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.

11. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 11/91 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

13. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 13/91 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.

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

28. 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

29. 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

30. 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

31. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 32/91 • 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

32. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 33/91 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”

33. 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.

34. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 36/91 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

35. 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

36. 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

37. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 39/91

38.  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)

39. 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

40. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 43/91 Mechanisms of action of Saccharomyces boulardii(Sb)

43. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 46/91 What happen during diarrhea Gut dysbiosis

44. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 47/91 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

45. Mode of action of probiotics in intestinal recovery

46. 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

47. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 50/91 Metabolic Activity 1. Girard-Pipau F et al. Microbial Ecology In Health And Disease. 2002;14:220-227

48. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 51/91 Saccharomyces boulardii CNCM I-745

49. 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%

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

51. 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

52. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 56/91 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

53. 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

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

55. 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

56. 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

57. 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

58. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 62/91 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

59. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 63/91  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

60. Sb training exclusively for internal use. No copy for external communication_ 4.Sb/Mode of action/Aug 2009_Final Some studies may not belong to your SmPC (Summary of Product Characteristics) 64/91 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

61. 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.

62. 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.

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