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Helicobacter pylori infection

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  • Gram-negative bacterium with helical rod shape.Prominent flagellae facilitating penetration of thick mucous layer in the stomach.
  • Flagellum: اهداب
  • Koch's postulates (or Henle-Koch postulates) are four criteria designed to establish a causal relationship between a causative microbe and a disease. The postulates were formulated by Robert Koch (German physician & bacteriologist ) and Friedrich Loeffler in 1884 and refined and published by Koch in 1890. Koch applied the postulates to establish the etiology of anthrax and tuberculosis, but they have been generalized to other diseases.However, Koch abandoned the second part of the first postulate altogether when he discovered asymptomatic carriers of cholera[1] and, later, Typhoid Mary. Asymptomatic carriers are now known to be a common feature of many infectious diseases, especially viruses such as polio, herpes simplex, HIV and hepatitis C. As a specific example, all doctors and virologists agree that poliovirus causes paralysis in just a few infected subjects, and the success of the polio vaccine in preventing disease supports the conviction that the poliovirus is the causative agent.The third postulate specifies "should", not "must", because as Koch himself proved in regard to both tuberculosis and cholera, not all organisms exposed to an infectious agent will acquire the infection. This may be due to chance, to acquired immunity, or to genetic immunity. An example of genetic immunity: human immunodeficiency virus (HIV) seems to be normally unable to infect persons who carry the deletion CCR5 Δ32.
  • In spite of frequent variations of media, and temperatures of incubation, from these 34 specimens, however, spiral bacteria were notcultured, because incubation was limited to 48 hours.
  • A silver stain (Warthin Starry) of HP (black wiggly things) on gastric mucus-secreting epithelial cells (x1000). This picture is notorious because it is of Dr. Marshall's stomach biopsy taken 8 days after he drank a culture of H. pylori. The experiment was published in 1985 (Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ. Attempt to fulfill Koch's postulates for pyloric Campylobacter. Med J Aust 1985; 142: 436-439).
  • Barry Marshall receiving his Nobel Prize from His Majesty the King Carl XVI Gustaf of Sweden at the Stockholm Concert Hall, 10 December 2005.
  • When the t(11,18) translocation is present, HP eradication is usually ineffective & these patients need adjunctive & alternative treatments.
  • H pylori-positive patients eradication treatment improves the bioavailability of thyroxine and l-dopa.
  • Serological test: serological tests are not all equivalent. Only validated IgG serology tests should be used owing to variability in the accuracy of different commercial tests.Validated IgG serology may be used in setting of recent use of antimicrobial* and antisecretory drugs, or ulcer bleeding, atrophy and gastric malignancies.Fecal antigen test:Not often used despite its high sensitivity and specificity before and after treatment.Should have a more prominent place, as it is inexpensive and noninvasive.PCR: Sensitive and specific – Not standardized.Finger-stick serology testVery poor and cannot be equated with ELISA serology
  • In special cases where a gastric ulcer or gastric MALT lymphoma has been diagnosed, follow-up is necessary with upper digestive endoscopy and then biopsy-based tests can be performed.On considère que la masse bactérienne revient à sa valeur initiale en un mois.Au cas où le malade ne pourrait arrêter son traitement antisécrétoire, la prise de pansements gastriques qui n’ont pas ces conséquences peut être envisagée.
  • On considère que la masse bactérienne revient à sa valeur initiale en un mois.Au cas où le malade ne pourrait arrêter son traitement antisécrétoire, la prise de pansements gastriques qui n’ont pas ces conséquences peut être envisagée.
  • Rapid urease tests. Another indirect test for Helicobacter pylori, the rapid urease test, is based on metabolism of urea by urease. In this test, a mucosal biopsy is inoculated into a well that contains urea and a pH-sensitive dye (phenol red). If urease is present in the biopsy, urea in the medium is converted to NH4+, which will raise the pH. In response to an elevation in pH, the pH sensitive dye causes the well to change colors. This figure is an example of a rapid urease test, the CLOtestTM (Delta West Limited, Bentley, Western Australia). In this test, presence of H. pylori in a mucosal biopsy will be evidenced by a color change from yellow to red.
  • Clinicians should prescribe therapies providing grade A resultsIf not obtainable, grade B therapies should be prescribedGrade F therapies should be avoided
  • Patients with NUD, pangastritis, diabetes, smokers, or those with a high bacterial load may be predicted to be at a higher risk of failure with the standard 7-day triple therapy.Compliance: Compliance to therapy plays a major role.12% of patients prematurely stopped the eradication therapy as a result of side effects.Gastric acid secretion:Small proportion of subjects shows a high basal acid output, despite normal values of the gastrin. In these hypersecretor subjects, who probably have a larger parietal cell mass, lower eradication rates have been reported.Genetic polymorphism of CYP 450:Subjects are subgrouped into poor, intermediate, and extensive metabolizers.Although some controversial data do exist, standard PPI doses seem to be insufficient in extensive metabolizers to achieve an adequate pH inhibition needed for antibiotic activity in gastric mucosa, with consequent lower eradication rates.Gastroduodenal disease:Several studies reported lower H. pylori cure rates in patients with NUD as compared with those with peptic ulcer disease (PUD).Infection with different less virulent HP strains: cagA negative; vacA s2 or m2 genotype) & slow-proliferating strains.Infection recurrence has also been found to be significantly higher in NUD as compared with PUD patients.Gastritis pattern:Patients with pangastritis achieve lower eradication rates as compared with those with antral gastritis. Obesity:BMI significantly affected the H. pylori eradication rate after a standard 7-day triple therapy.However, this phenomenon was not confirmed when a prolonged 14-day triple therapy regimen was used.Smoking: Ongoing smoking has been consistently reported tonegatively affect therapeutic success rate after 7-day triple therapies.Smoking did not seem to significantly reduce eradication rate when either 14-day triple therapy or 10-day sequential therapy was used.Primary resistance to antibiotics:Resistance to different antibiotics undeniably plays a major role, & prevalence of H. pylori resistance seems to be increasing worldwide.Clarithromycinhas been found to be the main factor hampering the efficacy of standard therapiesMetronidazoleresistance seems to exert a minor impact on the therapeutic outcome.Primary resistance toward levofloxacin, an antibiotic generally used in second-line therapy regimens, is also increasing worldwide.Bacterial load in the stomach:High values being associated with lower eradication rates.Coccoid forms of H. pyloriNot susceptible to antibiotics, & their presence may have clinical relevance, due potential reactivation of HP in its spiral form after therapy.cagA status:cagA-negative H. pylori seems to be less susceptible to antibiotics as compared with cagA positive strains (eradication rate 11% lower). vacA alleles status:Presence of vacA s1m1 allele increases bacterial susceptibility as compared with vacA s2m2 allele.duodenal ulcer promoting (dup) status:H. pylori virulence factor affecting therapy efficacy. presence of dupA gene was found to be independent predictor of therapy failure [OR: 3.71; 95% CI, 1.07-12.83] at multivariate analysis.Data need to be confirmed in a larger and prospective series.Certain H pylori virulence factors and certain host genetic polymorphisms are known to affect the risk of any specific individual developing H. pylori-associated disease. However, there is no evidence that strategies based on testing for these factors are useful for an individual patient.
  • Clarithromycin must bind to ribosomes in order to kill H pylori. Resistance is associated with failure to bind to ribosomes, such that resistance cannot be overcome by increasing the dose or duration.
  • It must be stated that there is a cross-resistance in each family of antibiotics because the same resistance mechanism occurs: resistanceto clarithromycin indicates resistance to all macrolides, resistance to levofloxacin indicates resistance to all fluoroquinolonesincluding moxifloxacin, for example. There is no cross-resistance between different families of antibiotics which have different resistance mechanisms.
  • Concept described by Bigger in 1944 Dormant bacteria that can survive until antibiotics stopped Treatment failure without development of resistance Feature of dual therapy with PPI & amoxicillin Extended-duration therapy Bacteria oscillate between nonreplicating & replicating states Local pH < 6 maintains bacteria in nonreplicative state Theoretical basis of high-dose dual PPI therapy
  • Tuberculosis is a potentially good source of information as both it and H. pylori infection require treatment withmultiple drugs for a long duration.
  • High-dose PPIs increase cure rates by around 6 – 10% in comparison with standard doses.Increasing dose of PPI from, for example, 20 mg omeprazole twice daily to 40 mg of esomeprazole or rabeprazole twice daily may increase cure rates by 8 – 12%.Extending duration of triple therapy from 7 to 10 – 14 days improves eradication success by approximately 5% and may be considered.
  • treatment success fails to reach even 80% in most studies in the southern and central European countries of France, Italy, Spain and Turkey, populations which, as the Maastricht III report noted, tend to have a high prevalence (~18.5%) of clarithromycin resistance.triple therapy with a PPi, amoxicillin and clarithromycin should be avoided.
  • Overall, mean eradication rate with sequential regimen is higher than 90%, a tendency toward lower efficacy with this regimen is observed in the more recent studies.Almost all the studies analyzing sequential therapy have been performed in Italy & data obtained from Italy might not be readily extrapolated to other populations.Limitations of sequential therapy:Low validation outside ItalySmall sample size: < 50 in some protocolsLow quality of studies: Jadad score ≥3 in 1/10 studies in MA1Therapy complexity: reduced compliance in clinical practiceUnsuitable for dual clarithromycin & nitroimidazole resistanceUnsuitable for penicillin allergy
  • We have observed that using a combination of both metronidazole and clarithromycinin quadruple regimens is very effective at eradicating strains of H pylori resistant to either clarithromycin or metronidazole. In fact, only a negligible reduction in efficacy was observed when concomitant quadruple regimens containing a PPI, amoxicillin, clarithromycin and metronidazole (a nitroimidazole), were given to patients with either nitromidazole- or clarithromycin-resistant H pylori.
  • Widespread acceptance of this regimen was not forthcoming, possibly related to the requirement for dosing three or preferably four times daily, the administration of a large number of pills, a lack of availability of bismuth in many areas, and perhaps most importantly, until recently, the absence of a pharmaceutical sponsor to assist in education and marketing of the regimen.Capsule containing bismuth subcitrate (140 mg), metronidazole (125 mg), and tetracycline (125 mg) is available and FDA approved. The dosing is three capsules four times daily plus a PPI twice daily.
  • Antibiotic combination should be chosen according to local H pylori antibiotic resistance patterns.
  • Antibiotic combination should be chosen according to local H pylori antibiotic resistance patterns.
  • In case of clarithromycin resistance, rate of success of clarithromycin-containing triple therapy is very low (10-30%).After a first failure, if an endoscopy is carried out, culture (and standard susceptibility testing) should be considered in all regions before giving a second-line treatment because the chance of having a resistant organism is high, in the range of 60 - 70% for clarithromycin.Metronidazole susceptibility testing lacks reproducibility and no molecular alternative exists.Increasing metronidazole dosage and treatment duration may partially overcome resistance.Accuracy of fluoroquinolone molecular testing is not as reliable as for clarithromycin.
  • (14 days)PPI (omeprazole 40 mg qid or lansoprazole 30 mg qid) Amoxicillin (500 mg, qid)
  • We provide patients with information sheet that cautions against aged cheese, sausage including bologna, salami & pepperoni, lima beans, lentils, snow peas, soybeans, canned figs & raisins, beer, ale & wines, licorice, soy sauce, monamineoxidase inhibitors, phenylpropanolamine, ephedrine, phenylephrine.
  • H. pylori resistance to amoxicillin is extremely rare.Therefore, rifabutin (together with a PPI and amoxicillin) can be administered as a rescue treatment without the need for a prior antibiogram.The ideal length of treatment remains unclear, but 10- to 12-day regimens are generally recommended.
  • Antibiotic combination should be chosen according to local H pylori antibiotic resistance patterns.
  • Inflammation of the gastric mucosa leads to an increase in both PGI and PGII serum levels, usually with a more marked increase of PGIIand thus a decrease in the PGI/II ratio. With the development of atrophy and loss of specialized cells, both PGI and PGII may decrease, but PGI usually shows a more marked decrease than PGII, thus there is a further decline in the PGI/II ratio (see review by Kuipers EJ: “In through the out door: serology for atrophic gastritis,” Eur J GastroenterolHepatol 2003: 877–879). Thus, a low PGI level, a lowPGI/II ratio, or both, are good indicators of atrophic changes in the gastric mucosa.Subjects with severe gastric atrophy, in whom H pylori has disappeared and who are therefore serologically negative for H pylori, are at a particularly high risk.
  • both the oxyntic and the antral mucosa have to be “explored”and also considering the incisuraangularis “highly informative” for purpose of establishing earliest onset of atrophic–metaplastic transformation.
  • Patients on PPI, H. pylori may be difficult (or even impossible) to identify histologically at antral or corpus level, in which case coexisting inflammatory lesions (polymorphs and lymphoid infiltrate) may suggest the bacterium’s presence and a comment on the suspectedbacterial etiology (“suspicious for H. pylori infection”) should be added (whatever the stage of atrophy recorded).
  • Antral atrophy scoreCorpus atrophy score
  • Transcript

    • 1. Helicobacter pylori infectionSamir Haffar M.D.Assistant Professor of Gastroenterology
    • 2. Helicobacter pylori infection Discovery of H. pylori Epidemiology of H. pylori Indications for treatment Diagnosis of infection Treatment of infection Prevention of gastric cancer
    • 3. Giulio Bizzozero (1846 – 1901)Italian pathologist• Desribed for first time presence ofhelicobacters in stomach of dogs• Communicated his discovery to TurinMedial Academy (18th March 1892)• Spirilli described by Bizzozzero werepresumably H. beilmannii or H. felisFigura N et al. In Marshall BJ, ed. Helicobacter pioneers.Victoria, Australia: Blackwell, 2002.
    • 4. Bizzozero’s drawingBacteria live in acid producing cellsThese bacteria must be acid tolerant or must turn off acid secretionFigura N et al. In Marshall BJ, ed. Helicobacter pioneers.Victoria, Australia: Blackwell, 2002.
    • 5. First detailed histological & USultrastructural studies on human HP• Done by Steer in Southampton in 1975• Spiral bacteria closely apposed to mucus secreting cellsbacteria possessed at least one flagellum• Polymorphonuclear leucocytes migrated through gastricmucosa, presumably in response to bacteria• Culture of endoscopic biopsy yielded onlyPseudomonas aeruginosa (not a spiral organism)Steer HW. J Clin Pathol 1975 ; 28 : 639 – 46.
    • 6. Royal Perth hospital, Perth, Western Australia1982• R Warren Expert in gastric pathology & bacterialstaining in pathological specimens• B Marshall Registrar in trainingLearning gastroenterology for 6 months• JAArmstrong Head of electron microscopy unit• CS Goodwin Head of microbiology departmentGoodwin C S. Gut 1993 ; 34 : 293 – 294.
    • 7. Kochs postulates (1890)Causal relationship between a microbe & a disease Microorganism must be present in every case of disease Microorganism must be isolated from diseased organism& grown in pure culture Cultured microorganism should cause disease whenintroduced into a healthy organism Microorganism must be recoverable from experimentalinfected hostKoch R. J Hyg Inf 1893 ; 14 : 319 – 333.
    • 8. Protocol for H. pylori cultureGastric biopsy from 100 patients started March 1982The first 34 culturesSpiral bacteria seen in Gram stain in sixSpiral bacteria were not culturedIncubation was limited to 48 hoursThe 35th cultureIncubating during Easter holiday (5 days in Australia)Pure growth of 1 mm transparent coloniesH. pylori had been finally cultured (14 April 1982)Goodwin C S. Gut 1993 ; 34 : 293 – 294.
    • 9. Marshalls stomach biopsyNotorious pictureMarshall BJ et al. Attempt to fulfill Kochs postulates for Campylobacter Pylori.Med J Aust 1985 ; 142 : 436 – 439.Silver stain of HP on gastric epithelial cells (x1000)Marshalls stomach biopsy taken 8 days after he drank culture of HP
    • 10. Warren & Marshall receiving the Nobel Prizefrom the King Carl XVI Gustaf of SwedenStockholm Concert Hall, 10 December 2005Robin Warren Barry Marshall
    • 11. Helicobacter pylori infection Discovery of H. pylori Epidemiology of H. pylori Indications for treatment Diagnosis of infection Treatment of infection Prevention of gastric cancer
    • 12. Morphology of H. pyloriMicro-aerophilicGram-negativeSlow growingSpiral-shapedFlagellated
    • 13. Prevalence of H. pylori infectionMost common chronic bacterial infection of humans100806040200% individuals infected0 10 20 30 40 50 60 70 80 Age (years)Marshall 1994DevelopingcountriesWesterncountriesCarrier state fromchildhood infection(before 1945)Rapid acquisitionin childhood≈ 50% ofworld’s population
    • 14. Natural history of H. pylori infectionLongo DL et al. Harrison’s gastroenterology & hepatology.McGraw-Hill, New York, USA, 2010.
    • 15. Conditions arising from H. pylori infection
    • 16. H. Pylori infection & gastric acid secretionKuipers EJ. Gut 2006 ; 55 : 1217 – 1221.Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.Antral predominant gastritisDuodenal ulcerNon-ulcer dyspepsiaCorpus predominant gastritisGastric ulcerPremalignant gastric lesionsPattern of gastritis determine disease outcomes
    • 17. Conditions associated with PUDDuodenal ulcer Gastric ulcerSleisenger & Fordtran’s gastrointestinal & liver disease.Saunders-Elsevier, Philadelphia, PA , USA, 9th edition , 2010.H. pylori infection & NSAID use often coexist
    • 18. Helicobacter pylori infection Discovery of H. pylori Epidemiology of H. pylori Indications for treatment Diagnosis of infection Treatment of infection Prevention of gastric cancer
    • 19. Indications for treatment of H. pylori infectionGastric diseases• Past or present duodenal/gastric ulcer• Dyspepsia• Atrophic gastritis• Low grade MALT lymphoma: early stages (Lugano I/II)• Following resection of gastric cancer• First-degree relatives with gastric cancer• Patient’s wishes* WGO global guideline. J Clin Gastroenterol 2011 ; 45 : 383 – 388.** Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.
    • 20. H. pylori & NSAID or low-dose aspirin• HP & NSAID use are independent risk factors for PUD• Naïve NSAID users Beneficial to eradicate HP• Long-term NSAID No clear benefitEradication less effective than PPIPPI as well as HP eradication• Low dose aspirin Eradication in pts with PU historyMalfertheiner P et al. Management of HP infection: Maastricht IV/Florence consensus report.Gut 2012 ; 61: 646 – 664.
    • 21. H pylori & GERD• Epidemiological studies show negative association betweenprevalence of HP & severity of GERD & incidence ofesophageal adenocarcinoma (Grade A)• H pylori eradication does not exacerbate pre-existing GERDor affect treatment efficacy (Grade A)Malfertheiner P et al. Management of HP infection: Maastricht IV/Florence consensus report.Gut 2012; 61: 646 – 664.
    • 22. H pylori & long-term treatment with PPI• Long-term treatment with PPIs in HP-positive patientsassociated with development of corpus-predominantgastritis leading to atrophic gastritis (Grade A)• Eradication of HP in pts receiving long-term PPIs healsgastritis & prevents progression to atrophic gastritis butno evidence of reducing risk of gastric cancer (Grade A)Malfertheiner P et al. Management of HP infection: Maastricht IV/Florence consensus report.Gut 2012; 61: 646 – 664.
    • 23. Malfertheiner P et al. Management of HP infection: Maastricht IV/Florence consensus report.Gut 2012 ; 61: 646 – 664.AssociationUnexplained iron deficiency anemiaIdiopathic thrombocytopenic purpura (ITP)Vitamin B12 deficiencyFurther researchAsthma & atopyObesity & related illnessesCardiovascular disordersNeurological disordersNo associationIndications for treatment of H. pylori infectionExtra-gastric diseases
    • 24. Helicobacter pylori infection Discovery of H. pylori Epidemiology of H. pylori Indications for treatment Diagnosis of infection Treatment of infection Prevention of gastric cancer
    • 25. Diagnosis of H pylori infectionTests Sensitivity SpecificityNon-endoscopic methodsSerologyValidated ELISA IgG85 – 92%79 – 83%Not for confirming eradicationUrea breath test 95% 96%Fecal antigen testELIZA - monoclonal95% 94%Endoscopic methodsRapid urease test1 antrum & 1 corpus98% 99%Histology1 antrum & 1 corpus> 95% > 95%Culture 70 – 90% 100%WGO global guideline. J Clin Gastroenterol 2011 ; 45 : 383 – 388.Malfertheiner P et al. Gut 2012; 61: 646 – 664.
    • 26. Serology for diagnosis of HP• Chronic infection IgG detection only• Favored method ELISA• Some kits with accuracy > 90% Use validated tests only• Not affected by low bacterial load Use of antibioticsUse of antisecretoryBleeding ulcerGastric atrophyGastric malignanciesMalfertheiner P et al. Gut 2012; 61: 646 – 664.
    • 27. Mégraud F. Presse Med. 2010 ; 39 : 815 – 822.Malfertheiner P et al. Gut 2012; 61: 646 – 664.Antibiotics Stopped for at least 4 weeksPPIs Stopped for 14 daysH2RA Stopped for 7 daysAntacids Not stoppedUBT, monoclonal stool test, & cultureNo role for serology to confirm eradication
    • 28. Urea breath test / C13 and C14Mégraud F. Presse Med. 2010 ; 39 : 815 – 822.
    • 29. Rapid Urease Test (RUT)Available RUT kitsCLO testHpFastHUT-testPronto DryPyloritekOverall performance of different tests comparable
    • 30. Helicobacter pylori infection Discovery of H. pylori Epidemiology of H. pylori Indications for treatment Diagnosis of infection Treatment of infection Prevention of gastric cancer
    • 31. Clinical trial of H. pylori therapyGraham DY & Dore MP. Helicobacter 2011 ; 16 : 343 – 345.100% or near 100% success expectedNo placebo responseFailure almost always explainable: Resistance – Flawed regimen
    • 32. Grading system of H. pylori therapyGraham DY et al. Helicobacter 2007 ; 12 : 275 – 278.Grade Cure rate (ITT) ScoreA ≥ 95% ExcellentB 90 – 94 % GoodC 85 – 89 % AcceptableD 81 – 84 % PoorF≤ 80% UnacceptableSimilar to grade performance of school childrenFailed
    • 33. Bacterial factorsPrimary resistance to antibioticsBacterial load in stomachBacterial coccoid formscagA status (negative)vacA alleles status (s2m2 allele)dup A status*Factors affecting H. pylori eradication success* dup: duodenal ulcer promotingZullo A et al. J Clin Gastroenterol 2012 ; 46 : 259 – 261.Host factorsCompliance to therapyGastric acid hypersecretionGenetic polymorphism of CYP 450Gastroduodenal disease (NUD)Gastritis pattern (pangastritis)ObesitySmoking
    • 34. H. pylori resistance to antibiotics• Clarithromycin Not overcome by increasing dose & duration‘all or none’ Should not be used if prevalence > 15 – 20%• Levofloxacine Not overcome by increasing dose & duration‘all or none’ Rapidly increasing worldwide• Metronidazole Overcome by increasing dose & duration‘not all or none’ Should not be used if prevalence > 40%• Amoxicillin Rare in most regions• Tetracycline Rare in most regions• Bismuth Does not occurGraham DY et al. Drugs 2008 ; 68 : 725 – 736.
    • 35. H. pylori & antibiotic resistanceCountry No.testedAMO%MTZ%CLA%Quinolones%TET%Furazolidone%Iran2007101 21 73 9 5 5 9Egypt200448 2 100 4 2KSA2002223 1 80 4 0.5Kuwait200696 0 70 0 0WGO global guideline. J Clin Gastroenterol 2011 ; 45 : 383 – 388.
    • 36. H. Pylori & antibiotic resistance• Cross-resistance in each family of antibioticsResistance to clarithromycin → resistance to all macrolidesResistance to levofloxacin → resistance to all fluoroquinolones• No cross-resistance between different families of antibiotics• Important to use compound indicated to get good resultsClarithromycin for macrolidesTetracycline HCl and not doxycyclineLevofloxacin but not ciprofloxacin for fluoroquinolonesMalfertheiner P et al. Gut 2012 ; 61: 646 – 664.
    • 37. Phenotypical antibiotic resistance & HPBigger JW. Lancet 1944 ; 247 : 497 – 500.Scott D et al. Gut 1998 ; 43(Suppl 1): S56 – S60.Graham et al. Gut 2010 ; 59 : 1143 – 1153.pH 4 – 8: H. pylori survivespH 4 – 6: Non-dividing H. pylori – Phenotypical resistancepH 6 – 8: Dividing H. pylori – Susceptible to AMO or CLA
    • 38. Difficulties associated with cure of H. pylori• Development of H pylori resistance to many agents:Metronidazole, clarithromycin & fluoroquinolones• Huge number of HP organisms present in the stomach,which produces an inoculum effect• H. pylori organisms can reside in variety of niches:Intracellularly or in highly acidic gastric mucus gel layer• High rate of reinfection in developing countriesRimbara E. et al. Nat Rev Gastroenterol Hepatol 2011 ; 8 : 79 – 88.H. pyori, like tuberculosis, requires treatment withmultiple drugs for long duration
    • 39. Annual recurrence of H. pylori after successfuleradication in developing countriesEach bar represents a different studyRecurrence of original infection or reinfection with new strainRimbara E. et al. Nat Rev Gastroenterol Hepatol 2011 ; 8 : 79 – 88.
    • 40. Optimal antimicrobial therapies• Dosage• Dosing intervals• Formulation• Route of administration• Duration of therapyEstablish parameters that will provide the bestoutcome from a particular regimen:Rimbara E. et al. Nat Rev Gastroenterol Hepatol 2011 ; 8 : 79 – 88.
    • 41. Treatment of H. pylori infectionFirst line treatmentStandard triple therapySequential therapyConcomitant therapySequential-concomitant therapyBismuth quadruple therapyLegacy triple therapyFive plus five day therapyNon-bismuth quadruple therapyHybrid therapyUnderutilized in practiceSecond line treatment (one treatment failure)Levofloxacin triple therapyThird line treatment (at least 2 treatment failures)Culture-guided therapyHigh-dose dual PPI therapyFurazolidone quadruple therapyRifabutin-based triple therapyRecommendedEmpiricalEmpiricalEmpirical – Last resortMalfertheiner P et al. Gut 2012 ; 61: 646 – 664.
    • 42. Standard triple therapy (PAC)Most widely used & approved therapy• PPI Standard dose, bid• Amoxicillin 1 g, bid• Clarithromycin 500 mg, bidFor 7 – 10 – 14 daysStandard triple therapy without prior susceptibility testingshould be abandoned when Clari-R > 15 – 20%Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.
    • 43. PPIs (½ hour before meal)Generic name Trade name Standard dose Refractory patientDelayed release PPIsOmeprazole Losec® 20 mg/d 80 mg/dLanzoprazole Lanzor® 30 mg/d 120 mg/dPantoprazole Protonix® 40 mg/d 160 mg/dRabeprazole Pariet® 20 mg/d 80 mg/dEsomeprazole Nexium® 40 mg/d 80 mg/dImmediate release PPIsOMP bicarbonate Zegerid® 20 mg/dBlock the H+K+ ATPase of parietal cell
    • 44. Treatment success for triple therapyintention-to-treat analysis (ITT)Line at 80% treatment successDemarcation between acceptable & unacceptably success rateEach bar represents a different studyGraham DY & Fischbach L. Gut 2010 ; 59 : 1143 – 1153.
    • 45. Improving standard triple therapy (PAC)• Increase dose of PPIEsomeprazole 40 mg bid increases eradication by 8 – 12%• Increase length of treatment10-day treatment Increases eradication by 4%14-day treatment Increases eradication by 5 – 6%• Adjuvant treatment Lactoferrin – S. boulardiiPromising resultsMore studies neededMalfertheiner P et al. Gut 2012 ; 61: 646 – 664.
    • 46. • PPI Standard dose, bid• Metronidazole 500 mg, bid• Clarithromycin 500 mg, bidFor 7 – 10 – 14 daysPAC & PMC regimens are equivalentShould not be used if metronidazole resistance > 40%Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.Standard triple therapy (PMC)Most widely used & approved therapy
    • 47. Sequential therapy‘‘five plus five’’ day therapy• 1st five days PPI (standard dose, bid)Amoxicillin (1 g bid)• 2nd five days PPI (standard dose, bid)Clarihromycin (500 mg, bid)Metronidazole/Tinidazole (500 mg, bid)For 10 daysGisbert JP et al. J Clin Gastroenterol 2010 ; 44 : 313 – 325.Indicated in clarithromycin or nitroimidazole resistance strainsNo indicated in dual clarithromycin & metronidazole resistance
    • 48. Sequential versus standard triple therapy15 RCTs – ITT – Random effect modelGisbert JP et al. J Clin Gastroenterol 2010 ; 44 : 313 – 325.Eradication rate: 76.7% (75 – 79%) versus 91.7% (90 – 93%)
    • 49. Concomitant therapy“Non-bismuth quadruple therapy”• PPI Standard dose, bid• Amoxicillin 1 g, bid• Clarithromycin 500 mg, bid• Metronidazole/Tinidazole 500 mg, bidRimbara E & Graham DY. Nat Rev Gastroenterol Hepatol 2011 ; 8 : 79 – 88.Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.For 10 – 14 daysNo indicated in high prevalence of Clari-R (> 20 – 30%)No indicated in dual clarithromycin & metronidazole resistance
    • 50. Concomitant therapy for treatment of H pyloriMeta-analysis – 15 RCTs (1723 pts) – Random effectGisbert J P et al. Aliment Pharmacol Ther 2011 ; 34 : 604 – 617.
    • 51. Sequential-concomitant therapy‘‘Hybrid therapy’’• 1st seven days PPI (standard dose, bid)Amoxicillin (1 g, bid)• 2nd seven days PPI (standard dose, bid)Amoxicillin (1 g, bid)Clarihromycin (500 mg, bid)Metronidazole/Tinidazole (500 mg, bid)Hsu PI et al. Gastroenterology 2010 ; 138 (Suppl. 1), S111.For 14 daysTreatment success (117 patients): 97% (ITT) – 99% (PP)High efficacy in dual clarithromycin & metronidazole resistance
    • 52. Bismuth quadruple therapy (BMT)Underutilized in clinical practice• PPI Standard dose, bid• Bismuth subcitrate 420 mg, qid• Metronidazole/Tinidazole 500 mg, tid• Tetracycline 500 mg, qidFor 10 – 14 daysHighly effective: eradication rate 92%Highly cost effectiveRimbara E & Graham DY. Nat Rev Gastroenterol Hepatol 2011 ; 8 : 79 – 88.
    • 53. Treatment regimen according to areas of Clari-RMalfertheiner P et al. Gut 2012 ; 61: 646 – 664.1st linePPI-Amoxicillin-ClarithroBismuth quadrupleBismuth quadrupleSequential or ConcomitantRegion with low Clari-R< 20%Region with high Clari-R> 20%
    • 54. Confirmation of eradication for H pylori• Indications H. pylori–associated ulcerPersistent symptoms in dyspepsiaGastric MALT lymphomaResection for early gastric cancer• Methods Urea breath test or fecal antigen testEndoscopy if it is requiredMégraud F. Presse Med. 2010 ; 39 : 815 – 822.McColl KEL. N Engl J Med 2010 ; 362 : 1597 – 1604.
    • 55. Treatment of H pylori-positive peptic ulcer• Uncomplicated DUProlongs PPI not recommended after HP treatment (Grade A)• GU & complicated DUProlongs PPI treatment is recommended (Grade A)• Bleeding ulcerHP eradication started at introduction of oral feeding (Grade A)Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.
    • 56. Treatment of H. pylori infectionFirst line treatmentStandard triple therapySequential therapyConcomitant therapySequential-concomitant therapyBismuth quadruple therapy“legacy triple therapy”“five plus five day therapy”“non-bismuth quadruple therapy”“hybrid therapy”underutilized in practiceSecond line treatment (one treatment failure)Levofloxacin triple therapyThird line treatment (at least 2 treatment failures)Culture-guided therapyHigh-dose dual PPI therapyFurazolidone quadruple therapyRifabutin-based triple therapyRecommendedEmpiricalEmpiricalEmpirical – Last resortMalfertheiner P et al. Gut 2012 ; 61: 646 – 664.
    • 57. Levofloxacin-based triple therapySecond line therapy• PPI Standard dose, bid• Amoxicillin 1 g, bid• Levofloxacin 500 mg, qdMalfertheiner P et al. Gut 2012 ; 61: 646 – 664.For 10 – 14 daysRising rates of levofloxacin resistance
    • 58. Treatment regimen according to areas of Clari-RRegion with low Clari-R< 20%Region with high Clari-R> 20%1st linePPI-Amoxicillin-ClarithroBismuth quadrupleBismuth quadrupleSequential or Concomitant2nd line*Bismuth quadruplePPI-Amoxicillin-LevofoxacinPPI-Amoxicillin-LevofoxacinMalfertheiner P et al. Gut 2012 ; 61: 646 – 664.* Regimen should not include antibiotics given previously
    • 59. Treatment of H. pylori infectionFirst line treatmentStandard triple therapySequential therapyConcomitant therapySequential-concomitant therapyBismuth quadruple therapy“legacy triple therapy”“five plus five day therapy”“non-bismuth quadruple therapy”“hybrid therapy”underutilized in practiceSecond line treatment (one treatment failure)Levofloxacin triple therapyThird line treatment (at least 2 treatment failures)Culture-guided therapyHigh-dose dual PPI therapyFurazolidone quadruple therapyRifabutin-based triple therapyRecommendedEmpiricalEmpiricalEmpirical – Last resortMalfertheiner P et al. Gut 2012 ; 61: 646 – 664.
    • 60. Culture-guided therapyRecommended third line therapy• PPI Standard dose, bid• Bismuth 2 tablets, qid• 1st antibiotic Selected by antimicrobial sensitivity tests• 2nd antibiotic Selected by antimicrobial sensitivity testsFor 10 – 14 daysMalfertheiner P et al. Gut 2012 ; 61: 646 – 664.
    • 61. Susceptibility testing• Culture & standard susceptibility testing (preferable)Practical for Clarithromycin & Levofloxacin resistanceMetronidazole susceptibility testing lacks reproducibility• Molecular tests (if culture not possible)Detect mutations in HP genome that result in resistanceRT PCR/nested PCR on gastric biopsies (or stool specimens)Practical for Clari-R & possibly fluoroquinolone resistance• Fluorescence in situ hybridization (FISH)On gastric biopsiesMalfertheiner P et al. Gut 2012 ; 61: 646 – 664.
    • 62. High-dose dual PPI therapyEmpirical third line therapy• PPI (high dose) Omeprazole 40 mg, qidorLansoprazole 30 mg, qid• Amoxicillin 500 mg, bidRimbara E & Graham DY. Nat Rev Gastroenterol Hepatol 2011 ; 8 : 79 – 88.For 14 daysStudies needed to confirm the success seen in Japan
    • 63. Furazolidone-based quadruple therapyEmpirical third line therapy• PPI Standard dose, bid• Bismuth subcitrate 420 mg, qid• Tetracyclin 500 mg, qid• Furazolidone 100 mg, tidGraham DY & Lu H. Saudi J Gastroenterol 2012 ; 18 : 1 – 2.For 10 – 14 days
    • 64. Furazolidone• Produced commercially since 1955• Antibacterial & antiprotozoal in human & veterinary medicine• No longer marketed in US since 2005 (market too small)• No approved by the EMA1 for human medicine or animal use• Classified by the IARC2 as group 3 drug in 1998• Monamine oxidase inhibitor & may interact with food & drugs• Variable resistance: 1 – 25 % in Iran & 0 – 40% in China1 EMA: European Medicines Agency2 IARC: International Agency for Research on CancerGraham DY & Lu H. Saudi J Gastroenterol 2012 ; 18 : 1 – 2.Zullo A et al. Saudi J Gastroenterol 2012 ; 18 : 11 – 17.
    • 65. Furazolidone-based quadruple therapySystematic reviewZullo A et al. Saudi J Gastroenterol 2012 ; 18 : 11 – 17.
    • 66. Rifabutin-based triple therapyEmpirical third line therapy – Drug of last resort• PPI Standard dose, bid• Amoxicillin 1 g, bid• Rifabutin 150 mg, bidGisbert J P et al. Aliment Pharmacol Ther 2012 ; 35 : 209 – 221.For 10 – 12 daysAdministered as rescue therapy without prior antibiogram
    • 67. RifabutinRifamycin-S derivative• Indications Mycobacteria including MAC*Third line treatment of H pylori• Eradication 3rd line: 342 patients – 66% (55–77%)4th / 5th line: 95 patients – 70% (60–79%)• Resistance 2982 pts: 1.3% (95% CI: 0.9% to 1.7%)• Adverse effects Myelotoxicity: Most significant – RareRecovered of leucopenia in few days* MAC: Mycobacterium Avium-intracellulare ComplexGisbert J P et al. Aliment Pharmacol Ther 2012 ; 35 : 209 – 221.
    • 68. Rifabutin-based triple therapyEmpirical third line therapyGisbert J P et al. Aliment Pharmacol Ther 2012 ; 35 : 209 – 221.
    • 69. 2nd line*Bismuth quadruplePPI-Amoxicillin-LevofoxacinPPI-Amoxicillin-LevofoxacinTreatment regimen according to areas of Clari-RMalfertheiner P et al. Gut 2012 ; 61: 646 – 664.* Regimen should not include antibiotics given previouslyRegion with low Clari-R< 20%Region with high Clari-R> 20%1st linePPI-Amoxicillin-ClarithroBismuth quadrupleBismuth quadrupleSequential or Concomitant3rd line Based on susceptibility testing only
    • 70. Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.* Regimen should not include antibiotics given previouslyTreatment in patients with penicillin allergyRelatively common subgroup of patients2nd line*PPI – Clarithromycin – LevofoxacinRegion with low levofloxacin resistance1st linePPI-Clarithro-Metronidazole Bismuth quadrupleRegion with low Clari-R< 20%Region with high Clari-R> 20%
    • 71. General recommendations for H. pylori treatment• 1st line therapy Avoid CLA if given for any indicationAvoid LEV if given for any indicationUse 4 drugs : sequential, bismuth, hybridUse higher doses of drugsUse 14 day duration• 2nd line therapy Do not reuse same drugs• 3rd line therapy Use culture-guided therapy if availableRifabutin-based therapy as last resortGraham DY & Fischbach L. Gut 2010 ; 59 : 1143 – 1153.
    • 72. Helicobacter pylori infection Discovery of H. pylori Epidemiology of H. pylori Indications for treatment Diagnosis of infection Treatment of infection Prevention of gastric cancer
    • 73. Risk factor for gastric cancer• H. pylori Most consistent risk factorEradication reduces risk of cancer• Genetic factors Cytokines: IL-1β, IL-8, IL-10, TNF-αNo recommended marker at present• Environmental factors N-nitroso compoundsSalted foods, tobacco, alcoholSubordinate to effect of HP infectionProtective effect of NSAID & aspirinMalfertheiner P et al. Gut 2012 ; 61: 646 – 664.
    • 74. Gastric cancer pathwaysEradication of H pylori reduces risk of gastric cancerBut not eliminate cancer due to predetermined genetic pathways:Hereditary diffuse gastric cancers & autoimmune gastritisTalley NJ. Lancet 2008 ; 372 : 350 – 352.
    • 75. Carcinogenicity of H. pyloriAtrophic corpus gastritisH. pylori infectionHypochlorhydriaOvergrowth of non-HPorganismsReduce nitrates to nitrites& N-nitrosaminesReduced/absent concentrationsof ascorbic acidAscorbic acid scavengescarcinogenic N-nitrosaminesMalfertheiner P et al. Gut 2012 ; 61: 646 – 664.
    • 76. Prevention of gastric cancerIdentification of subjects with high risk of gastric cancer• Non-invasive tests Validated serology for H. pyloriLow incidence + Markers of atrophy (pepsinogens)PGI: chief cellPGII: chief cell – pyloric glandsLow PGI or low PG1/PGII → atrophy• Invasive test Gastroscopy & biopsiesHigh incidence OLGA staging system** OLGA: Operative Link for Gastritis AssessmentDinis-Ribeiro M et al. Endoscopy 2012 ; 44 : 74 – 94.Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.
    • 77. OLGA staging system for gastritisInternational group of gastroenterologists & pathologists• Applies histology reporting format for chronic hepatitis• Given number of portal tracts for staging of hepatitisWell-defined biopsy protocol Antrum (3) – Corpus (2)• Main lesion of cirrhosis risk FibrosisMain marker of gastric cancer Mucosal atrophy• Staging by combining degree of atrophy & topography• Assess risk of gastric cancer Stage 0 to stage 4OLGA: Operative Link for Gastritis AssessmentRugge M & Genta RM. Gastroenterology 2005 ; 129 : 1807 – 8 .
    • 78. Gastric biopsy sampling protocolA1 – A2Greater & lesser curvatures of distal antrumA3Lesser curvature at incisura angularisC1 – C2Anterior & posterior walls of proximal corpusAt least five biopsiesRugge M et al. Dig Liver Dis 2008 ; 40 : 650 – 658.
    • 79. Normal & atrophic glandular units in stomachNl mucosecreting gland Non-metaplastic atrophyNormal oxyntic gland Non-metaplastic atrophy Metaplastic atrophyPseudopyloric metaplasiaMetaplastic atrophyIntestinal metaplasiaRuggea M et al. Dig Liver Dis 2008 ; 40 : 650 – 658.AntrumCorpus
    • 80. OLGA staging system for gastritisCombining degree of atrophy & location• Atrophy No atrophy (0%) Score 0Mild (1 – 30%) Score 1Moderate (31 – 60%) Score 2Severe (> 60%) Score 3• Location Antral atrophy score (Aas) Mean A1 + A2 + A3Corpus atrophy score (Cas) Mean C1 + C2• OLGA Overall Aas & Cas Stage 0, 1, 2: low riskStage 3, 4: high riskRugge M et al. Dig Liver Dis 2008 ; 40 : 650 – 658.
    • 81. OLGA staging system for gastritisRuggea M et al. Dig Liver Dis 2008 ; 40 : 650 – 658.AntrumNo atrophyScore 0Mild atrophyScore 1Moderate atrophyScore 2Severe atrophyScore 3Stage 0 Stage I Stage II Stage IIStage I Stage I Stage II Stage IIIStage II Stage II Stage III Stage IVStage III Stage III Stage IV Stage IVAtrophy scoreCorpusNo atrophyScore 0Mild atrophyScore 1Moderate atrophScore 2Severe atrophyScore 3
    • 82. Assessment of elementary lesions• H. pylori status Positive – NegativeAbsent in PPI user & atrophic gastritis• Inflammation Lympho-monocytic – PolymorphicMay suggest presence of HP• Metaplasia Intestinal – Pseudo-pyloric• Precancerous lesions IEN (formerly dysplasia)** IEN: Intra-Epithelial NeoplasiaRugge M et al. Dig Liver Dis 2011 ; 43S : S373 – S384.Information on likely etiology: H. pylori, autoimmune,..
    • 83. Stage II gastritisRugge M et al. Dig Liver Dis 2011 ; 43S : S373 – S384.Stages 0, I, and II are associated with DU more than GU
    • 84. Stage III gastritisRugge M et al. Dig Liver Dis 2011 ; 43S : S373 – S384.GU encountered more frequently than in OLGA stages 0 – I – II
    • 85. Stage III gastritisCorpus predominant atrophy should suggest an autoimmune etiologyRugge M et al. Dig Liver Dis 2011 ; 43S : S373 – S384.
    • 86. Stage IV gastritisPan-atrophic gastritisEndoscopic surveillance in stage III–IV patientsRugge M et al. Dig Liver Dis 2011 ; 43S : S373 – S384.
    • 87. Eradicating epidemic gastric cancer has long been a dreamNow this dream can come trueRugge M et al. Nat Rev Gastroenterol Hepatol 2012 ; 9 : 128 – 129.
    • 88. References
    • 89. Thank You

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