Overview of  Helicobacter pylori  Microbiology, Pathogenesis and Treatment Options
Objectives  - Case Based Presentations <ul><li>To discuss the epidemiology, pathogenesis, and  diagnosis of  H. pylori </l...
Case MB –  H. pylori  General Information <ul><li>MB is 29 Cambodian and has been in the US for 5 years. </li></ul><ul><li...
Case MB –  H. pylori  General Information <ul><li>Describe the epidemiology of  H. pylori. </li></ul><ul><li>Review the pa...
Epidemiology <ul><li>Estimated 50-60% of the world population is infected </li></ul><ul><li>Person to Person Transmission ...
National Prescribing Patterns for Eradication ®2007 ZS Associates
History  of  H. pylori <ul><li>1890’s:  Spirochetes  in  animal  stomachs </li></ul><ul><li>1900’s:  Spirochetes  in  huma...
Economics of  H. pylori <ul><li>$6 billion / yr in health care costs due to peptic ulcer disease (PUD)  1 </li></ul><ul><l...
Immune and Inflammatory Response to  H. pylori Inflammatory Response Immune Response H. pylori Mucosa Tissue damage Activa...
H. pylori  pathologic associations <ul><li>Majority of infected patients do not develop clinically significant disease 1-3...
Case MB –  H. pylori  General Information <ul><li>Demographics – Cambodian, inner city </li></ul><ul><li>Pathogenesis: imm...
<ul><li>SH is 34 y/o middle income social worker in Austin, TX. </li></ul><ul><li>Receiving proton pump inhibitor (PPI). <...
<ul><li>Describe active and passive tests for detection of  H. pylori . </li></ul><ul><li>Discuss  various diagnostic test...
Diagnostic Test Comparison <ul><li>Invasive / active tests </li></ul><ul><li>Noninvasive / passive tests 1,2 </li></ul><ul...
Diagnostic Test Comparison <ul><ul><li>§ Need to account for false negatives with PPIs   </li></ul></ul>UBT = urea breath ...
AGA Recommendations Talley NJ et al.  Gastroenterology  2005;129:1756-1780 Negative Positive Fails Fails Fails American Ga...
Adherence to Test and Treat Guidelines <ul><li>Results </li></ul><ul><ul><li>1/3 antibiotics for  H. pylori  had no test <...
<ul><li>High prevalence area – Austin. </li></ul><ul><li>Test and treat guidelines apply. </li></ul><ul><li>PPI therapy fa...
Case # CV -  H. pylori  Eradication Therapy <ul><li>CV is 34 y/o Latino, with suspected ulcer – post-prandial bloating and...
Case CV -  H. pylori  Eradication Therapy <ul><li>Compare study results of new 3-in-1 bismuth subcitrate potassium, metron...
Treatment  of  Peptic  Ulcers <ul><li>“  The  modern  treatment  of  peptic  ulcers  places emphasis  on  diet  and  rest....
Antibiotic Pharmacodynamics 3  Helicobacter pylori: Physiology and Genetics. ASM Press 2001 1  Micromedex 2006, Thomson He...
Bismuth <ul><li>Bismuth minimally absorbed transmucosally </li></ul><ul><li>Considered a topical agent </li></ul><ul><ul><...
<ul><li>Bismuth subcitrate potassium, metronidazole tetracycline (BMT)  </li></ul><ul><ul><li>not bismuth subsalicylate </...
H. pylori  eradication with BMT +/- PPI 1 de Boer WA et al.  Am J Gastroenterol  2000;95:641-45  2 de Boer WA et al.  Alim...
OBMT vs OAC, Laine et al. <ul><li>Objective 10 day therapy </li></ul><ul><ul><li>3 BMT (triple capsule) QID + omeprazole (...
OBMT vs OAC, Laine et al. Laine L et al.  Am J Gastroenterol  2003;98:562-67  <ul><li>Baseline  H. pylori  testing </li></...
Laine L et al.  Am J Gastroenterol  2003;98:562-67  BID QID OBMT vs OAC, Laine et al. * NNS * * MITT = modified intent to ...
Clarithromycin Resistance <ul><li>Resistance rates as high as 20% 1 </li></ul><ul><li>In vitro  cross-resistance with macr...
Laine L et al.  Am J Gastroenterol  2003;98:562-67  OBMT vs OAC, Laine et al. Comparison: Eradication Rates and Pretreatme...
Metronidazole Resistance <ul><li>In vitro  resistance varies with test method </li></ul><ul><ul><li>39% (690/1768) E-test ...
<ul><li>Objectives </li></ul><ul><ul><li>to assess the efficacy and safety BMT + omeprazole in the eradication of  H. pylo...
<ul><li>Methods </li></ul><ul><ul><li>open label, international multicenter </li></ul></ul><ul><ul><li>dyspepsia +/- PUD, ...
<ul><li>DU = duodenal  ulcer </li></ul>OBMT, O’Morain et al. O’Morain C et al.  Aliment Pharmacol Ther  2003;17:415-20  MI...
H. pylori  eradication with LAC Prevpac ®  Package Labeling August 2004 Fennerty MB et al.  Arch Intern Med  1998;158:1651...
H. pylori  eradication with RAC Vakil N, et al.  Aliment Pharmacol Ther  2004; 20: 99–107 Intent to Treat Eradication Rate...
<ul><li>DU healing with histamine-2 receptor antagonist (H2RA) vs. H2RA based quadruple therapy </li></ul><ul><li>Bismuth ...
Case CV -  H. pylori  Eradication Therapy <ul><li>Greatest eradication rates with quadruple therapy. </li></ul><ul><li>10-...
Pylera Product Information
Pylera™ Product Information <ul><li>Pylera contains the following in each capsule: </li></ul><ul><ul><li>metronidazole 125...
Pylera Indication <ul><li>Pylera + omeprazole is indicated for the eradication of  H. pylori  in: </li></ul><ul><ul><li>H....
Pylera Black Boxed  Warning <ul><ul><ul><li>MTZ has been shown to be carcinogenic in mice and rats </li></ul></ul></ul><ul...
<ul><li>Known hypersensitivity or intolerance to: </li></ul><ul><ul><li>bismuth subcitrate potassium </li></ul></ul><ul><u...
Pylera  Warning <ul><li>Metronidazole </li></ul><ul><ul><li>seizures </li></ul></ul><ul><ul><li>peripheral neuropathy  cha...
Pylera  Warning <ul><li>Tetracycline </li></ul><ul><ul><li>use in patients < 8 years old may cause permanent discoloration...
<ul><li>Bismuth: darkening of tongue and/or black stool </li></ul><ul><li>Metronidazole: history of blood dyscrasias </li>...
Pylera Drug Interactions <ul><li>Tetracycline: </li></ul><ul><ul><li>prolonged INR in patients on warfarin </li></ul></ul>...
Pylera Drug Interactions <ul><li>Metronidazole: </li></ul><ul><ul><li>may increase lithium levels </li></ul></ul><ul><ul><...
Pylera Common Adverse Events <ul><li>Most common adverse events </li></ul><ul><ul><li>Stool abnormality (15.6%) </li></ul>...
Commercial Available Products
Conclusion <ul><li>H. pylori  is the major cause of DU and it should be  eradicated in all patients testing positive </li>...
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  • 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.
  • 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.
  • 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 4.1-4.4) and Hispanics (RR 3.1-4.2) 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
  • This is 2006 national prescription claims data for branded HP treatments from IMS via ZS Associates.
  • 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.
  • 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 Pylera Training Slides v 55
  • Good slide to know. Provides good discussions with the physicians. H. Pylori is &amp;quot;thought to be a&amp;quot; major cause of DU.  Some experts believe that it&apos;s not so clear cut. Majority of infected patients do not develop clinically significant disease due to the following m echanisms: 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-3 2005 Consensus Report
  • 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?
  • 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
  • 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;129:547-550 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.
  • ALARM FEATURES Age &gt; 55 with new onset Family history of upper GI cancer Previous GI malignancy or peptic ulcer Unintended/unexplained weight loss (&gt;10%) GI Bleeding, persistent vomiting, jaundice Dysphagia, odynophagia, early satiety Unexplained Iron deficiency anemia Palpable mass/lymphadenopathy Gastroenterology 2005;129:1756-1780 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 &lt; 55 with no alarm symptoms Am J Gastroenterol 2005;100:2324-2337 Am J Gastroenterol 1998;93(12):2330-8 Gastroenterology 2005;129:1756-1780 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&amp;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-3 2005 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
  • Large health plan new antisecretory claim, H. pylori test, or endoscopy continuous enrollment from 2001 – 2004 Medical claim for PUD, NUD, GERD
  • Good point here to determine what test physicians use most frequently? Do physicians test for susceptibilities? Do physicians test for eradication?
  • 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.
  • 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 &amp; Gilman&apos;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
  • Bismuth absorbed transmucosally in the stomach, however about 0.2-0.3% 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 &amp; 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 &amp; 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, 1559-1566.
  • 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.
  • 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 H 2 RA 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 open label study, no control group Cure rates: ITT = 86% (56/65) PPG = 88% (56/64) 92% (59/64) pts reported 100% compliance
  • 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 &gt;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 .
  • 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 &gt;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
  • Note the comparable eradication rates and compliance rates
  • 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;53:1374-84 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 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 2002 136 13-24
  • Clarithromycin resistant H. pylori e radication 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
  • 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 2002 136 13-24
  • 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 &gt;75% compliance Compliance measured as &gt;75% of drug taken
  • 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 &gt;75% compliance Compliance measured as &gt;75% of drug taken
  • 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 &gt;75% compliance Compliance measured as &gt;75% of drug taken
  • 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 &gt;90% compliance 38% vs 34% (10D v 14d) reported adverse events
  • 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.
  • 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: C 13 UBT serology (IgG) culture histologic evaluation Eradication no evidence of H. pylori by any test &gt; 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 &gt;70% of medication taken
  • What therapies are you using first and second line?
  • It is dosed 3 capsules 4 times a day.
  • 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.
  • 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.
  • TCN a 2 nd contraceptive method should be used if women are of childbearing age
  • TCN a 2 nd contraceptive method should be used if women are of childbearing age
  • 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)
  • uploads/Pylera_Scientific_Content_Presentation_vv_073007.ppt ...

    1. 1. Overview of Helicobacter pylori Microbiology, Pathogenesis and Treatment Options
    2. 2. Objectives - Case Based Presentations <ul><li>To discuss the epidemiology, pathogenesis, and diagnosis of H. pylori </li></ul><ul><li>To highlight test and treat practice guidelines </li></ul><ul><li>To compare and contrast clinical trial results between quadruple and triple therapy </li></ul><ul><li>To review antibiotic treatments </li></ul>
    3. 3. Case MB – H. pylori General Information <ul><li>MB is 29 Cambodian and has been in the US for 5 years. </li></ul><ul><li>She lives in the inner city of Los Angeles. </li></ul><ul><li>History: 1 - month of moderate mid-epigastric, upper abdominal pain. </li></ul><ul><li>No complaints of gas, darkening stool, or heartburn. </li></ul><ul><li>Non-smoker, no other medical problems, occasional ibuprofen usage. </li></ul>
    4. 4. Case MB – H. pylori General Information <ul><li>Describe the epidemiology of H. pylori. </li></ul><ul><li>Review the pathogenesis of H. pylori and associated symptoms. </li></ul>
    5. 5. Epidemiology <ul><li>Estimated 50-60% of the world population is infected </li></ul><ul><li>Person to Person Transmission </li></ul><ul><ul><li>fecal-oral, oral-oral, gastro-oral </li></ul></ul><ul><li>Increased risk of infection </li></ul><ul><ul><li>younger age </li></ul></ul><ul><ul><li>underdeveloped countries </li></ul></ul><ul><ul><li>lower socioeconomic status </li></ul></ul>Go MF. Aliment Pharmacol Ther 2002;16(Supp 1):3-15
    6. 6. National Prescribing Patterns for Eradication ®2007 ZS Associates
    7. 7. History of H. pylori <ul><li>1890’s: Spirochetes in animal stomachs </li></ul><ul><li>1900’s: Spirochetes in human stomachs </li></ul><ul><li>1954: No bacteria in gastric biopsies of 1000 patients </li></ul><ul><li>1975: Gram negative bacteria in 80% of GU’s (Pseudomonas) </li></ul><ul><li>1983: Warren and Marshall characterize H. pylori </li></ul><ul><li>2005 Nobel prize in 2005 </li></ul>
    8. 8. Economics of H. pylori <ul><li>$6 billion / yr in health care costs due to peptic ulcer disease (PUD) 1 </li></ul><ul><li>Up to 93% cure rate quadruple therapy 2 </li></ul><ul><li>0-10% of ulcer recurrence after antibiotic (ABX) treatment 3 </li></ul><ul><li>1-3% re-infection rate after ABX treatment 3 </li></ul>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. 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. 10. H. pylori pathologic associations <ul><li>Majority of infected patients do not develop clinically significant disease 1-3 </li></ul><ul><li>Significant manifestations 1-3 </li></ul><ul><ul><li>peptic ulcer disease (PUD) </li></ul></ul><ul><ul><ul><li>gastric and duodenal ulcers </li></ul></ul></ul><ul><ul><li>chronic gastritis </li></ul></ul><ul><ul><li>mucosa associated lymphoid tissue (MALT) </li></ul></ul><ul><ul><li>gastric adenocarcinoma </li></ul></ul>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
    11. 11. Case MB – H. pylori General Information <ul><li>Demographics – Cambodian, inner city </li></ul><ul><li>Pathogenesis: immune and inflammatory response contribute to symptoms </li></ul>
    12. 12. <ul><li>SH is 34 y/o middle income social worker in Austin, TX. </li></ul><ul><li>Receiving proton pump inhibitor (PPI). </li></ul><ul><li>6 - month history of dyspepsia with no improvement in symptoms. </li></ul><ul><li>Smoker and no family history of GI cancer. </li></ul><ul><li>Never had endoscopy. </li></ul>Case SH – H. pylori Diagnostic Tests
    13. 13. <ul><li>Describe active and passive tests for detection of H. pylori . </li></ul><ul><li>Discuss various diagnostic tests for H. pylori . </li></ul><ul><li>Review practice guidelines and application for test and treat. </li></ul>Case SH – H. pylori Diagnostic Tests
    14. 14. Diagnostic Test Comparison <ul><li>Invasive / active tests </li></ul><ul><li>Noninvasive / passive tests 1,2 </li></ul><ul><li>Determination of presence of H. pylori </li></ul><ul><ul><li>antibodies in blood, serum, or saliva </li></ul></ul><ul><ul><li>antigen in stool </li></ul></ul><ul><ul><li>functional tests of the bacterium's urease enzyme with a carbon-labeled urea breath test ( 13 C-UBT) </li></ul></ul>1Howden CW et al. Am J Gastroenterol 1998;93(12):2330-8 2 Gisbert JP et al. Helicobacter 2004;9(4):347-68
    15. 15. Diagnostic Test Comparison <ul><ul><li>§ Need to account for false negatives with PPIs </li></ul></ul>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 Testing Characteristics Serology 1 UBT 1 SAT 2 Biopsy 1 <ul><ul><li>Sensitivity / Specificity § </li></ul></ul>85% / 79% 95% / 96% 96% / 97% 95% / 99% <ul><ul><li>Detects previous infection </li></ul></ul>Yes No No No <ul><ul><li>Tests for eradication </li></ul></ul>No Yes Yes Yes Low cost $$ $$$ $$$ $$$$
    16. 16. AGA Recommendations Talley NJ et al. Gastroenterology 2005;129:1756-1780 Negative Positive Fails Fails Fails American Gastroenterology Association (AGA) <ul><li>Alarm Features </li></ul><ul><li>Age > 55 with new onset </li></ul><ul><li>Family history of upper GI cancer </li></ul><ul><li>Previous GI malignancy or peptic ulcer </li></ul><ul><li>Unintended/unexplained weight loss (>10%) </li></ul><ul><li>GI Bleeding, persistent vomiting, jaundice </li></ul><ul><li>Dysphagia, odynophagia, early satiety </li></ul><ul><li>Unexplained Iron deficiency anemia </li></ul><ul><li>Palpable mass/lymphadenopathy </li></ul>Dyspepsia without GERD or NSAIDs 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
    17. 17. Adherence to Test and Treat Guidelines <ul><li>Results </li></ul><ul><ul><li>1/3 antibiotics for H. pylori had no test </li></ul></ul><ul><ul><li>1/3 post-treatment PCPs used serologic test </li></ul></ul><ul><ul><li>2/3 ages 50 - 64 years underwent endoscopy </li></ul></ul><ul><ul><li>1/3 ages 18 - 49 years had an endoscopy within 30 days of their index date </li></ul></ul><ul><ul><li>18% GERD patients tested for H. pylori </li></ul></ul><ul><li>“ Substantial noncompliance with guidelines” </li></ul><ul><li>“ Better understanding of test and treat” </li></ul>Howden CW, et al. Am J Manag Care . 2007;13:37-44
    18. 18. <ul><li>High prevalence area – Austin. </li></ul><ul><li>Test and treat guidelines apply. </li></ul><ul><li>PPI therapy false negative on UBT and SAT. </li></ul><ul><li>Hold PPI 2 weeks prior to UBT and SAT. </li></ul><ul><li>Wait 1 month post eradication therapy to recheck. </li></ul>Case SH – H. pylori Diagnostic Tests
    19. 19. Case # CV - H. pylori Eradication Therapy <ul><li>CV is 34 y/o Latino, with suspected ulcer – post-prandial bloating and mid-epigastric pain. </li></ul><ul><li>Treated at primary care physician (PCP). </li></ul><ul><li>Receiving PPI once daily. </li></ul><ul><li>H. pylori serology positive. </li></ul><ul><li>No family history of gastric cancer. </li></ul><ul><li>Penicillin (PCN) allergy. </li></ul>
    20. 20. Case CV - H. pylori Eradication Therapy <ul><li>Compare study results of new 3-in-1 bismuth subcitrate potassium, metronidazole, tetracycline regimen to other available H. pylori eradication therapies. </li></ul>
    21. 21. Treatment of Peptic Ulcers <ul><li>“ The modern treatment of peptic ulcers places emphasis on diet and rest. </li></ul><ul><li>The patient is fed a bland diet, and small meals are given at frequent intervals. </li></ul><ul><li>Milk, cream and protein hydrolysates are often prescribed between meals. </li></ul><ul><li>Rest is essential. Some gastroenterologist routinely recommend hospitalization for several weeks….. </li></ul><ul><li>Mild sedatives are frequently beneficial.” </li></ul>The Pharmacologic Basis of Therapeutics, Eds. Goodman and Gilman, 2 nd Edition, 1955
    22. 22. 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 ANTIBIOTIC MOA 1-3 DYNAMICS 1-3 RESISTANCE 3 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
    23. 23. Bismuth <ul><li>Bismuth minimally absorbed transmucosally </li></ul><ul><li>Considered a topical agent </li></ul><ul><ul><li>antiseptic agent 1 </li></ul></ul><ul><ul><li>prevents bacterial adhesion </li></ul></ul><ul><ul><li>inhibits urease, phospholipase, and proteolytic activity and is synergistic with antibiotics 1,2 </li></ul></ul><ul><ul><li>lyse H. pylori near the gastric surface 3 </li></ul></ul>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. 24. <ul><li>Bismuth subcitrate potassium, metronidazole tetracycline (BMT) </li></ul><ul><ul><li>not bismuth subsalicylate </li></ul></ul><ul><ul><li>3-in-1 capsule </li></ul></ul><ul><li>Four studies with BMT 2-3 capsules QID for 7-10 days ± PPI 1-4 </li></ul><ul><li>Up to 93% compliance, >75% medication taken 3 </li></ul>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. 25. H. pylori eradication with BMT +/- PPI 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 n=53 n=65 n=170 n=138
    26. 26. OBMT vs OAC, Laine et al. <ul><li>Objective 10 day therapy </li></ul><ul><ul><li>3 BMT (triple capsule) QID + omeprazole (O) 20 mg BID </li></ul></ul><ul><ul><li>vs. </li></ul></ul><ul><ul><li>amoxicillin + clarithromycin (AC) BID + O 20 mg BID </li></ul></ul><ul><li>Design </li></ul><ul><ul><li>prospective, multicenter, randomized, evaluator-blinded </li></ul></ul><ul><li>Inclusion Criteria </li></ul><ul><ul><li>DU (>3 mm) or history of DU (within 5 years) </li></ul></ul>Laine L et al. Am J Gastroenterol 2003;98:562-67
    27. 27. OBMT vs OAC, Laine et al. Laine L et al. Am J Gastroenterol 2003;98:562-67 <ul><li>Baseline H. pylori testing </li></ul><ul><ul><li>13 C-urea breath test </li></ul></ul><ul><ul><li>antral and body biopsies </li></ul></ul><ul><ul><li>histology and/or culture </li></ul></ul><ul><ul><li>antibiotic susceptibility </li></ul></ul><ul><li>Follow-up </li></ul><ul><ul><li>13 C-UBT 29 & 57 days post therapy </li></ul></ul><ul><ul><li>both tests needed to be negative to = eradication </li></ul></ul>
    28. 28. Laine L et al. Am J Gastroenterol 2003;98:562-67 BID QID OBMT vs OAC, Laine et al. * NNS * * MITT = modified intent to treat n=138 n=137
    29. 29. Clarithromycin Resistance <ul><li>Resistance rates as high as 20% 1 </li></ul><ul><li>In vitro cross-resistance with macrolides can occur after one exposure 1 </li></ul><ul><li>Pre-treatment resistance has negative impact on efficacy by a mean of 55.4% 2 </li></ul><ul><li>No strategy overcomes resistance </li></ul>1 Megraud F. Gut 2004;53:1374-84 2 Meyer JM et al. Ann Intern Med 2002;136:13-24
    30. 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. 31. Metronidazole Resistance <ul><li>In vitro resistance varies with test method </li></ul><ul><ul><li>39% (690/1768) E-test </li></ul></ul><ul><ul><li>25.7% (317/1234) agar dilution </li></ul></ul><ul><li>Strategies to combat resistance </li></ul><ul><ul><li>longer duration, PPI-BMT, high dose MTZ </li></ul></ul>Meyer JM et al. Ann Intern Med 2002;136:13-24
    32. 32. <ul><li>Objectives </li></ul><ul><ul><li>to assess the efficacy and safety BMT + omeprazole in the eradication of H. pylori </li></ul></ul><ul><ul><li>to investigate effect of MTZ resistance and disease type (peptic ulcer vs. non-ulcer dyspepsia) on the eradication rates </li></ul></ul>OBMT, O’Morain et al. O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20
    33. 33. <ul><li>Methods </li></ul><ul><ul><li>open label, international multicenter </li></ul></ul><ul><ul><li>dyspepsia +/- PUD, testing positive for H. pylori by 13 C-UBT </li></ul></ul><ul><ul><li>histology and ⁄ or culture of 5 pre-treatment biopsies </li></ul></ul><ul><ul><li>3 BMT QID + OME 20mg BID X 10 days </li></ul></ul><ul><ul><li>29 & 57 days post therapy 2 negative 13 C -UBT after treatment </li></ul></ul>OBMT, O’Morain et al. O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20
    34. 34. <ul><li>DU = duodenal ulcer </li></ul>OBMT, O’Morain et al. O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20 MITT = modified intent to treat N = 170 n = 39 / 43
    35. 35. H. pylori eradication with LAC Prevpac ® Package Labeling August 2004 Fennerty MB et al. Arch Intern Med 1998;158:1651-56 LAC = lansoprazole, amoxicillin, clarithromycin * NNS 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)
    36. 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 = 187 n = 166 n = 177 / 179
    37. 37. <ul><li>DU healing with histamine-2 receptor antagonist (H2RA) vs. H2RA based quadruple therapy </li></ul><ul><li>Bismuth subsalicylate </li></ul><ul><li>Patients were assessed for H. pylori infection via: </li></ul><ul><ul><li>13 C UBT </li></ul></ul><ul><ul><li>serology (IgG) </li></ul></ul><ul><ul><li>culture </li></ul></ul><ul><ul><li>histologic evaluation </li></ul></ul><ul><li>Low eradication rates (81%) </li></ul>BMT + H2RA, Graham et al. Graham DY, et al Annals of Internal Medicine 1991:115:266-269 .
    38. 38. Case CV - H. pylori Eradication Therapy <ul><li>Greatest eradication rates with quadruple therapy. </li></ul><ul><li>10-day regimen is effective. </li></ul><ul><li>Equivalent compliance between quadruple and triple therapy. </li></ul><ul><li>PCN allergy. </li></ul>
    39. 39. Pylera Product Information
    40. 40. Pylera™ Product Information <ul><li>Pylera contains the following in each capsule: </li></ul><ul><ul><li>metronidazole 125 mg </li></ul></ul><ul><ul><li>tetracycline 125 mg </li></ul></ul><ul><ul><li>bismuth subcitrate potassium 140 mg </li></ul></ul><ul><li>3-in-1 capsule available with these ingredients in the US </li></ul>Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
    41. 41. Pylera Indication <ul><li>Pylera + omeprazole is indicated for the eradication of H. pylori in: </li></ul><ul><ul><li>H. pylori infected patients and </li></ul></ul><ul><ul><li>patients with active or a history (within 5 years) of duodenal ulcer </li></ul></ul><ul><li>Recommended Dosage </li></ul><ul><ul><li>3 Pylera capsules QID after meals </li></ul></ul><ul><ul><li>omeprazole 20 mg BID with breakfast and supper </li></ul></ul>Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
    42. 42. Pylera Black Boxed Warning <ul><ul><ul><li>MTZ has been shown to be carcinogenic in mice and rats </li></ul></ul></ul><ul><ul><ul><li>Unnecessary use of the drug (Pylera) should be avoided and it should be reserved for the conditions described in the indication </li></ul></ul></ul><ul><ul><ul><li>Precaution </li></ul></ul></ul><ul><ul><ul><ul><li>mild leukopenia, but no persistent hematologic abnormalities attributable to MTZ have been observed </li></ul></ul></ul></ul>Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
    43. 43. <ul><li>Known hypersensitivity or intolerance to: </li></ul><ul><ul><li>bismuth subcitrate potassium </li></ul></ul><ul><ul><li>metronidazole or other nitroimidazoles </li></ul></ul><ul><ul><li>tetracyclines </li></ul></ul><ul><ul><li>components of the formulation </li></ul></ul><ul><li>Renal or hepatic impairment </li></ul><ul><li>Pregnant and nursing women </li></ul><ul><li>Pediatric patients </li></ul>Pylera Contraindications Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
    44. 44. Pylera Warning <ul><li>Metronidazole </li></ul><ul><ul><li>seizures </li></ul></ul><ul><ul><li>peripheral neuropathy characterized mainly by numbness or paresthesia of an extremity </li></ul></ul><ul><ul><li>avoid alcohol throughout treatment and at least 1 day after treatment </li></ul></ul><ul><li>Bismuth </li></ul><ul><ul><li>rare reports of neurotoxicity associated with excessive doses of various bismuth-containing products </li></ul></ul><ul><ul><li>reversible after discontinuation of drug </li></ul></ul>Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
    45. 45. Pylera Warning <ul><li>Tetracycline </li></ul><ul><ul><li>use in patients < 8 years old may cause permanent discoloration of teeth </li></ul></ul><ul><ul><li>pregnancy (Category D) and crosses the placenta </li></ul></ul><ul><ul><li>photosensitivity treatment should be stopped with first evidence of skin erythema </li></ul></ul><ul><ul><li>elevated BUN patients with significantly impaired renal function, higher serum levels of tetracycline may lead to azotemia, hyperphosphatemia, and acidosis </li></ul></ul>Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
    46. 46. <ul><li>Bismuth: darkening of tongue and/or black stool </li></ul><ul><li>Metronidazole: history of blood dyscrasias </li></ul><ul><li>Tetracycline: candidiasis </li></ul><ul><li>Avoid tanning booths, use sunscreen </li></ul><ul><li>Avoid alcohol </li></ul><ul><li>Missed doses continuing dosing schedule until the medication is gone and do not take double doses </li></ul><ul><li>If more than 4 doses are missed, the prescriber should be contacted </li></ul>Pylera Precautions Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
    47. 47. Pylera Drug Interactions <ul><li>Tetracycline: </li></ul><ul><ul><li>prolonged INR in patients on warfarin </li></ul></ul><ul><ul><li>reduced absorption with antacids, including calcium, magnesium, aluminum. </li></ul></ul><ul><ul><li>reduced absorption with iron, zinc, multivitamins </li></ul></ul><ul><ul><li>concurrent use of may render oral contraceptives less effective and patients should be advised to use a different or additional form of contraception </li></ul></ul>Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
    48. 48. Pylera Drug Interactions <ul><li>Metronidazole: </li></ul><ul><ul><li>may increase lithium levels </li></ul></ul><ul><ul><li>Disulfiram reaction with alcohol </li></ul></ul><ul><ul><li>prolonged INR in patients on warfarin </li></ul></ul><ul><ul><li>metabolism may be increased by phenytoin or phenobarbital </li></ul></ul>Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
    49. 49. Pylera Common Adverse Events <ul><li>Most common adverse events </li></ul><ul><ul><li>Stool abnormality (15.6%) </li></ul></ul><ul><ul><li>Diarrhea (8.8%) </li></ul></ul><ul><ul><li>Dyspepsia (8.8%) </li></ul></ul><ul><ul><li>Abdominal Pain (8.8%) </li></ul></ul><ul><ul><li>Nausea (8.2%) </li></ul></ul><ul><ul><li>Headache (8.2%) </li></ul></ul><ul><ul><li>Taste perversion (4.8%) </li></ul></ul><ul><ul><li>Vaginitis (4.1%) </li></ul></ul>Pylera Package Insert. Axcan Scandipharm Inc. Birmingham, AL USA. 2006
    50. 50. Commercial Available Products
    51. 51. Conclusion <ul><li>H. pylori is the major cause of DU and it should be eradicated in all patients testing positive </li></ul><ul><li>H. pylori relationship with the development of MALT and gastric cancer </li></ul><ul><li>As high as 93% (158/170) eradication rate of H. pylori when quadruple therapy is used 1 </li></ul><ul><li>Eradication rates vary between triple and quadruple therapies </li></ul>1 O’Morain C et al. Aliment Pharmacol Ther 2003;17:415-20

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