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 guidelines
3. To compare and contrast clinical trial results
between quadruple and triple therapy
4. 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 midepigastric, 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
Economics of H. pylori
• $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
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 H. pylori
Gastric ulcer
H. pylori
Adhesion of bacteria
Mucosa
Inflammatory
Mediators
Tissue damage
Activation
Activated T cell
Recruitment
Inflammatory Response
Immune Response
H. pylori pathologic associations
• Majority of infected patients do not develop clinically
1-3
significant disease
1-3
• Significant manifestations
– 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
3Helico Go MF. Aliment Pharmacol Ther 2002;16(Supp 1):3-15
Case MB – H. pylori General
Information
• Demographics – Cambodian, inner city
• Pathogenesis: immune and inflammatory
response contribute to symptoms
Case SH – H. pylori Diagnostic Tests
• 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.
Diagnostic 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):2330-8
2 Gisbert JP et al. Helicobacter 2004;9(4):347-68
Diagnostic Test Comparison
Serology1
Testing Characteristics
§
Sensitivity / Specificity
UBT1
SAT2
85% / 79% 95% / 96% 96% / 97%
Biopsy1
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):2330-8
2 Gisbert JP et al. Helicobacter 2004;9(4):347-68
AGA Recommendations
Dyspepsia without GERD or NSAIDs
Age >55 or
Alarm Features Present
Age ≤ 55 and
No Alarm Features
EGD
Test for H. pylori
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
Positive
Negative
PPI Trial 4-6 Weeks
American Gastroenterology Association (AGA)
Talley NJ et al. Gastroenterology 2005;129:1756-1780
Treat for H. pylori
Fails
Fails
PPI Trial 4 Weeks
Fails
Reassurance, Reassess Diagnosis
Consider EGD
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
Case SH – H. pylori Diagnostic Tests
• 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 # 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.
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.
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 Pharmacodynamics
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
Susceptibility testing of H. pylori for MTZ has not been standardized. No interprative criteria have been
established for testing metronidazole against H. Pylori
1
Micromedex 2006, Thomson Healthcare
2 AHFS Drug Information 2005; 854-864
3
Helicobacter pylori: Physiology and Genetics. ASM Press 2001
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
2
1 Megraud et al. Aliment Pharmacol Ther 2003;17:1333-43
deBoer WA. Expert Opin Investig Drugs 2001:10;8,1559-1566
3
Klotz U. Clin Pharmacokinet 2000;38:243-70
H. pylori eradication with BMT
• 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
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
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
n=170
n=138
3 O’MorainC et al. Aliment Pharmacol Ther 2003;17:415-20
4 Laine L et al. Am J Gastroenterol 2003;98:562-67
OBMT vs OAC, Laine et al.
• 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.
• 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
Laine L et al. Am J Gastroenterol 2003;98:562-67
OBMT vs OAC, Laine et al.
Q
I
D
n=138
B
I
D
n=137
*
*
* NNS
MITT = modified intent to treat
Laine L et al. Am J Gastroenterol 2003;98:562-67
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;53:1374-84
2 Meyer JM et al. Ann Intern Med 2002;136:13-24
OBMT vs OAC, Laine et al.
Comparison: Eradication Rates and Pretreatment MICs
* p < 0.05
Laine L et al. Am J Gastroenterol 2003;98:562-67
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
OBMT, O’Morain et al.
• 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.
N = 170
n = 39 / 43
DU = duodenal ulcer
MITT = modified intent to treat
O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20
H. pylori eradication with LAC
Study
Duration
%Eradication (ITT)
M93-131
M95-392
14 D
14 D
86% (n=55)
83% (n=70)
M95-399*
14 D
10 D
82% (n=126)
81% (n=135)
(Fennerty et al)
Combined
82% (n=386)
* NNS
LAC = lansoprazole, amoxicillin, clarithromycin
Prevpac® Package Labeling August 2004
Fennerty MB et al. Arch Intern Med 1998;158:1651-56
H. pylori eradication with RAC
Intent to Treat Eradication Rates
73%
n = 187
RAC = rabeprazole, amoxicillin, clarithromycin
OAC = omeprazole, amoxicillin, clarithromycin
n = 166
n = 177 / 179
Vakil N, et al. Aliment Pharmacol Ther 2004; 20: 99–107
BMT + H2RA, Graham et al.
• 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.
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.
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 Indication
• 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 Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
Pylera Black Boxed Warning
• 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 Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
Pylera Contraindications
• 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 Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
Pylera Warning
• 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 Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
Pylera Warning
• 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 Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
Pylera Precautions
•
•
•
•
•
•
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 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