Overview of Helicobacter pylori Microbiology, Pathogenesis and

Treatment Options

Objectives - Case Based Presentations

1. To discuss the epidemiology, pathogenesis, and diagnosis of H. pylori

2. To highlight test and treat practice guidelines3. To compare and contrast clinical trial results

between quadruple and triple therapy4. To review antibiotic treatments

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.

Case MB – H. pylori General Information

• Describe the epidemiology of H. pylori.• Review the pathogenesis of H. pylori and

associated symptoms.

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

National Prescribing Patterns for Eradication

®2007 ZS Associates

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

• $6 billion / yr in health care costs due to peptic ulcer disease (PUD) 1

• Up to 93% cure rate quadruple therapy2

• 0-10% of ulcer recurrence after antibiotic (ABX) treatment3

• 1-3% re-infection rate after ABX treatment3

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

Immune and Inflammatory Response to Immune and Inflammatory Response to H. pyloriH. pylori

Inflammatory Response Immune Response

H. pylori

Mucosa

Tissue damage

Activated T cell

Adhesion of bacteria

Inflammatory Mediators

Activation

Recruitment

Gastric ulcer

• Majority of infected patients do not develop clinically significant disease1-3

• Significant manifestations1-3

– peptic ulcer disease (PUD)– gastric and duodenal ulcers

– chronic gastritis– mucosa associated lymphoid tissue (MALT)– gastric adenocarcinoma

1Houghton J, et al. Gastroenterology 2005;128;1567-15782Portal-Celhay C et al. Clin Sci 2006;110:305-314

3Helico Go MF. Aliment Pharmacol Ther 2002;16(Supp 1):3-15

H. pylori pathologic associations

Case MB – H. pylori General Information

• Demographics – Cambodian, inner city• Pathogenesis: immune and inflammatory

response contribute to symptoms

• 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

• 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

Diagnostic Test ComparisonDiagnostic Test Comparison

• Invasive / active tests• Noninvasive / passive tests1,2

• 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 (13C-UBT)

1Howden CW et al. Am J Gastroenterol 1998;93(12):2330-82 Gisbert JP et al. Helicobacter 2004;9(4):347-68

Diagnostic Test ComparisonDiagnostic Test Comparison

Testing Characteristics Serology1 UBT1 SAT2 Biopsy1

Sensitivity / Specificity§

85% / 79% 95% / 96% 96% / 97% 95% / 99%

Detects previous infection Yes No No No

Tests for eradication No Yes Yes Yes

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):2330-82 Gisbert JP et al. Helicobacter 2004;9(4):347-68

AGA Recommendations

Talley NJ et al. Gastroenterology 2005;129:1756-1780

Dyspepsia without GERD or NSAIDs

Age ≤ 55 andNo 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

Fails

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

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

• 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

Case # CV - Case # CV - H. pyloriH. pylori Eradication Therapy 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.

Case CV - Case CV - H. pyloriH. pylori Eradication Therapy Eradication Therapy

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

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, 2nd Edition, 1955

ANTIBIOTIC MOA1-3 DYNAMICS1-3 RESISTANCE3

Metronidazole (MTZ) DNA synthesis Static +/- cidal Pre-treatment MIC does not always correlate with treatment outcomes

Tetracycline (TCN) RNA synthesis Static +/- cidal Rare

Clarithromycin (CLAR) RNA synthesis Static Pre-treatment MIC does not always correlate with treatment outcomes

Amoxicillin (AMOX) Cell wall Cidal Rare

Antibiotic PharmacodynamicsAntibiotic Pharmacodynamics

3 Helicobacter pylori: Physiology and Genetics. ASM Press 2001

1 Micromedex 2006, Thomson Healthcare2 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

Bismuth

• Bismuth minimally absorbed transmucosally• Considered a topical agent

– antiseptic agent1

– prevents bacterial adhesion– inhibits urease, phospholipase, and proteolytic activity

and is synergistic with antibiotics1,2

– lyse H. pylori near the gastric surface3

1 Megraud et al. Aliment Pharmacol Ther 2003;17:1333-432deBoer WA. Expert Opin Investig Drugs 2001:10;8,1559-1566

3 Klotz U. Clin Pharmacokinet 2000;38:243-70

• 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 ± PPI1-4

• Up to 93% compliance, >75% medication taken3

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

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

• Objective 10 day therapy– 3 BMT (triple capsule) QID + omeprazole (O) 20 mg BIDvs.– 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.

Laine L et al. Am J Gastroenterol 2003;98:562-67

• Baseline H. pylori testing– 13C-urea breath test– antral and body biopsies– histology and/or culture– antibiotic susceptibility

• Follow-up - 13C-UBT 29 & 57 days post therapy- both tests needed to be negative to = eradication

OBMT vs OAC, Laine et al.

Laine L et al. Am J Gastroenterol 2003;98:562-67

BID

QID

OBMT vs OAC, Laine et al.OBMT vs OAC, Laine et al.

* NNS

* *

MITT = modified intent to treat

n=138 n=137

Clarithromycin Resistance

• Resistance rates as high as 20%1

• In vitro cross-resistance with macrolides can occur after one exposure1

• Pre-treatment resistance has negative impact on efficacy by a mean of 55.4%2

• No strategy overcomes resistance

1 Megraud F. Gut 2004;53:1374-842 Meyer JM et al. Ann Intern Med 2002;136:13-24

Laine L et al. Am J Gastroenterol 2003;98:562-67

OBMT vs OAC, Laine et al.OBMT vs OAC, Laine et al.

Comparison: Eradication Rates and Pretreatment MICsComparison: Eradication Rates and Pretreatment MICs

* p < 0.05

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

• 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.

• Methods– open label, international multicenter– dyspepsia +/- PUD, testing positive for H. pylori by 13C-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 13C-UBT after

treatment

O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20

OBMT, O’Morain et al.

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

H. pylori eradication with LAC

Study Duration %Eradication (ITT)

M93-131 14 D 86% (n=55)M95-392 14 D 83% (n=70)

M95-399*(Fennerty et al)

14 D 82% (n=126)10 D 81% (n=135)

Combined 82% (n=386)

Prevpac® Package Labeling August 2004Fennerty MB et al. Arch Intern Med 1998;158:1651-56

LAC = lansoprazole, amoxicillin, clarithromycin

* NNS

H. pylori eradication with RAC

Vakil N, et al. Aliment Pharmacol Ther 2004; 20: 99–107

Intent to Treat Eradication Rates

RAC = rabeprazole, amoxicillin, clarithromycinOAC = omeprazole, amoxicillin, clarithromycin

73%

n = 187 n = 166 n = 177 / 179

• DU healing with histamine-2 receptor antagonist (H2RA) vs. H2RA based quadruple therapy

• Bismuth subsalicylate• Patients were assessed for H. pylori infection via:

– 13C 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.

Case CV - Case CV - H. pyloriH. pylori Eradication Therapy Eradication Therapy

• Greatest eradication rates with quadruple therapy.

• 10-day regimen is effective.• Equivalent compliance between

quadruple and triple therapy.• PCN allergy.

Pylera Product Information

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

• 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

• 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

• 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

• 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

• 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

• 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

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

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

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

Commercial Available Products

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 used1

• Eradication rates vary between triple and quadruple therapies

1 O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20