1. Treatment of H. pylori infection
Maastricht IV/ Florence consensus report
Samir Haffar M.D.
Assistant Professor of Gastroenterology
2. European Helicobacter Study Group
Founded in1987
• 1996 Maastricht I consensus report
Eur J Gastroenterol Hepatol 1997 ; 9 : 1 – 2.
• 2000 Maastricht II consensus report
Aliment Pharmacol Ther 2002 ; 16 : 167 – 80.
• 2005 Maastricht III consensus report
Malfertheiner P et al. Gut 2007 ; 56 : 772 – 81.
• 2010 Maastricht IV/ Florence consensus report
44 experts from 24 countries
Malfertheiner P et al. Gut 2012 ; 61 : 646 – 664.
3. Responses to therapy for typical GI disease
IBS, IBD
Graham DY et al. Helicobacter 2011 ; 16 : 343 – 345.
< 100% success expected
Placebo generally needed
4. Clinical trial of H. pylori therapy
Graham DY & Dore MP. Helicobacter 2011 ; 16 : 343 – 345.
100% or near 100% success expected
No placebo response
Failure almost always explainable: Resistance – Flawed regimen
5. Grading system of H. pylori therapy
Graham DY et al. Helicobacter 2007 ; 12 : 275 – 278.
Grade Cure rate (ITT) Score
A ≥ 95% Excellent
B 90 – 94 % Good
C 85 – 89 % Acceptable
D 81 – 84 % Poor
F ≤ 80% Unacceptable
Similar to grade performance of school children
Failed
6. Bacterial factors
Primary resistance to antibiotics
Bacterial load in stomach
Bacterial coccoid forms
cagA status (negative)
vacA alleles status (s2m2 allele)
dup A status*
Factors affecting H. pylori eradication success
* dup: duodenal ulcer promoting
Zullo A et al. J Clin Gastroenterol 2012 ; 46 : 259 – 261.
Host factors
Compliance to therapy
Gastric acid hypersecretion
Genetic polymorphism of CYP 450
Gastroduodenal disease (NUD)
Gastritis pattern (pangastritis)
Obesity
Smoking
7. 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 occur
Graham DY et al. Drugs 2008 ; 68 : 725 – 736.
9. H. Pylori & antibiotic resistance
• Cross-resistance in each family of antibiotics
Resistance to clarithromycin → resistance to all macrolides
Resistance to levofloxacin → resistance to all fluoroquinolones
• No cross-resistance between different families of antibiotics
• Important to use compound indicated to get good results
Clarithromycin for macrolides
Tetracycline HCl and not doxycycline
Levofloxacin but not ciprofloxacin for fluoroquinolones
Malfertheiner P et al. Management of HP infection: the Maastricht IV/Florence consensus report.
Gut 2012 ; 61: 646 – 664.
10. HP & phenotypical antibiotic resistance
Scott D et al. Gut 1998 ; 43(Suppl 1): S56 – S60.
Graham et al. Gut 2010 ; 59 : 1143 – 1153.
pH 4 – 8: H. pylori survives
pH 4 – 6: Non-dividing H. pylori – Phenotypical resistance
pH 6 – 8: Dividing H. pylori – Susceptible to AMO or CLA
11. Smoking & eradication of H. pylori
22 studies – 5538 patients – Random effect
Suzuki T et al. Am J Med 2006 ; 119 : 217 – 224.
Differences of smokers & nonsmokers 8.4% (95% CI: 3.3-13.5%)
12. 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 countries
Rimbara E. et al. Nat Rev Gastroenterol Hepatol 2011 ; 8 : 79 – 88.
H. pyori, like tuberculosis, requires treatment with
multiple drugs for long duration
13. Annual recurrence of H. pylori after successful
eradication in developing countries
Each bar represents a different study
Recurrence of original infection or reinfection with new strain
Rimbara E. et al. Nat Rev Gastroenterol Hepatol 2011 ; 8 : 79 – 88.
14. Optimal antimicrobial therapies
• Dosage
• Dosing intervals
• Formulation
• Route of administration
• Duration of therapy
Establish parameters that will provide the best
outcome from a particular regimen:
Rimbara E. et al. Nat Rev Gastroenterol Hepatol 2011 ; 8 : 79 – 88.
15. Treatment of H. pylori infection
First line treatment
Standard triple therapy
Sequential therapy
Concomitant therapy
Sequential-concomitant therapy
Bismuth quadruple therapy
“legacy triple therapy”
“five plus five day therapy”
“non-bismuth quadruple therapy”
“hybrid therapy”
underutilized in practice
Second line treatment (one treatment failure)
Levofloxacin triple therapy
Third line treatment (at least 2 treatment failures)
Culture-guided therapy
High-dose dual PPI therapy
Furazolidone quadruple therapy
Rifabutin-based triple therapy
Recommended
Empirical
Empirical
Empirical – Last resort
16. Standard triple therapy (PAC)
Most widely used & approved therapy
• PPI Standard dose, bid
• Amoxicillin 1 g, bid
• Clarithromycin 500 mg, bid
For 7 – 10 – 14 days
Standard triple therapy without prior susceptibility testing
should be abandoned when Clari-R > 15 – 20%
Malfertheiner P et al. Management of HP infection: the Maastricht IV/Florence consensus report.
Gut 2012 ; 61: 646 – 664.
17. Treatment success for triple therapy
intention-to-treat analysis (ITT)
Line at 80% treatment success
Demarcation between acceptable & unacceptably success rate
Each bar represents a different study
Graham DY & Fischbach L. Gut 2010 ; 59 : 1143 – 1153.
18. Improving standard triple therapy (PAC)
• Increase dose of PPI
Esomeprazole 40 mg bid increases eradication by 8 – 12%
• Increase length of treatment
10-day treatment Increases eradication by 4%
14-day treatment Increases eradication by 5 – 6%
• Adjuvant treatment Lactoferrin – S. boulardii
Promising results
More studies needed
Malfertheiner P et al. Management of HP infection: the Maastricht IV/Florence consensus report.
Gut 2012 ; 61: 646 – 664.
19. • PPI Standard dose, bid
• Metronidazole 500 mg, bid
• Clarithromycin 500 mg, bid
For 7 – 10 – 14 days
PAC & PMC regimens are equivalent
Should not be used if metronidazole resistance > 40%
Standard triple therapy (PMC)
Most widely used & approved therapy
Malfertheiner P et al. Management of HP infection: the Maastricht IV/Florence consensus report.
Gut 2012 ; 61: 646 – 664.
20. 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 days
Gisbert JP et al. J Clin Gastroenterol 2010 ; 44 : 313 – 325.
Indicated in clarithromycin or nitroimidazole resistance strains
Not indicated in dual clarithromycin & metronidazole resistance
21. Rationale of sequential therapy
Sequential antibiotic administration not recommended
“fear to promote drug resistance”.
• Sequential administration
1st five days Lower bacterial load in stomach
Prevent selection of secondary Clari-R
Drug rarely results in resistance (ampicillin)
Eradiation rate at least 50%
2nd five days Eradicate small population of viable organisms
• Larger number of antibiotics (3 drugs)
Gisbert JP et al. J Clin Gastroenterol 2010 ; 44 : 313 – 325.
22. Sequential versus standard triple therapy
15 RCTs – ITT – Random effect model
Gisbert JP et al. J Clin Gastroenterol 2010 ; 44 : 313 – 325.
Eradication rate: 76.7% (75 – 79%) versus 91.7% (90 – 93%)
23. Limitations of sequential therapy
• Low validation outside Italy
• Small sample size: < 50 in some protocols
• Low quality of studies: Jadad score ≥3 in 1/10 studies in MA1
• Reduced compliance in clinical practice
• Unsuitable for dual clarithromycin & nitroimidazole resistance
• Unsuitable for penicillin allergy
1 Tong JL et al. J Clin Pharm Ther. 2009 ; 34 : 41 – 53.
2 Gisbert JP et al. J Clin Gastroenterol 2010 ; 44 : 313 – 325.
24. Concomitant therapy
“Non-bismuth quadruple therapy”
• PPI Standard dose, bid
• Amoxicillin 1 g, bid
• Clarithromycin 500 mg, bid
• Metronidazole/Tinidazole 500 mg, bid
Rimbara E & Graham DY. Nat Rev Gastroenterol Hepatol 2011 ; 8 : 79 – 88.
Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.
For 10 – 14 days
Not indicated in high prevalence of Clari-R (> 20 – 30%)
Not indicated in dual clarithromycin & metronidazole resistance
25. Concomitant therapy for treatment of H pylori
Meta-analysis – 15 RCTs (1723 pts – Random effect
Gisbert J P et al. Aliment Pharmacol Ther 2011 ; 34 : 604 – 617.
26. 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, P. I. et al. Gastroenterology 2010 ; 138 (Suppl. 1), S111.
For 14 days
Treatment success (117pts): 97% (ITT) – 99% (PP)
High efficacy in dual clarithromycin & metronidazole resistance
27. 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, qid
For 10 – 14 days
Highly effective: Eradication rate 92%
Cost effective: Cost of 14-day course < $50
Rimbara E & Graham DY. Nat Rev Gastroenterol Hepatol 2011 ; 8 : 79 – 88.
28. Treatment regimen according to areas of Clari-R
Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.
1st line
PPI-Amoxicillin-Clarithro
Bismuth quadruple
Bismuth quadruple
Sequential or Concomitant
Region with low Clari-R
< 20%
Region with high Clari-R
> 20%
29. Mégraud F. Presse Med. 2010 ; 39 : 815 – 822.
Malfertheiner P et al. Gut 2012; 61: 646 – 664.
Antibiotics Stopped for at least 4 weeks
PPIs Stopped for 14 days
H2RA Stopped for 7 days
Antacids Not stopped
Confirmation of eradication for H. pylori
UBT & monoclonal stool test
No role for serology
30. Confirmation of eradication for H. pylori
Non-endoscopic methods
Tests Sensitivity Specificity
Serology
ELISA IgG
70 – 90%
70 – 90%
Not to confirm eradication
Urea breath test 85 – 95% 85 – 95%
Fecal antigen test
“monoclonal”
85 – 95% 85 – 95%
WGO global guideline. J Clin Gastroenterol 2011 ; 45 : 383 – 388.
Fischbach W et al. Dtsch Arztebl Int 2009 ; 106 : 801 – 8.
31. Treatment of H pylori-positive peptic ulcer
• Uncomplicated DU
Prolongs PPI not recommended after HP treatment (Grade A)
• GU & complicated DU
Prolongs PPI is recommended (Grade A)
• Bleeding ulcer
HP eradication started at introduction of oral feeding (Grade A)
Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.
32. Treatment of H. pylori infection
First line treatment
Standard triple therapy
Sequential therapy
Concomitant therapy
Sequential-concomitant therapy
Bismuth quadruple therapy
“legacy triple therapy”
“five plus five day therapy”
“non-bismuth quadruple therapy”
“hybrid therapy”
underutilized in practice
Second line treatment (one treatment failure)
Levofloxacin triple therapy
Third line treatment (at least 2 treatment failures)
Culture-guided therapy
High-dose dual PPI therapy
Furazolidone quadruple therapy
Rifabutin-based triple therapy
Recommended
Empirical
Empirical
Empirical – Last resort
33. Levofloxacin-based triple therapy
Second line therapy
• PPI Standard dose, bid
• Amoxicillin 1 g, bid
• Levofloxacin 500 mg, qd
For 10 – 14 days
Rising rates of levofloxacin resistance
Malfertheiner P et al. Management of HP infection: the Maastricht IV/Florence consensus report.
Gut 2012 ; 61: 646 – 664.
34. Treatment regimen according to areas of Clari-R
Region with low Clari-R
< 20%
Region with high Clari-R
> 20%
1st line
PPI-Amoxicillin-Clarithro
Bismuth quadruple
Bismuth quadruple
Sequential or Concomitant
2nd line*
Bismuth quadruple
PPI-Amoxicillin-Levofoxacin
PPI-Amoxicillin-Levofoxacin
Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.
* Regimen should not include antibiotics given previously
35. Treatment of H. pylori infection
First line treatment
Standard triple therapy
Sequential therapy
Concomitant therapy
Sequential-concomitant therapy
Bismuth quadruple therapy
“legacy triple therapy”
“five plus five day therapy”
“non-bismuth quadruple therapy”
“hybrid therapy”
underutilized in practice
Second line treatment (one treatment failure)
Levofloxacin triple therapy
Third line treatment (at least 2 treatment failures)
Culture-guided therapy
High-dose dual PPI therapy
Furazolidone quadruple therapy
Rifabutin-based triple therapy
Recommended
Empirical
Empirical
Empirical – Last resort
36. Culture-guided therapy
Third line therapy
• PPI Standard dose, bid
• Bismuth 2 tablets, qid
• 1st antibiotic Selected by antimicrobial sensitivity tests
• 2nd antibiotic Selected by antimicrobial sensitivity tests
For 10 – 14 days
Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.
37. Susceptibility testing
• Culture & standard susceptibility testing (preferable)
Practical for Clarithromycin & Levofloxacin resistance
Metronidazole susceptibility testing lacks reproducibility
• Molecular tests (if culture not possible)
Detect mutations in HP genome that result in resistance
RT PCR/nested PCR on gastric biopsies (or stool specimens)
Practical for Clari-R & possibly fluoroquinolone resistance
• Fluorescence in situ hybridization (FISH)
On gastric biopsies
Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.
38. Fluorescence in situ hybridisation (FISH)
Clarithromycin susceptibility of HP on gastric biopsy
Rimbara E & Graham DY. Nat Rev Gastroenterol Hepatol 2011 ; 8 : 79 – 88.
Correlate well with results of culture & susceptibility testing
Detection of H. pylori
Susceptible & resistant
Isothiocyanate-labeled probe
Clari-resistant only
Rhodamine-labeled probe
Clari-resistant: yellow
Clari-susceptible: green
Combined image
39. High-dose dual PPI therapy
Empirical third line therapy
• PPI (high dose) Omeprazole 40 mg, qid
or
Lansoprazole 30 mg, qid
• Amoxicillin 500 mg, bid
Rimbara E & Graham DY. Nat Rev Gastroenterol Hepatol 2011 ; 8 : 79 – 88.
For 14 days
Studies needed to confirm the success seen in Japan
40. Furazolidone-based quadruple therapy
Empirical third line therapy
• PPI Standard dose, bid
• Bismuth Standard dose, qid
• Tetracyclin 500 mg, qid
• Furazolidone 100 mg, tid
Graham DY & Lu H. Saudi J Gastroenterol 2012 ; 18 : 1 – 2.
For 10 – 14 days
41. 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 China
1 EMA: European Medicines Agency
2 IARC: International Agency for Research on Cancer
Graham DY & Lu H. Saudi J Gastroenterol 2012 ; 18 : 1 – 2.
Zullo A et al. Saudi J Gastroenterol 2012 ; 18 : 11 – 17.
43. Rifabutin-based triple therapy
Empirical third line therapy – Drug of last resort
• PPI Standard dose, bid
• Amoxicillin 1 g, bid
• Rifabutin 150 mg, bid
Gisbert J P et al. Aliment Pharmacol Ther 2012 ; 35 : 209 – 221.
For 10 – 12 days
Administered as rescue treatment without prior antibiogram
44. Rifabutin
Rifamycin-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 – Rare
Recovered of leucopenia in few days
* MAC: Mycobacterium Avium-intracellulare Complex
Gisbert J P et al. Aliment Pharmacol Ther 2012 ; 35 : 209 – 221.
46. 2nd line*
Bismuth quadruple
PPI-Amoxicillin-Levofoxacin
PPI-Amoxicillin-Levofoxacin
Treatment regimen according to areas of Clari-R
Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.
* Regimen should not include antibiotics given previously
Region with low Clari-R
< 20%
Region with high Clari-R
> 20%
1st line
PPI-Amoxicillin-Clarithro
Bismuth quadruple
Bismuth quadruple
Sequential or Concomitant
3rd line Based on susceptibility testing only
47. Malfertheiner P et al. Gut 2012 ; 61: 646 – 664.
* Regimen should not include antibiotics given previously
Treatment in patients with penicillin allergy
Relatively common subgroup of patients
1st line
PPI-Clarithro-Metronidazole Bismuth quadruple
2nd line*
PPI – Clarithromycin – Levofoxacin
Region with low levofloxacin resistance
Region with low Clari-R
< 20%
Region with high Clari-R
> 20%
48. Cautions associated with anti-HP antimicrobials
• Nitroimidazole Carcinogenicity (Group 2B – IARC)
Antibuse-like reaction
• Furazolidone Carcinogenicity (Group 3 – IARC)
Monamine oxidase inhibitor
Avoid some food & drugs
• Fluoroquinolone Tendinitis & tendon rupture especially:
> 60 year, organ transplants, steroids
• Rifabutin Induces CYP3A enzymes
Last resort Interacts with long list of drugs
Increasing resistance of mycobacteria
* IARC: International Agency for Research on Cancer
Graham DY & Fischbach L. Gut 2010 ; 59 : 1143 – 1153.
49. General recommendations for H. pylori treatment
• 1st line therapy Avoid CLA if given for any indication
Avoid LEV if given for any indication
Use 4-drug treatment: sequential, bismuth,.
Use higher doses of drugs
Use 14 day duration
• 2nd line therapy Do not reuse same drugs
• 3rd line therapy Use culture-guided therapy if available
Rifabutin-based therapy as last resort
Graham DY & Fischbach L. Gut 2010 ; 59 : 1143 – 1153.
Gram-negative bacterium with helical rod shape.Prominent flagellae facilitating penetration of thick mucous layer in the stomach.
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 Needs therapy of extended-duration 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.
Clarithromycin resistance: Sequential therapy significantly more effective than standard triple therapy in pts with clarithromycin-resistant strains (89 vs 29% in study of Vaira, 78% vs. 17% in study of Zullo). Nitroimidazole resistance:Sequential therapy significantly more effective than standard triple therapy in pts with metronidazole-resistant strains (96 vs 78% in meta-analysis of Jafri). Dual clarithromycin & metronidazole resistance:In the study by Vaira et al, none of the 4 patients with double clarithromycin and metronidazole-resistant strains achieved eradication with the sequential treatment, whereas 2 out of 7 patients achieved eradication with the standard triple regimen.Sequential therapy may not be good option in regions where both clarithromycin & metronidazole resistance are common, or for treatment after multiple failed therapies.
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.
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.
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.
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
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.
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.
International Agency for Research on CancerGroup 1 Carcinogenic to humansGroup 2 A Probably carcinogenic to humans Sufficient evidence in animal studies Lesser degree of evidence in humansGroup 2 B Possibly carcinogenic to humans Sufficient evidence in animal tests or degrees of evidence considered appropriateGroup 3 Unclassifiable as to carcinogenicity in humansGroup 4 Probably not carcinogenic to humans
