufficient evidence Weak Moderate
BB12 No studies
BB12 + Str therm TH4 Insufficient evidence Weak Weak
Bacillus clausii Insufficient evidence Weak Weak
E. faecium SF68 Can NOT be considered Strong Weak
E. coli Nissle 1917 Insufficient evidence Strong
S. boulardii Can be considered Strong Weak
Probiotics for the treatment of acute GE.
Position paper ESPGHAN working group on probiotics/prebiotics.
H. Szajewska, Vandenplas Y. JPGN 2014;58(4):531-9

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40.  Survives gastric acid
 Naturally resistant to all antibiotics
 Inhibited by standard antifungal drugs
 High steady-state levels
 No permanent colonization
 No alteration of normal flora
 No translocation out of the gut
What is Saccharomyces boulardii ?
S.b. is a tropical wild yeast ; discovered in Indochina in 1923 by the Henry
Boulard (French scientist), Isolated from the skins of lychee and mangosteen)

41. Saccharomyces boulardii and
Salmonella typhimurium
Scanning electronic microscopy
S. boulardii and S. typhimurium.
Electron micrograph
Salmonella
typhimurium
Salmonella
typhimurium
S. Boulardii CNCM I-745
Czerucka, et al. Aliment Pharmacol Ther 2007;26:767-78
S. boulardii CNCM I-745: larger than bacteria
Sb CNCM I-745

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Mechanisms of action of Saccharomyces boulardii(Sb)

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Mechanisms of action of Saccharomyces boulardii(Sb)

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Mechanisms of action of Saccharomyces boulardii(Sb)

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What happen during diarrhea
Gut dysbiosis

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Short chain Fatty Acid 1,2
1. Scheppach W. Gut .1994.S1:35-38.
2. Girard-Pipau F et al. Microbial Ecology In Health And Disease. 2002;14:220-227

48. Mode of action of probiotics in intestinal recovery

49. Saccharomyces boulardii CNCM I-745
Anti-inflammatory activity
Sb acts at cellular level decreasing the
synthesis of inflammatory mediators
Anti-inflammatory action
Beneficial in all types of diarrhea
Reduction of inflammation
Many different studies demonstrate that S. boulardii elicits, via secreted
factors, pronounced anti-inflammatory & antisecretory effects
1 - Moré, Margret I., Alexander Swidsinski. "Saccharomyces boulardii CNCM I-745 supports regeneration of the intestinal
microbiota after diarrheic dysbiosis–a reviewClinical and Experimental Gastroenterology 11 (2015): 237

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Metabolic Activity
1. Girard-Pipau F et al. Microbial Ecology In Health And Disease. 2002;14:220-227

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Saccharomyces boulardii CNCM I-745

52. Randomized, double-blind, placebo-controlled study
Duration of follow-up: 14 days
Effects of Saccharomyces boulardii in children with acute diarrhoea
Kurugöl Z & Koturoğlu G Acta Paediatr. 2005 Jan;94(1):44-7
Placebo
Saccharomyces
boulardii
0
1
2
3
4
5
Duration of watery diarrhoea (days)
p < 0.001
Placebo
Saccharomyces
boulardii
0
1
2
3
4
5
Length of hospitalization (days)
p < 0.001
- 25%

54. Probiotic: Cell membrane-receptor, SIgA,
Binding toxin, Secrete polyamine –lactase level increase
Decrease Cl- heypesecretion, close intercellular junction

55. s
Antibiotics
Disruption of
Tight
Junctions
Decreased Short
Chain
Fatty Acids
Normal Gut
Flora
Disruption of
normal
flora on
exposure to
Antibiotics
(Shown in
white)
Disturbed
normal
microflora and
infection
(e.g., C. difficile)
Increased
Osmosis
in the Lumen
Increased
Inflammation
Diarrhea
Bouhnik Y. Gut Microflora Digestive Physiology And Pathology. Paris; 2009:181-197.
Mechanism of gut microbiota alteration by antibiotics

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Generalized Scheme of the effects of antibiotic
dysbiosis on bacterial concentration
During ATB treatment
Microbial population during
ATB treatment
Sb administration
After ATB treatment
“Saccharomyces boulardii can support a faster regeneration of the microbial population”1
The optimal treatment would be to administer Saccharomyces boulardii simultaneously
With antibiotic treatment, plus subsequently for at least 2 weeks
Moré, Margret I., Alexander Swidsinski. "Saccharomyces boulardii CNCM I-745 supports regeneration of the intestinal microbiota after diarrheic dysbiosis–a reviewClinical and
Experimental Gastroenterology 11 (2015): 237

57. Probiotics in acute diarrhea:
What has been proven?
 Reduces duration, severity of viral diarrhea
 Reduces risk of traveler’s diarrhea
 Reduces incidence of diarrhea in day care centers
 Reduces relapsing Clostridium difficile diarrhea
 Reduces incidence of antibiotic-associated diarrhea

58. Food for diarrhea fight malabsorption
Milk and milk products
Rice-based food
Food believed to help stop diarrhea
High potassium diet

59. Shorter duration of diarrhea with
lactose-free versus lactose-containing
formulas
Simakachorn et al. J Med Assoc Thai 2004;87:641-9.
Kaplan-Meier survival estimates, by group
analysis time
0 50 100 150 200
0.00
0.25
0.50
0.75
1.00
group 1
group 2
lactose-containing milk
lactose free

60. How to reduce stool volume
in the first 24 h?
 Conventional treatment
hospitalization 3.5 days
 Intervention reduce to 2.3-2.7 days
 Adjunct therapy ? Probiotics ,
antisecretory

61. 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).
Safety issues with probiotics are related to bacterial translocation and
sepsis and to the risk of antibiotic resistance.
The following probiotics showed benefit in metaanalyses of RCTs:
 Lactobacillus GG (I, A)
 Saccharomyces boulardii (I, A).
ESPGHAN-ESPID 2008

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62
NICE guidelines
 Probiotics:
Research recommendation
Are probiotics effective and safe compared with a placebo in the treatment of
children with gastroenteritis in the UK?
Which specific probiotic is most effective and in what specific treatment
regimen?
Lactobacillus rhamnosus GG [EL = 1+],  duration of diarrhoea by 1
day
Lactobacillus acidophilus LB, no statistically significant differences
(NS)
Lactobacillus paracasei strain ST11 : NS
Lactobacillus rhamnosus strains 573L/1, 573L/2 and EL =
1+i573L/3: NS]
Saccharomyces boulardi duration of diarrhoea by 1 day
http://www.nice.org.uk/nicemedia/pdf/CG84FullGuideline.pdf

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 Treatment
“Oral rehydration is the cornerstone of
child treatment, inducing less side effetcs
than intravenous rehydration.
Continuing normal feeding.
Practical clinical guidelines Ibero
Latin American
P. Gutierrez Castrellon, Guia de practica clinica Ibero-
Latinoamaerica, An Pediatr (Barc). 2009

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Take home message :
 Rehydration ORS/ORT, IV
 Stop malabsorption: CHO-based food
Lactose free milk
Probiotics - Sb, Lactobacilli help digest
lactose and promote absorption; SCFA
 Stop inflammation-drugs for bacterial diarrhea
 Enhance epithelial restoration
-Trophic action; proved-efficacy probiotics
-Zinc

65. Zinc supplementation
UNICEF and WHO recommend zinc
supplementation (10 mg < 6 mo, and
20 mg in older infant and children for
10-14 days) as a universal treatment
for children with diarrhea.
Santosham et al. Lancet 2010; 376: 63-7.

66. Strategies for management of acute
diarrhoea in developing countries
Zinc
• 12 h mean reduction in duration of acute diarrhoea
episodes
• 16 h mean reduction in duration of persistent
diarrhoea episodes
• 29% lower relative risk of diarrhoea continuation
to the 7th day
• 34% decreased frequency of diarrhoea in 2–3
months after treatment
• 51% decrease in overall mortality
Santosham et al. Lancet 2010; 376: 63-7.