1 Microbiota GI tract consists of approximately 10 15 /mL - PDF document

Sm all I ntestinal Bacterial Overgrow th The old and the new Jack A. Di Palm a, M.D. University of South Alabam a Mobile, Alabam a The “Old” The ”New ” 1

Microbiota GI tract consists of approximately 10 15 /mL  (Million trillion)  30 genera and over 500 species Quantity and characteristics of bacteria vary depend  on anatomic site  Newborns colon colonized within 6 days Anaerobes – B. fragilis Vaginal Birth 60%; Cesarean section 9% Commensals- No great benefit, no great harm  Bacterial Effects  Metabolism of androgens and estrogens  Production of nutrients folate and Vitamin K  Production of short chain fatty acids Helps support integrity of colonic mucosa Conserves energy May play role in regulation of normal enteric flora  Degradation of protein and urea  Metabolism of drugs  Helps prevent colonization by pathogenic bacteria 2

GI Bacterial Presence  Stomach < 10 3 / ml  < 10 3 / ml Jejunum < 10 8 / ml  Ileum  Colon < 10 10 / ml Health: Gram -positive, aerobic Overgrow th: Gram -negative, anerobic Physiological Suppression of Overgrow th  Low gastric pH  Secretory IgA  Defensins/ other Paneth cell products  Gastric and small bowel motility Migrating motor complex during fasting  Ileocecal valve Sm all Bow el Bacterial Overgrow th  Malabsorption due to bile acid deconjugation  Low B12 Iron deficiency High folate  Abnormal small bowel mucosa 3

Clinical Presentation  Steatorrhea, weight loss, malabsorption, malnutrition  Metabolic bone disease  Nutritional deficiencies  Low B12, high folate  Diarrhea, bloating cramps Bacterial Overgrow th  Accounts for 20-43% of chronic diarrhea in diabetes  Results from UGI surgery  50% of neonatal diarrhea  Probably significant in the elderly  and in I BS and constipation Prevalence of SI BO*  Healthy volunteers 20%  Celiac Disease 66%  Neuropathic dysmotility 55% (Including renal failure)  Diabetes with diarrhea 43%  Chronic alcohol 90% * varying by testing method used 4

Prevalence of SI BO*  H2RA 17%  PPI 53%  Chronic diarrhea 33%  Older patients 14.5-15.6%  IBS 10-78% * varying by testing method used Clinical Predictors of SI BO Choung, Alim ent Pharm Ther 2 0 1 1  675 who had duodenal aspirates  8% positive for SIBO  Associated: Older age Steatorrhea Narcotic use IBD SB diverticula Pancreatitis Setting for I BS  Hypochlorhydria Gastric disease or drugs  Immunodeficiency IgA  Dysmotility Diabetes, Scleroderma, Pseudo-obstruction  Structure Blind Loop Diverticulosis, stricture, fistula 5

The “Old”  Scleroderma  Steatorrhea/ Malnutrition  Structural disorders  Immunodeficiency  Sprue  Malnutrition The “New ”  Diarrhea  Older age  Hypochlorhydria  IBD  Pancreatitis  Colorectal cancer  Fatty liver  Rosacea  Any dysmotility- Disease, IBS, medications, narcotics W hat are the diagnostic options? 6

Diagnostic Options  Jejunal aspiration for bacterial colony counts and strain identification  Schilling’s test  Nuclide tests 14 C-glycocholic acid 14 C-D-xylose 14 C-sorbitol  Hydrogen and methane testing after glucose or lactulose challenge Lim itations of Culture Testing  Invasive  Oral flora contamination  Culture transport difficulties  Miss distal overgrowth  Unclear relevance of increased bacterial colonization in the elderly 7

H2 Response to Lactulose Challenge Fasting elevation, early rise Double-peak Call for Good Testing Methods  Hydrogen and methane  Standard dose of challenge  Confirm fasting state when fasting elevation found in lactose and fructose testing  Test 30d after antibiotics and before colon cleansing for colonoscopy (or 30d afterwards) 8

SI BO test results vary greatly by m ethodology Positivity criteria % positive tests Fasting H2 > 10ppm 22% Fasting H2+ 2X CH4> 10 43% Early rise H2 > 20ppm < 20min 4% Early rise H2+ CH4 > 20ppm < 20 min 11% Rise H2> 20ppm < 90min 37% Rise H2+ CH4> 20ppm < 90 min 45% Rise H2 + distinct 2 nd peak 17% Rise H2 + CH4 + 2 nd peak 21% Knudsen, Di Palma ACG 2010 Perform ance Characteristics of Breath Tests  Highly variable  Few careful studies of hydrogen vs. quantitative cultures  Glucose Sensitivity 27-93% Specificity 30-86%  Lactulose Sensitivity 17-89% Specificity 44-100% Sm artPill Capsule pH SENSOR TRANSMITTER  Senses and records pH, pressure and temperature data  Wirelessly transmits data to BATTERIES the SmartPill Data Receiver PRESSURE SENSOR MICROPROCESSOR 9

Diagnostic Options  Jejunal aspiration for bacterial colony counts and strain identification  Schilling’s test  Nuclide tests 14 C-glycocholic acid 14 C-D-xylose 14 C-sorbitol  Hydrogen and methane testing after glucose or lactulose challenge  Em piric Treatm ent W hat are the treatm ent options? Treatm ent for Bacterial Overgrow th  Correct the underlying condition Surgery Prokinetic agents  Nutrition Lactose-restricted, low residue diet Increase calories Micronutrient supplementation (B12, fat soluble vitamins, trace elements)  Antibiotics 10

W hich antibiotic? Antibiotic choices  Tetracyclines  Amoxicillin/ clavulanic acid  Cephalexin and metronidazole  Trimethoprim/ sulfamethoxazole  Quinolones  Chloramphenicol Rifaxim in Di Stefano, Alim ent Pharm acol 2 0 0 0  Non-absorbable rifamycin derivative  Design: Randomized, blinded  Study subjects: 21 defined by H 2 responses to 50g glucose  Methods: Received rifaximin 1200mg or chlortetracycline 1g for 7d  Results: H 2 normalized in 70% after rifaximin and 27% after chlortetracycline 11

Comparison of Antibiotics ANTIBIOTIC EFFICACY IN SIBO Flagyl <20% Neomycin 25% Augmentin or 30-40% Doxycycline Rifaximin 70%* DiStefano M, Aliment Pharm Ther, 2000. Do prokinetics help? Prokinetics  Stasis and outflow  No proven benefit of metoclopramide, cisapride  Erythromycin in small reports  Low dose octreotide 50ug daily in scleroderma  Optimism for 5HT3, 5HT4 agents 12

W hat about probiotics? Probiotics in SI BO  Experimental studies in animals suggest that probiotics enhance the mucosal barrier, inhibit bacterial growth, modulate immune system and have anti-inflammatory effects that might benefit patients with SBBO  Human studies suggest benefit with some agents, but no large studies reported yet Quigley EMM, Gastroenterology 2006 LR Schiller I rritable Bow el Syndrom e? 13

Prevalence of SI BO in I BS based on lactulose breath test Author Type of Gases # Prevalence subjects Breath test Measured (% ) Galatola, 1995 Xylose H2 80 56 Pimentel, 2000 Lactulose H2/ CH4 202 76 Pimentel, 2003 Lactulose H2/ CH4 111 57-84 Nucera, 2004 Lactulose H2/ CH4 200 75 Nucera, 2005 Lactulose H2/ CH4 98 65 Walters, 2005 Lactulose H2 39 10 RIFAXIMIN IN IBS Percent Global Improvement 50 No Active Treatment 45 40 35 30 25 20 Treatment 15 Active 10 Placebo Rifaximin 5 0 1 2 3 4 5 6 7 8 9 10 Weeks after Rifaximin *P=0.02 Mixed Longitudinal Model for 10-week difference Pimentel, et al, Ann Intern Med, Oct., 2006 Sustained relief Pim ental, TARGET 1 and 2 DDW 2 0 1 0 Rifaxim in Placebo Adequate 40.7% 31.7% relief of I BS sym ptom s Adequate 40.2% 30.3% relief of I BS bloating Rifaximin 500mg TID, n=1260, 12w response after 2w treatment 14

I rritable Bow el Syndrom e Global Assessment of Symptom Relief Global Assessment of Symptom Relief 80 80 P=0.0118 P=0.0118 70 70 % answering “yes” at Week 4 % answering “yes” at Week 4 60 60 50 50 40 40 30 30 N=90 N=92 B. infantis 1X10 10 B. infantis 1X10 10 B. infantis 1X10 8 B. infantis 1X10 8 B. infantis 1x10 6 B. infantis 1x10 6 placebo placebo Whorwell, Am J Gastroenterol 2006 LR Schiller Does CHO Testing Predict Clinical Response in SI BO? Long, DiPalm a DDW 2 0 1 5 Lactulose challenge test, n= 100 Clinical Response No criteria 67% One 76% Three 85% Four 77% Overall 73% Criteria-Fasting elevation, early rise in 2 0 or 6 0 m inutes, second, colon peak Constipation? 15

Methane revisited in IBS subjects 100 90 80 Chi-square=16.6, p<0.001 70 % of patients 60 Constipation 50 Diarrhea 40 30 20 10 0 H2 CH4 and H2 CH4 Pimentel, DDS 2003 Rifaxim in and Neom ycin for Methane I BS Low , Am J Gastro 2 0 1 0  Design: Retrospective  Subjects: Methane producing IBS patients  I nterventions: Neomycin 500mg BID for 10d, Rifaximin 400mg TID for 10 days, or both Rifaxim in and Neom ycin for Methane I BS Low , Am J Gastro 2 0 1 0 Clinical Methane n Response Eradication Neomycin 8 63% 33% Rifaximin 39 56% 28%* Both 27 85% 87% *Of these who did not eradicate methane, 66% who had subsequent treatment with both drugs normalized their breath test 16

Proton Pum p I nhibitors SI BO and PPI Lom bardo CG and H 2 0 1 0 PPI n=200, IBS n=200, controls n=50 Take Aw ay Message  SIBO is clinically significant  Underdiagnosed Elderly Medications (Motility, PPI) Chronic diarrhea IBS Constipation  Diagnostic testing options limited  Antibiotic choices 17