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Overview of Helicobacter pylori Microbiology, Pathogenesis and Treatment Options.

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Presentation on theme: "Overview of Helicobacter pylori Microbiology, Pathogenesis and Treatment Options."— Presentation transcript:

1 Overview of Helicobacter pylori Microbiology, Pathogenesis and Treatment Options

2 Objectives - Case Based Presentations 1.To discuss the epidemiology, pathogenesis, and diagnosis of H. pylori 2.To highlight test and treat practice guidelines 3.To compare and contrast clinical trial results between quadruple and triple therapy 4.To review antibiotic treatments

3 Case MB – H. pylori General Information MB is 29 Cambodian and has been in the US for 5 years. She lives in the inner city of Los Angeles. History: 1 - month of moderate mid- epigastric, upper abdominal pain. No complaints of gas, darkening stool, or heartburn. Non-smoker, no other medical problems, occasional ibuprofen usage.

4 Case MB – H. pylori General Information Describe the epidemiology of H. pylori. Review the pathogenesis of H. pylori and associated symptoms.

5 Epidemiology Estimated 50-60% of the world population is infected Person to Person Transmission –fecal-oral, oral-oral, gastro-oral Increased risk of infection –younger age –underdeveloped countries –lower socioeconomic status Go MF. Aliment Pharmacol Ther 2002;16(Supp 1):3-15

6 National Prescribing Patterns for Eradication ®2007 ZS Associates

7 History of H. pylori 1890’s: Spirochetes in animal stomachs 1900’s: Spirochetes in human stomachs 1954: No bacteria in gastric biopsies of 1000 patients 1975: Gram negative bacteria in 80% of GU’s (Pseudomonas) 1983: Warren and Marshall characterize H. pylori 2005 Nobel prize in 2005

8 $6 billion / yr in health care costs due to peptic ulcer disease (PUD) 1 Up to 93% cure rate quadruple therapy 2 0-10% of ulcer recurrence after antibiotic (ABX) treatment 3 1-3% re-infection rate after ABX treatment 3 Economics of H. pylori 1 Sonnenberg A et al. Am J Gastroenterol 1997;92:614-620. 2 O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20 3 Taylor JL et al. Arch Intern Med 1997;157:87

9 Immune and Inflammatory Response to H. pylori Inflammatory Response Immune Response H. pylori Mucosa Tissue damage Activated T cell Adhesion of bacteria Inflammatory Mediators Activation Recruitment Gastric ulcer

10 Majority of infected patients do not develop clinically significant disease 1-3 Significant manifestations 1-3 –peptic ulcer disease (PUD) –gastric and duodenal ulcers –chronic gastritis –mucosa associated lymphoid tissue (MALT) –gastric adenocarcinoma 1 Houghton J, et al. Gastroenterology 2005;128;1567-1578 2 Portal-Celhay C et al. Clin Sci 2006;110:305-314 3 Helico Go MF. Aliment Pharmacol Ther 2002;16(Supp 1):3-15 H. pylori pathologic associations

11 Case MB – H. pylori General Information Demographics – Cambodian, inner city Pathogenesis: immune and inflammatory response contribute to symptoms

12 SH is 34 y/o middle income social worker in Austin, TX. Receiving proton pump inhibitor (PPI). 6 - month history of dyspepsia with no improvement in symptoms. Smoker and no family history of GI cancer. Never had endoscopy. Case SH – H. pylori Diagnostic Tests

13 Describe active and passive tests for detection of H. pylori. Discuss various diagnostic tests for H. pylori. Review practice guidelines and application for test and treat. Case SH – H. pylori Diagnostic Tests

14 Diagnostic Test Comparison Invasive / active tests Noninvasive / passive tests 1,2 Determination of presence of H. pylori –antibodies in blood, serum, or saliva –antigen in stool –functional tests of the bacterium's urease enzyme with a carbon-labeled urea breath test (13 C-UBT) 1Howden CW et al. Am J Gastroenterol 1998;93(12):2330-8 2 Gisbert JP et al. Helicobacter 2004;9(4):347-68

15 Diagnostic Test Comparison Testing CharacteristicsSerology 1 UBT 1 SAT 2 Biopsy 1 Sensitivity / Specificity § 85% / 79%95% / 96%96% / 97%95% / 99% Detects previous infectionYesNo Tests for eradicationNoYes Low cost$$$$$ $$$$ § Need to account for false negatives with PPIs UBT = urea breath test SAT = stool antigen test 1Howden CW et al. Am J Gastroenterol 1998;93(12):2330-8 2 Gisbert JP et al. Helicobacter 2004;9(4):347-68

16 AGA Recommendations Talley NJ et al. Gastroenterology 2005;129:1756-1780 Dyspepsia without GERD or NSAIDs Age ≤ 55 and No Alarm Features Age ≤ 55 and No Alarm Features EGD Age >55 or Alarm Features Present Test for H. pylori PPI Trial 4-6 Weeks Treat for H. pylori PPI Trial 4 Weeks Reassurance, Reassess Diagnosis Consider EGD Negative Positive Fails American Gastroenterology Association (AGA) Alarm Features Age > 55 with new onset Family history of upper GI cancer Previous GI malignancy or peptic ulcer Unintended/unexplained weight loss (>10%) GI Bleeding, persistent vomiting, jaundice Dysphagia, odynophagia, early satiety Unexplained Iron deficiency anemia Palpable mass/lymphadenopathy

17 Adherence to Test and Treat Guidelines Results –1/3 antibiotics for H. pylori had no test –1/3 post-treatment PCPs used serologic test –2/3 ages 50 - 64 years underwent endoscopy –1/3 ages 18 - 49 years had an endoscopy within 30 days of their index date –18% GERD patients tested for H. pylori “Substantial noncompliance with guidelines” “Better understanding of test and treat” Howden CW, et al. Am J Manag Care. 2007;13:37-44

18 High prevalence area – Austin. Test and treat guidelines apply. PPI therapy false negative on UBT and SAT. Hold PPI 2 weeks prior to UBT and SAT. Wait 1 month post eradication therapy to recheck. Case SH – H. pylori Diagnostic Tests

19 Case # CV - H. pylori Eradication Therapy CV is 34 y/o Latino, with suspected ulcer – post-prandial bloating and mid-epigastric pain. Treated at primary care physician (PCP). Receiving PPI once daily. H. pylori serology positive. No family history of gastric cancer. Penicillin (PCN) allergy.

20 Case CV - H. pylori Eradication Therapy Compare study results of new 3-in-1 bismuth subcitrate potassium, metronidazole, tetracycline regimen to other available H. pylori eradication therapies.

21 Treatment of Peptic Ulcers “ The modern treatment of peptic ulcers places emphasis on diet and rest. The patient is fed a bland diet, and small meals are given at frequent intervals. Milk, cream and protein hydrolysates are often prescribed between meals. Rest is essential. Some gastroenterologist routinely recommend hospitalization for several weeks….. Mild sedatives are frequently beneficial.” The Pharmacologic Basis of Therapeutics, Eds. Goodman and Gilman, 2 nd Edition, 1955

22 ANTIBIOTICMOA 1-3 DYNAMICS 1-3 RESISTANCE 3 Metronidazole (MTZ)DNA synthesisStatic +/- cidalPre-treatment MIC does not always correlate with treatment outcomes Tetracycline (TCN)RNA synthesisStatic +/- cidalRare Clarithromycin (CLAR)RNA synthesisStaticPre-treatment MIC does not always correlate with treatment outcomes Amoxicillin (AMOX)Cell wallCidalRare Antibiotic Pharmacodynamics 3 Helicobacter pylori: Physiology and Genetics. ASM Press 2001 1 Micromedex 2006, Thomson Healthcare 2 AHFS Drug Information 2005; 854-864 Susceptibility testing of H. pylori for MTZ has not been standardized. No interprative criteria have been established for testing metronidazole against H. Pylori

23 Bismuth Bismuth minimally absorbed transmucosally Considered a topical agent –antiseptic agent 1 –prevents bacterial adhesion –inhibits urease, phospholipase, and proteolytic activity and is synergistic with antibiotics 1,2 –lyse H. pylori near the gastric surface 3 1 Megraud et al. Aliment Pharmacol Ther 2003;17:1333-43 2 deBoer WA. Expert Opin Investig Drugs 2001:10;8,1559-1566 3 Klotz U. Clin Pharmacokinet 2000;38:243-70

24 Bismuth subcitrate potassium, metronidazole tetracycline (BMT) –not bismuth subsalicylate –3-in-1 capsule Four studies with BMT 2-3 capsules QID for 7-10 days ± PPI 1-4 Up to 93% compliance, >75% medication taken 3 H. pylori eradication with BMT 1 de Boer WA et al. Am J Gastroenterol 2000;95:641-45 2 de Boer WA et al. Aliment Pharmacol Ther 2000;14:85-89 3 O’MorainC et al. Aliment Pharmacol Ther 2003;17:415-20 4 Laine L et al. Am J Gastroenterol 2003;98:562-67

25 1 de Boer WA et al. Am J Gastroenterol 2000;95:641-45 2 de Boer WA et al. Aliment Pharmacol Ther 2000;14:85-89 3 O’MorainC et al. Aliment Pharmacol Ther 2003;17:415-20 4 Laine L et al. Am J Gastroenterol 2003;98:562-67 H. pylori eradication with BMT +/- PPI n=53 n=65 n=170 n=138

26 Objective 10 day therapy –3 BMT (triple capsule) QID + omeprazole (O) 20 mg BID vs. –amoxicillin + clarithromycin (AC) BID + O 20 mg BID Design –prospective, multicenter, randomized, evaluator-blinded Inclusion Criteria –DU (>3 mm) or history of DU (within 5 years) Laine L et al. Am J Gastroenterol 2003;98:562-67 OBMT vs OAC, Laine et al.

27 Laine L et al. Am J Gastroenterol 2003;98:562-67 Baseline H. pylori testing – 13 C-urea breath test –antral and body biopsies –histology and/or culture –antibiotic susceptibility Follow-up - 13 C-UBT 29 & 57 days post therapy -both tests needed to be negative to = eradication OBMT vs OAC, Laine et al.

28 Laine L et al. Am J Gastroenterol 2003;98:562-67 BIDBID QIDQID OBMT vs OAC, Laine et al. * NNS * * MITT = modified intent to treat n=138n=137

29 Clarithromycin Resistance Resistance rates as high as 20% 1 In vitro cross-resistance with macrolides can occur after one exposure 1 Pre-treatment resistance has negative impact on efficacy by a mean of 55.4% 2 No strategy overcomes resistance 1 Megraud F. Gut 2004;53:1374-84 2 Meyer JM et al. Ann Intern Med 2002;136:13-24

30 Laine L et al. Am J Gastroenterol 2003;98:562-67 OBMT vs OAC, Laine et al. Comparison: Eradication Rates and Pretreatment MICs * p < 0.05

31 Metronidazole Resistance In vitro resistance varies with test method –39% (690/1768) E-test –25.7% (317/1234) agar dilution Strategies to combat resistance –longer duration, PPI-BMT, high dose MTZ Meyer JM et al. Ann Intern Med 2002;136:13-24

32 Objectives –to assess the efficacy and safety BMT + omeprazole in the eradication of H. pylori –to investigate effect of MTZ resistance and disease type (peptic ulcer vs. non-ulcer dyspepsia) on the eradication rates O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20 OBMT, O’Morain et al.

33 Methods –open label, international multicenter –dyspepsia +/- PUD, testing positive for H. pylori by 13 C-UBT –histology and ⁄ or culture of 5 pre-treatment biopsies –3 BMT QID + OME 20mg BID X 10 days –29 & 57 days post therapy 2 negative 13 C-UBT after treatment O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20 OBMT, O’Morain et al.

34 DU = duodenal ulcer O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20 OBMT, O’Morain et al. MITT = modified intent to treat N = 170 n = 39 / 43

35 H. pylori eradication with LAC StudyDuration%Eradication (ITT) M93-13114 D86% (n=55) M95-39214 D83% (n=70) M95-399* (Fennerty et al) 14 D82% (n=126) 10 D81% (n=135) Combined82% (n=386) Prevpac ® Package Labeling August 2004 Fennerty MB et al. Arch Intern Med 1998;158:1651-56 LAC = lansoprazole, amoxicillin, clarithromycin * NNS

36 H. pylori eradication with RAC Vakil N, et al. Aliment Pharmacol Ther 2004; 20: 99–107 Intent to Treat Eradication Rates RAC = rabeprazole, amoxicillin, clarithromycin OAC = omeprazole, amoxicillin, clarithromycin 73% n = 187n = 166 n = 177 / 179

37 DU healing with histamine-2 receptor antagonist (H2RA) vs. H2RA based quadruple therapy Bismuth subsalicylate Patients were assessed for H. pylori infection via: – 13 C UBT –serology (IgG) –culture –histologic evaluation Low eradication rates (81%) Graham DY, et al Annals of Internal Medicine 1991:115:266-269. BMT + H2RA, Graham et al.

38 Case CV - H. pylori Eradication Therapy Greatest eradication rates with quadruple therapy. 10-day regimen is effective. Equivalent compliance between quadruple and triple therapy. PCN allergy.

39 Pylera Product Information

40 Pylera™ Product Information Pylera contains the following in each capsule: –metronidazole 125 mg –tetracycline 125 mg –bismuth subcitrate potassium 140 mg 3-in-1 capsule available with these ingredients in the US Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

41 Pylera + omeprazole is indicated for the eradication of H. pylori in: –H. pylori infected patients and –patients with active or a history (within 5 years) of duodenal ulcer Recommended Dosage –3 Pylera capsules QID after meals –omeprazole 20 mg BID with breakfast and supper Pylera Indication Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

42 MTZ has been shown to be carcinogenic in mice and rats Unnecessary use of the drug (Pylera) should be avoided and it should be reserved for the conditions described in the indication Precaution mild leukopenia, but no persistent hematologic abnormalities attributable to MTZ have been observed Pylera Black Boxed Warning Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

43 Known hypersensitivity or intolerance to: –bismuth subcitrate potassium –metronidazole or other nitroimidazoles –tetracyclines –components of the formulation Renal or hepatic impairment Pregnant and nursing women Pediatric patients Pylera Contraindications Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

44 Metronidazole –seizures –peripheral neuropathy characterized mainly by numbness or paresthesia of an extremity –avoid alcohol throughout treatment and at least 1 day after treatment Bismuth –rare reports of neurotoxicity associated with excessive doses of various bismuth-containing products –reversible after discontinuation of drug Pylera Warning Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

45 Tetracycline –use in patients < 8 years old may cause permanent discoloration of teeth –pregnancy (Category D) and crosses the placenta –photosensitivity treatment should be stopped with first evidence of skin erythema –elevated BUN patients with significantly impaired renal function, higher serum levels of tetracycline may lead to azotemia, hyperphosphatemia, and acidosis Pylera Warning Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

46 Bismuth: darkening of tongue and/or black stool Metronidazole: history of blood dyscrasias Tetracycline: candidiasis Avoid tanning booths, use sunscreen Avoid alcohol Missed doses continuing dosing schedule until the medication is gone and do not take double doses If more than 4 doses are missed, the prescriber should be contacted Pylera Precautions Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

47 Pylera Drug Interactions Tetracycline: –prolonged INR in patients on warfarin –reduced absorption with antacids, including calcium, magnesium, aluminum. –reduced absorption with iron, zinc, multivitamins –concurrent use of may render oral contraceptives less effective and patients should be advised to use a different or additional form of contraception Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

48 Pylera Drug Interactions Metronidazole: –may increase lithium levels –Disulfiram reaction with alcohol –prolonged INR in patients on warfarin –metabolism may be increased by phenytoin or phenobarbital Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

49 Pylera Common Adverse Events Most common adverse events –Stool abnormality (15.6%) –Diarrhea (8.8%) –Dyspepsia (8.8%) –Abdominal Pain (8.8%) –Nausea (8.2%) –Headache (8.2%) –Taste perversion (4.8%) –Vaginitis (4.1%) Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

50 Commercial Available Products

51 Conclusion H. pylori is the major cause of DU and it should be eradicated in all patients testing positive H. pylori relationship with the development of MALT and gastric cancer As high as 93% (158/170) eradication rate of H. pylori when quadruple therapy is used 1 Eradication rates vary between triple and quadruple therapies 1 O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20


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