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Objectives - Case Based Presentations

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Presentation on theme: "Objectives - Case Based Presentations"— Presentation transcript:

1 Overview of Helicobacter pylori Microbiology, Pathogenesis and Treatment Options

2 Objectives - Case Based Presentations
To discuss the epidemiology, pathogenesis, and diagnosis of H. pylori To highlight test and treat practice guidelines To compare and contrast clinical trial results between quadruple and triple therapy To review antibiotic treatments OPENING SLIDE – Discuss how the presentation will review a new and unique 3:1 deliver system, greatest efficacy of any product on the market, lowest pill burden with these high eradication rates, good compliance, and low cost. Discuss that the bismuth does not contain ASA and why is this product needed. This disease is not getting any better we need to continue to address how it is developed and attacked. Goal is test and treat for PCPs. Stress that MTZ pre-treatment MIC values do not correlate with treatment outcomes. Stress that CLAR pre-treatment MIC values do correlate with poor treatment outcomes due to resistance.

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. Setting up the remainder slides for general information on HP. Epidemiology and Pathologic Associations. The patients pain partially relieved by CaCO3 tablets and no bloating.

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 FYI. Unclear why only ½ of world population is infected give the prevalence Approximately 30% prevalence in US High prevalence in Asian Countries African Americans (RR ) and Hispanics (RR ) have higher rates High concordance rate with Hepatitis A Increased number of siblings, crowded living conditions younger age lower socioeconomic status ethnicity geographic location underdeveloped countries genetics? Gastro-oral (vomit) Go MF. Aliment Pharmacol Ther 2002;16(Supp 1):3-15 Go MF. Aliment Pharmacol Ther 2002;16(Supp 1):3-15

6 National Prescribing Patterns for Eradication
This is 2006 national prescription claims data for branded HP treatments from IMS via ZS Associates. ®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 patients 1975: Gram negative bacteria in 80% of GU’s (Pseudomonas) 1983: Warren and Marshall characterize H. pylori Nobel prize in 2005

8 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 This might be a slide to hit quickly. Resistance could impact the economics. According to 2 different studies in the Alaskan Indian Population the re-infection rate is very high. Dr Ben Gold out of the CDC has been working on this for many years. Possibly due to several issues – families, water, food, sanitation, etc. Dr Gold is starting new epi and tx studies looking at if a family member is positive and requires retx, they would provide tx to the whole family, even if the family does not test positive. 1 Sonnenberg A et al. Am J Gastroenterol 1997;92: 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
Pylera Training Slides v 55 Immune and Inflammatory Response to H. pylori Gastric ulcer H. pylori Adhesion of bacteria Mucosa Inflammatory Mediators Activation This is a very technical slide. You might want to spend sometime on this area. A lot of work is going into this area – extragastric symptoms associated with HP. Induction of mucosal immune response inflammatory recruitment and activation interleukin Production of substances toxic to local area Increased gastrin, gastric acid secretion, and decreased antral somatostatin Note that B-cells are not listed on the figure, but the B-cells do play a role in the immune reaction. Immune reaction and response to infectious agents depend on a complex network involving the host immune system, the microorganism and the environment (e.g. dietary factors). H. pylori infect the human gastric mucosa causing tissue injury and, in some individuals clinical disease. H. pylori acquisition is associated with rapid host recognition in the form of both innate and acquired immune responses by the host. This response is manifested by the release of cytokines by the epithelial cells and infiltration of the gastric mucosa by neutrophils, macrophages and lymphocytes.6,8,9,10 \ Host responses to H. pylori infection H. pylori is equipped with an impressive range of mechanisms that facilitate colonization and infection of the host. The bacterium uses these mechanisms to evade or down regulate both the innate and acquired host immune system.6 (see Chapter 2, Helicobacter pylori infection, immunity) The recognition of TLRs by the gastric epithelial cells act as a warning system against invading pathogens. Thus far, most of the studies on innate immune responses to H. pylori infection have focused on TLR4. However, recent data indicates that gastric epithelial cells also recognize and respond to H. pylori infection at least in part via TLR2 and TLR5.5,11 Normally, activation of the TLR signal leads to the initiation of numerous functions in host defense. The ability of H. pylori to induce inflammation suggests that the bacterium may be capable of evading detection by the innate immune system. The mechanisms by which H. pylori is able to avoid immune recognition are still unclear.12 Acquired (adaptive) immunity Acquired immune responses towards H. pylori infection have also been identified. Upon infection with H. pylori, host epithelial cells release cytokines such as IL. These cytokines are involved in the recruitment of macrophages, neutrophils, B and T lymphocytes to the site of inflammation. These cells enhance the immune reaction even more by secretion of other inflammatory mediators, such as INF and TNF.6,9,11,12 The number of immunoglobulin A (IgA)-producing cells increases during H. pylori infection. IgG- and IgM-producing cells are also detected.7 The immune reaction against H. pylori is further characterized by an oxidative burst that creates damage to the gastroduodenal epithelium. This damage is believed to cause most of the inflammation that is associated with H. pylori infection.9 PYLERA TRAINING MANUAL Activated T cell Tissue damage Recruitment Inflammatory Response Immune Response 9

10 H. pylori pathologic associations
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 Good slide to know. Provides good discussions with the physicians. H. Pylori is "thought to be a" major cause of DU.  Some experts believe that it's not so clear cut. Majority of infected patients do not develop clinically significant disease due to the following mechanisms: Bacterial virulence factors Host or environmental factors Mechanical damage Alteration in gastric secretion Spontaneous clearance is uncommon Duodenal Ulcer- Cause of more than 90% of DU Gastric Ulcer- May cause 50-80% of GU Gastritis- Very common association, esp with nonulcer dyspepsia, 100% of infected patients develop chronic gastritis Neutrophilic infiltrate Approximately 80% of patients remain asymptomatic Differing physiologic effects depending on the affected area of the stomach Antral predominant =  acid secretion (gastrin) Corpus predominant = atrophy and ↓ acid secretion Go MF. Aliment Pharmacol Ther 2002;16(Supp 1):3-15 Hardin FJ et al. Hosp Phys 2002;May:23-31 Gastric Adenocarcinoma- Strong assoc with HP Intestinal form is decreasing in incidence. It occurs in older patients and is associated with other environmental factors. Diffuse form occurs in younger patients, is more severe, and has not had a decrease in incidence Overall decrease in cancer incidence is due to reduction in H pylori infection in developed countries, as well as faster disappearance of Cag A + strains HP may trigger the onset of auto-immune atrophic gastritis in some patients with pernicious anemia Profound acid suppression affects the pattern and distribution of gastritis favoring corpus-dominant gastritis and may accelerate the process of loss of specialized glands leading to atrophic gastritis. H. pylori eradication halts the extension of atrophic gastritis and may lead to regression of atrophy. The effect on intestinal metaplasia is uncertain. Maastricht Consensus Report 1Houghton J, et al. Gastroenterology 2005;128; 2Portal-Celhay C et al. Clin Sci 2006;110: 3Helico Go MF. Aliment Pharmacol Ther 2002;16(Supp 1):3-15

11 Case MB – H. pylori General Information
Demographics – Cambodian, inner city Pathogenesis: immune and inflammatory response contribute to symptoms Good opportunity to wrap up with the physicians. How would they handle the case? What would they do with this patient? Diagnostics, treat without testing, use PPI empirically, Does this sound like a patient in your area? Do you have differences in response and symptoms based on the patient ethnic origin?

12 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.

13 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.

14 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) The methods of diagnosis for H. pylori infection have been traditionally divided into invasive and noninvasive. The invasive techniques require the demonstration of the organism on biopsy samples with endoscopy and biopsy. The noninvasive testing methods detect the presence of antibodies made against H. pylori and do not require endoscopic examination. Antibody test (rapid, qualitative test), accuracy less than other tests, least expensive Stool antigen test accuracy approaching breath test, ?Intermediate cost Urea breath test, very accurate, some extra time, expense required 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 Characteristics
Serology1 UBT1 SAT2 Biopsy1 Sensitivity / Specificity§ 85% / 79% 95% / 96% 96% / 97% 95% / 99% Detects previous infection Yes No Tests for eradication Low cost $$ $$$ $$$$ Numerous commercially available tests measure IgG antibodies to H. pylori Simple, relatively inexpensive Accuracy varies widely (by test, location) Sensitivity: 85% Specificity: 79% False positive tests, after therapy (72% positive at 3-4 yrs) atrophic gastritis, intestinal metaplasia Loy et al. AJG 1996;91:1138; Cutler et al. Am J Med 1998;105:18 Laine L et al. Ann Intern Med 1998;129: Background: Proton-pump inhibitor therapy may cause false-negative results on Helicobacter pylori diagnostic testing. Objective: To determine the frequency and duration of conversion of urea breath test results from positive to negative in patients given a proton-pump inhibitor. Setting: Two urban university gastroenterology clinics. Patients: Patients infected with H. pylori who had positive results on urea breath tests. Intervention: Lansoprazole, 30 mg/d for 28 days. Measurements: The urea breath test was repeated at 28 days. If the results were negative, testing was repeated 3, 7, 14, and 28 days after completion of therapy until the results reverted to positive. Results: 31 (33%) of 93 patients in whom H. pylori was not eradicated had a negative breath test result while receiving lansoprazole. The proportions of patients whose breath test results were positive after completion of lansoprazole therapy were 91% (95% CI, 83% to 96%) at 3 days, 97% (CI, 90% to 99%) at 7 days, and 100% (CI, 96% to 100%) at 14 days. * 31 patients receiving PPI therapy had a negative test result, 3 were not tested at day 3 after therapy was stopped, and 2 more dropped out of the study before day 7 after therapy was stopped. Conclusion: Patients should not receive proton-pump inhibitors for 2 weeks before receiving the urea breath test for H. pylori infection. §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 Dyspepsia without GERD or NSAIDs
AGA Recommendations Dyspepsia without GERD or NSAIDs Age >55 or Alarm Features Present Age ≤ 55 and No Alarm Features Test for H. pylori EGD Negative Positive 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 PPI Trial 4-6 Weeks Treat for H. pylori Fails Fails 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 Gastroenterology 2005;129: ACG GUIDELINES DIFFER High prevalence = immigrants Who should we consider testing? Who benefits? Testing only if treatment is intended “Test and treat” vs. acid suppression Active PUD Past history of PUD Gastric MALT lymphoma Patients age < 55 with no alarm symptoms Am J Gastroenterol 2005;100: Am J Gastroenterol 1998;93(12):2330-8 At this point it would be good to discuss the following definitions: Dyspepsia uninvestigated symptom Non-Ulcer Dyspepsia diagnosis after full evaluation Gastritis histologic diagnosis (H. pylori). Often applied to endoscopic findings not a symptom or cause of symptoms Dyspepsia Annual prevalence approximately 25% Accounts for 2-5% of all primary care visits Major impact on QOL, direct/indirect costs A test-and-treat approach was recommended in adult patients below 45 years of age – the age cut-off may vary locally – presenting in primary care with persistent dyspepsia having excluded those with predominantly GERD, NSAID use or with alarm symptoms. T&T was as effective but less expensive than endoscopy in patients not at risk of malignant disease and likely to be more effective than acid suppressive tx NUD small benefit of eradicating H. pylori in this context. Need to take into account the region of the country and prevalence rate. Empirical anti-secretory treatment may be less costly if the infection rate is less than 20%. THIS MIGHT BE AREA OF controversy Decrease costs avoid expensive tests (e.g., EGD), even in a minority of patients Small, if any, benefit in symptoms most patients will have recurrent symptoms after H. pylori therapy (most do not have ulcer disease) Maastricht Consensus Report Moayyedi P, et al BMJ 2000;321:659 Lassen AT, et al Lancet 2000;356:455 Talley et al. Gastro 2005;129:1756 PPI Trial 4 Weeks Fails Reassurance, Reassess Diagnosis American Gastroenterology Association (AGA) Consider EGD Talley NJ et al. Gastroenterology 2005;129:

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 years underwent endoscopy 1/3 ages 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” Large health plan new antisecretory claim, H. pylori test, or endoscopy continuous enrollment from 2001 – 2004 Medical claim for PUD, NUD, GERD Howden CW, et al. Am J Manag Care. 2007;13:37-44

18 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. Good point here to determine what test physicians use most frequently? Do physicians test for susceptibilities? Do physicians test for eradication?

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. Make sure you highlight that this is bismuth subcitrate and not bismuth subsalicylate. Pylera is a new approach and is the only product available that has all antibiotics in one capsule. Make sure that they know that the omeprazole is not in the capsule. Patients do not have to take individual components like those in PrevPac or Helidac.

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, 2nd Edition, 1955

22 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 Rare Clarithromycin (CLAR) Static Amoxicillin (AMOX) Cell wall Cidal MTZ MOA Reduction of the nitro group leads to the formation of free radicals which leads to DNA damage and lethal DNA mutations Aerobic and mammalian cells do not have the reductive capacity to activate nitroimidazoles, therefore the lack of susceptibility to other bacteria etc. H. pylori possesses several anaerobic like enzymes capable of converting imidazoles. Remember HP is a microaerophile. Some of these enzymes are listed below: oxygen-insensitive nitroreductase (rdxA) This is probably the most important one. pyruvate:flavodoxin oxidoreductase (porGDAB) 2-oxoglutarate:acceptor oxidoreductase (oorDABC) These enzymes are important when one considers the black box warning on MTZ. Possible mechanism of action for the mutations seen in animal models. Excellent diffusion through gastric mucosa, may further increase its antibacterial activity esp in cases of in vitro resistance The combination of Metronidazole and its hydroxy metabolite or either compound plus tetracycline or amoxicillin has demonstrated synergism in vitro against H pylori. Goodman & Gilman's The Pharmacological Basis of Therapeutics Time dependent killing concentration independent drug concentration should constantly be 4-5 X greater than the minimum inhibitory concentration (MIC) clarithromycin (CLAR) and amoxicillin Concentration dependent killing (MTZ) maximizing the drug concentration as high as possible above the MIC is MOST important 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; 3 Helicobacter pylori: Physiology and Genetics. ASM Press 2001

23 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 Bismuth absorbed transmucosally in the stomach, however about % of dose is absorbed May also help to decrease bacterial load Absorption increases with an increase in pH by a factor of 7 when given with a PPI Bismuth subsalicylate interferes with the integrity of the Helicobacter pylori cell and prevents adhesion of the organism to the gastric epithelium. Another mechanism by which bismuth compounds interferes with H pylori is by inhibiting its urease, phospholipase, and proteolytic activity (Walsh & Peterson, 1995b). By eliminating H pylori associated with peptic ulcers, the esophageal lesion healing rate is improved and the chance of recurrence is decreased (Lambert, 1991; Gorbach, 1990e; McNulty, 1990; Eberhardt & Kasper, 1990); (Anon, 1994). The in vitro minimum inhibitory concentration (MIC) of BISMUTH SUBSALICYLATE for H pylori ranges from 2 to 32 mcg/mL (McNulty, 1990; Lambert, 1991), and these concentrations are achieved locally in the gastric mucosa (McNulty, 1990). Bismuth is poorly absorbed systemically, and bismuth particles are found precipitated in the gastric mucus and near the bacteria due to local absorption. Bismuth works synergistically with antibiotics and when one drug is removed in the bismuth based triple therapy for the treatment of H pylori, the results are very disappointing. Only after combining the three compounds together were adequate cure rates documented. de Boer W. A novel therapeutic approach for Helicobacter pylor infection: the bismuth-based triple therapy moocapsule. Expert Opin Investig Drugs 2001 ;10:8, 1 Megraud et al. Aliment Pharmacol Ther 2003;17: 2deBoer WA. Expert Opin Investig Drugs 2001:10;8, 3 Klotz U. Clin Pharmacokinet 2000;38:243-70

24 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 days ± PPI1-4 Up to 93% compliance, >75% medication taken3 UNIQUE 3-IN-ONE FORMULATION Pylera that is written on the Pylera Capsule is a Red-Ink / Iron Oxide Based and is not of high enough to be of concern. The capsule cannot be broken and administered with food due to the interaction between BI and TCN. 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 H. pylori eradication with BMT +/- PPI
Please note compliance and eradication rates. DeBoer studies used ITT and DeBoer used BMT only, DeBoer 2 is BMT + lansprazole. Also, Laine and O’Morain used MITT eradication rates 1 de Boer 53 pts given 2 Pylera™ capsules QID x10 days No PPI or H2RA given during study Notice dose is 2/3 the indicated dose. Also this formulation of Pylera contained 60 mg colloidal bismuth subcitrate not the 140mg of biskalcitrate 53 pts given BMT 2 triple capsules QID x10 days open label study, no control group Cure rates: ITT = 94.4% (50/53) PPG = 97.9% (46/47) 90.4% (47/52) pts reported 100% compliance 2 de Boer 66 pts given BMT 2 triple capsules QID x 7 days and lansoprazole 30 mg BID ITT = 86% (56/65) PPG = 88% (56/64) 92% (59/64) pts reported 100% compliance n=53 n=65 n=170 n=138 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

26 OBMT vs OAC, Laine et al. Objective 10 day therapy Design
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) LAC (lansoproazole, amoxicillin, clarithromycin) 275 pts randomized to BMT 3 triple capsules QID (138) and omeprazole 20 mg BID or OAC (137) BID x 10 days 3 Pylera caps QID plus ome 20 bid vs Amox 1000mg/ clar 500mg/ Ome 20 mg BID All DU pts Cure rates: ITT: OBMT 87.7% (121/138) vs OAC 83.2% (114/137) p=.29 PPG: OBMT 92.5% (111/120) vs OAC 87.1% (108/124) p=.16 Compliance measured as >75% of drug taken Efficacy Testing Enrolled if positive C13 breath test, and confirmed with histology. Eradication defined as 2 negative C13 breath tests at 4 wks and 8wks post end of tx. Pts excluded if used PPi w/in 15d or H2RA or sucralfate w/in 7d of baseline. Post tx meds unknown. Laine L et al. Am J Gastroenterol 2003;98:562-67

27 OBMT vs OAC, Laine et al. Baseline H. pylori testing Follow-up
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 LAC (lansoproazole, amoxicillin, clarithromycin) 275 pts randomized to BMT 3 triple capsules QID (138) and omeprazole 20 mg BID or LAC (137) BID x 10 days 3 Pylera caps QID plus ome 20 bid vs Amox 1000mg/ clar 500mg/ Ome 20 mg BID All DU pts Cure rates: ITT: OBMT 87.7% (121/138) vs OAC 83.2% (114/137) p=.29 PPG: OBMT 92.5% (111/120) vs OAC 87.1% (108/124) p=.16 Compliance measured as >75% of drug taken Efficacy Testing Enrolled if positive C13 breath test, and confirmed with histology. Eradication defined as 2 negative C13 breath tests at 4 wks and 8wks post end of tx. Pts excluded if used PPi w/in 15d or H2RA or sucralfate w/in 7d of baseline. Post tx meds unknown. Exclusion Criteria antibiotics or bismuth within 30 days PPIs or H2RAs within 15 days sucralfate or misoprostol within 7 days chronic NSAID use (except ASA 325 mg) contraindication to study drugs pregnancy/lactation serious medical conditions clinically significant lab alterations Laine L et al. Am J Gastroenterol 2003;98:562-67

28 OBMT vs OAC, Laine et al. BID QID n=138 n=137 * * * NNS
Note the comparable eradication rates and compliance rates n=138 n=137 * * * NNS MITT = modified intent to treat Laine L et al. Am J Gastroenterol 2003;98:562-67

29 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 Resistance rates as high as 20% higher in areas of high macrolide usage for resp infections In vitro resistance equals in vivo resistance in contrast to metronidazole In tx failures with CLAR, a resistant bug has likely been selected for eradication Unsure if drugs have the same potential to select resistance Resistance is chromosomally mediated with point mutations A2142G and A2143G, A2142G is the most important. Many other mutant strands are not viable and decreased binding by macrolides to ribosome Graham Gastroenterology 2000:118; and Megraud Gut 2004;53: McMahon et al. Ann Intern Med 2003;139:463-69 Helicobacter pylori: Physiology and Genetics. ASM Press 2001 There are no NCCLS standards for HP susceptibility testing. Only suggestions. Many flaws associated with in vitro testing Up to an 80% eradication rate of MTZ resistant strains in quadruple therapy, using MTZ Multi enzyme processes involved in free radical production , all or only some may have mutated to a resistant form therefore the large spread in MIC and inconsistent reporting 8 mcg/ml has been proposed by NCCLS. Lack of standardized testing NCCLS recommends agar dilution read at 3 days. HP a slow growing organism. Using an E-test may increase resistance by 40% Agar dilution time consuming and costly, high levels of false resistance rates with other methods. European standards are similar but there are differences. No set breakpoint, most studies use 8 µg/ml. In vitro levels may not reflect levels in the gastric mucosa. Resistant isolates can be rendered susceptible with a period of anaerobic incubation Only 1 wk quadruple therapy was equally effective in eradicating MTZ susceptible and resistant strains Study objectives: Objectives To estimate the prevalence of H. pylori resistance to antimicrobials in the US To characterize risk factors associated with H. pylori antimicrobial resistance To explore the association between drug utilization and antimicrobial resistance patterns over time Methods Surveillance of H. pylori Antimicrobial Resistance Partnership (SHARP) meta-analysis using patient level data submitted from 20 pharmaceutical companies patients with active or inactive PUD clarithromycin, metronidazole, and amoxicillin susceptibility centralized laboratory via agar dilution E-test clarithromycin susceptibility, pretreatment clarithromycin minimal inhibitory concentration (MIC), method used to test for metronidazole susceptibility, pretreatment metronidazole MIC, method used to test for amoxicillin susceptibility, and pretreatment amoxicillin MIC MIC of at least 32 g/mL indicated resistance. This resistance breakpoint has been correlated with treatment failures in patients receiving clarithromycin, metronidazole, and omeprazole In the analysis of resistance rates by risk factor, we did not use an intermediate category for clarithromycin or metronidazole. Isolates that fell into the intermediate range were classified as susceptible. Results for clarithromycin resistance were similar with either method. 10% clarithromycin 37% MTZ but there were higher results with E-Test (p=0.001) Year was a significant factor in the multivariable model for metronidazole; however, the rates were highly variable over time. Resistance was highest during the years when the E-test was used (1994–1996). An odds ratio of 1 indicates that the condition or event under study is equally likely in both groups. An odds ratio greater than 1 indicates that the condition or event is more likely in the first group. And an odds ratio less than 1 indicates that the condition or event is less likely in the first group. The odds ratio must be greater than or equal to zero. As the odds of the first group approaches zero, the odds ratio approaches zero. As the odds of the second group approaches zero, the odds ratio approaches positive infinity. Complicated by the lack of a standard in vitro method for determining susceptibility THESE STUDIES DID NOT INDICATE METHOD OF SUSCEPT WAS USED (E-TEST) NOR DID THEY ELUDE TO OBMT 4 DRUG THERAPY 2 recent meta-analyses showed that pretreatment metronidazole resistance predicts poor outcome after treatment with a metronidazole-containing regimen. In one analysis, which examined all metronidazole-containing regimens (24), resistance was found to reduce effectiveness by an average of 37.7% (CI, 29.6% to 45.7%). In the second analysis (26), nitroimidazole-containing triple therapy regimens achieved 90% eradication in patients with susceptible strains but less than 75% eradication in patients with resistant strains. Only quadruple-therapy regimens (a proton-pump inhibitor, bismuth, tetracycline, and metronidazole) given for at least 1 week were equally effective in treating metronidazole-susceptible and metronidazole-resistant strains (92%) Meyer JM Ann Intern Med 1 Megraud F. Gut 2004;53: 2 Meyer JM et al. Ann Intern Med 2002;136:13-24

30 Comparison: Eradication Rates and Pretreatment MICs
OBMT vs OAC, Laine et al. Comparison: Eradication Rates and Pretreatment MICs Clarithromycin resistant H. pylori eradication rates ITT: OAC 21%, p=0.004 11% CLAR resistance in the study group Metronidazole (MTZ) pre-treatment MIC no impact on trial outcome 88% eradication rate * p < 0.05 Laine L et al. Am J Gastroenterol 2003;98:562-67

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 There are no NCCLS standards for HP susceptibility testing. Only suggestions. Many flaws associated with in vitro testing Up to an 80% eradication rate of MTZ resistant strains in quadruple therapy, using MTZ Multi enzyme processes involved in free radical production , all or only some may have mutated to a resistant form therefore the large spread in MIC and inconsistent reporting 8 mcg/ml has been proposed by NCCLS. Lack of standardized testing NCCLS recommends agar dilution read at 3 days. HP a slow growing organism. Using an E-test may increase resistance by 40% Agar dilution time consuming and costly, high levels of false resistance rates with other methods. European standards are similar but there are differences. No set breakpoint, most studies use 8 µg/ml. In vitro levels may not reflect levels in the gastric mucosa. Resistant isolates can be rendered susceptible with a period of anaerobic incubation Helicobacter pylori: Physiology and Genetics. ASM Press 2001 Only 1 wk quadruple therapy was equally effective in eradicating MTZ susceptible and resistant strains Study objectives: Objectives To estimate the prevalence of H. pylori resistance to antimicrobials in the US To characterize risk factors associated with H. pylori antimicrobial resistance To explore the association between drug utilization and antimicrobial resistance patterns over time Methods Surveillance of H. pylori Antimicrobial Resistance Partnership (SHARP) meta-analysis using patient level data submitted from 20 pharmaceutical companies patients with active or inactive PUD clarithromycin, metronidazole, and amoxicillin susceptibility centralized laboratory via agar dilution E-test clarithromycin susceptibility, pretreatment clarithromycin minimal inhibitory concentration (MIC), method used to test for metronidazole susceptibility, pretreatment metronidazole MIC, method used to test for amoxicillin susceptibility, and pretreatment amoxicillin MIC MIC of at least 32 g/mL indicated resistance. This resistance breakpoint has been correlated with treatment failures in patients receiving clarithromycin, metronidazole, and omeprazole In the analysis of resistance rates by risk factor, we did not use an intermediate category for clarithromycin or metronidazole. Isolates that fell into the intermediate range were classified as susceptible. Results for clarithromycin resistance were similar with either method. 10% clarithromycin 37% MTZ but there were higher results with E-Test (p=0.001) Year was a significant factor in the multivariable model for metronidazole; however, the rates were highly variable over time. Resistance was highest during the years when the E-test was used (1994–1996). An odds ratio of 1 indicates that the condition or event under study is equally likely in both groups. An odds ratio greater than 1 indicates that the condition or event is more likely in the first group. And an odds ratio less than 1 indicates that the condition or event is less likely in the first group. The odds ratio must be greater than or equal to zero. As the odds of the first group approaches zero, the odds ratio approaches zero. As the odds of the second group approaches zero, the odds ratio approaches positive infinity. Complicated by the lack of a standard in vitro method for determining susceptibility THESE STUDIES DID NOT INDICATE METHOD OF SUSCEPT WAS USED (E-TEST) NOR DID THEY ELUDE TO OBMT 4 DRUG THERAPY 2 recent meta-analyses showed that pretreatment metronidazole resistance predicts poor outcome after treatment with a metronidazole-containing regimen. In one analysis, which examined all metronidazole-containing regimens (24), resistance was found to reduce effectiveness by an average of 37.7% (CI, 29.6% to 45.7%). In the second analysis (26), nitroimidazole-containing triple therapy regimens achieved 90% eradication in patients with susceptible strains but less than 75% eradication in patients with resistant strains. Only quadruple-therapy regimens (a proton-pump inhibitor, bismuth, tetracycline, and metronidazole) given for at least 1 week were equally effective in treating metronidazole-susceptible and metronidazole-resistant strains (92%) Meyer JM Ann Intern Med Meyer JM et al. Ann Intern Med 2002;136:13-24

32 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 170 pts given 3 Pylera™ capsules QID x10 days and omeprazole 20 mg BID Used current formulation and dosage for Pylera Cure rates: Intention to Treat: 93% (158/170) Per Protocol Group: 97% (142/146) No diff in the type of ulcer, or country of study 93% (40/43) pts with a MTZ resistant strain were cured this is the ITT group, 95% 38/40 in the PPG 95% (162/170) pts reported >75% compliance Compliance measured as >75% of drug taken O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20

33 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 170 pts given 3 Pylera™ capsules QID x10 days and omeprazole 20 mg BID Used current formulation and dosage for Pylera Cure rates: Intention to Treat: 93% (158/170) Per Protocol Group: 97% (142/146) No diff in the type of ulcer, or country of study 93% (40/43) pts with a MTZ resistant strain were cured this is the ITT group, 95% 38/40 in the PPG 95% (162/170) pts reported >75% compliance Compliance measured as >75% of drug taken O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20

34 OBMT, O’Morain et al. DU = duodenal ulcer
Cure rates: Modified Intention to Treat: 93% (158/170) Per Protocol Group: 97% (142/146) No diff in the type of ulcer, or country of study Pylera only indicated for DU, but other cure rates were GU = 100%, and NUD = 94%. 93% (40/43) pts with a MTZ resistant strain were cured this is the ITT group, 95% 38/40 in the PPG 95% (162/170) pts reported >75% compliance Compliance measured as >75% of drug taken DU = duodenal ulcer MITT = modified intent to treat O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20

35 H. pylori eradication with LAC
Study Duration %Eradication (ITT) M93-131 14 D 86% (n=55) M95-392 83% (n=70) M95-399* (Fennerty et al) 82% (n=126) 10 D 81% (n=135) Combined 82% (n=386) Lansoprazole 30 mg BID, Amox 1g BID, Clarith 500mg BID All pts had active DU documented by endoscopy and confirmed by histology or culture. Efficacy Testing Eradication defined as histological tests and cultures negative at 4 wks post end of tx. 113 pts given LAC BID x10 days vs. 103 pts given LAC BID x14 days Cure rates: Intention to Treat 10 vs 14 day: 81% (110/135) vs 82% (103/126) Per Protocol Group 10 vs 14 day: 84% (103/123) vs 85% (96/113) 14% (17/124) of strains were CLAR resistant 8/17 CLAR res pts were deemed a cure. 90% pts in both groups reported >90% compliance 38% vs 34% (10D v 14d) reported adverse events * NNS LAC = lansoprazole, amoxicillin, clarithromycin Prevpac® Package Labeling August 2004 Fennerty MB et al. Arch Intern Med 1998;158:

36 H. pylori eradication with RAC
Intent to Treat Eradication Rates 73% Background: The ideal duration of Helicobacter pylori treatment in the United States and whether eradication therapy is as successful in nonulcer dyspepsia as in peptic ulcer disease are controversial topics. Aim: This study compared the efficacy of 3-, 7- and 10- day triple therapies with rabeprazole to a 10-day omeprazole control triple therapy for the eradication of Helicobacter pylori in patients with and without peptic ulcer disease in the United States. Methods: This was a multicentre, double-blind, randomized, parallel-group trial. A total of 803 patients with H. pylori infection (determined by [13C]urea breath test and rapid urease test or culture) received either rabeprazole 20 mg b.d., amoxicillin 1000 mg b.d., and clarithromycin 500 mg b.d. for 3, 7, or 10 days, or 10 days of omeprazole 20 mg b.d. with the same antibiotic regimen (control). H. pylori status was assessed by [13C]urea breath test ‡6 weeks after completing treatment. Results: In intent-to-treat patients, the eradication percentages achieved for the rabeprazole-based treatments were: 3-day, 27% (95% confidence interval: 21%–34%); 7-day, 77% (95% confidence interval: 71%–83%); and 10-day, 78% (95% confidence interval: 72%–84%). The eradication percentage with the 10-day omeprazole-based treatment was 73% (95% confidence interval: 67%–79%). There was no statistically significant difference between the 7-day rabeprazole- based regimen and the 10-day rabeprazole- and omeprazole-based regimens. Conclusions: Seven-day therapy with rabeprazole, clarithromycin, and amoxicillin is similar in efficacy to 10-day therapies and had similar efficacy in patients with and without ulcer disease. n = 187 n = 166 n = 177 / 179 RAC = rabeprazole, amoxicillin, clarithromycin OAC = omeprazole, amoxicillin, clarithromycin Vakil N, et al. Aliment Pharmacol Ther 2004; 20: 99–107

37 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%) Contains prepackaged BMT therapy bismuth subsalicylate 262 mg tablets (8) requires chewing metronidazole 250mg tablets (4) tetracycline 500mg capsules (4) Four times daily for 14 days H2RA prescribed separately (BID) Contains bismuth subsalicylate. Subsalicylate has similar effects to aspirin (ASA). Objective To determine whether duodenal ulcer healing with H2-receptor antagonists was further accelerated by the addition of therapy to eradicate H. pylori infection Outcomes Primary endpoint:The rate of duodenal ulcer healing (H2RA vs. H2RA based quadruple therapy) Safety measures: Assessed by adverse events Ulcers were identified by endoscopy entry and after 2, 4, 8, 12, and 16 weeks of therapy Ulcer status evaluated until healing achieved or until the end of the study at 16 weeks Drug Therapy (14 days) bismuth subsalicylate tablets (2 QID) tetracycline 500 mg (QID) metronidazole 250 mg tablets (TID) ranitidine 300 mg HS Patients were assessed for H. pylori infection via: C13 UBT serology (IgG) culture histologic evaluation Eradication no evidence of H. pylori by any test > 1 month after stopping triple therapy Ranitidine alone (n=52) 84% healing at 16 weeks Quadruple therapy (n=53) 98% healing at 16 weeks 51 of the 53 patients H. pylori positive 81% eradication (43 patients) 1 patient non compliant in quadruple therapy vs. 5 in ranitidine group >70% of medication taken Graham DY, et al Annals of Internal Medicine 1991:115:

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. What therapies are you using first and second line?

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 It is dosed 3 capsules 4 times a day. Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

41 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 The omeprazole should be taken twice a day with PYLERA™ after the morning and evening meal for 10 days. Clinicians might have to dose the omeprazole longer if they believe the patient has an ulcer. This allows the ulceration to heal. Typically, the omeprazole will be dosed for a total duration of between 6-8 weeks if there is an ulcer. Also, remember the PPI will need to be discontinued for at least 2 weeks before retesting for eradication. Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

42 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 AHFS Drug Information 2006,84:04.04 6 different studies in mice in which MTZ was administered intermittently (every 4 wks). Doses 1500mg/m2 (3 X recommended human dose). A statistical increase in the incidence of malignant liver tumors in male mice. In long term studies significant increase in various neoplasms in females – mammary and hepatic. Breast and colon cancer have been reported in Crohn’s disease who have been treated with high doses of MTZ (200 – 1200mg daily for 1 – 24 months). for prolonged periods. However, a direct causal relationship with the drug has not been established and patients with Crohn’s disease are known to have an increased incidence of GI and certain extraintestinal cancers. No excess chromosomal aberrations were observed in circulating human lymphocytes in patients receiving MTZ therapy for 8 months. Although there is not evidence to date that long-term use of MTZ in humans is associated with an increased risk of mutagenicity or carcinogenicity, some clinicians suggest more studies are needed. Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

43 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

44 Pylera Warning Metronidazole Bismuth 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 TCN a 2nd contraceptive method should be used if women are of childbearing age Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

45 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 TCN a 2nd contraceptive method should be used if women are of childbearing age Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006

46 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 Bi causes dark stools but does not interfere with standard tests for occult blood Patient education Take with adequate amount of fluids Back up method of contraception Store between 68-72° F (20-25° C) 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 used1 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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