What’s New in Helicobacter Pylori Therapy Waqar Qureshi, MD, Professor of Medicine, Clinical Director of Gastroenterology, Baylor College of Medicine, Houston, Texas

Helicobacter pylori H. pylori is a serious chronic transmissible infectious disease that causes damage to gastric structure and function and is a major cause of morbidity and mortality worldwide. The prevalence of H. pylori is inversely related to the general health and well being of a society. It should be eradicated

Kyoto Global Consensus Report on H. pylori gastritis “H pylori-infected individuals should be offered eradication therapy, unless there are competing considerations”. Gut: (in press)

OUTCOMES OF H. PYLORI INFECTION Gastric Cancer Environmental Factors Atrophic Gastritis Gastric Ulcer Acute Gastritis Acute-on-Chronic Gastritis Lymphoma Antral Predominant Gastritis Duodenal Ulcer Childhood Mid-life Old Age

WHOM TO TEST Dyspepsia (symptomatic Hp?) Ulcer Disease Gastric cancer Present or past history 1st degree relatives Gastric cancer Family history gastric cancer After endoscopic resection of gastric cancer

Evaluate Hp eradication Family members of infected WHOM TO TEST Plan to start therapy Chronic NSAID therapy Chronic PPI therapy (eg, GERD) Evaluate Hp eradication Family members of infected Patient desires to be tested

Whom to Treat for Hp All with active Hp infection unless there is a compelling reason not to

H. pylori Causes Peptic ulcer disease (1 in 6) Gastric cancer (1 to 19%) Progressive gastric damage Iron deficiency B12 deficiency Recuced absorption of drugs requiring an acid stomach such as L-dopa & throxine

Diagnosis Therapy Confirm cure STEPS IN THERAPY OF Hp All active Hp infection should be treated unless there is a compelling reason not to

Hp is an Infectious Disease Hp therapies either succeed or fail There is no partial success Primary causes of failure Resistance to one or more antibiotics Adherence with drug regimen

Scoring “Effective” Treatment Regimens Outcome Success* Excellent: >95% Good: >90% Borderline: 85-89% Unacceptable <84% * Per Protocol: reliably with susceptible strains.

The Present No new therapies approved for more than a decade Old therapies have become relatively ineffective (eg, 70% cure rates) Overall prevalence decreasing but still high in subpopulations (31% in VA population), 70%+ in Hispanic and Asian immigrants.

Current First Line Therapies Clarithromycin based therapy Bismuth based therapy Triple Quadruple 7, 10 or 14 days duration

PPI – Amox –Clari Therapy 100 Hong Kong n = 592 80 Taiwan n = 1200 U.S. n = 1255 Europe n = 3752 Korea n = 598 China n = 148 60 ITT Cure Rates (%; 95% CI) 40 Japan n = 1323 20 Results of Recent Trials

Clarithromycin-Containing Regimes Triple therapy (3 drugs) PPI+Amoxicillin+Clarithromycin Concomitant therapy (4 drugs) PPI+Amox+Clari+Metro Sequential therapy (4 drugs) PPI+Amox then PPI+Clari+Metro

Other Common Regimes Triple metronidazole therapy PPI+Amoxicillin+Metronidazole Triple fluroroquinolone therapy PPI+Amoxicillin+Levofloxacin Bismuth Quadruple therapy PPI+Bismuth+metro+tetracycline

Treatment Comparison - Susceptible Strains (PP) - Therapy Days Success Clarithromycin triple therapy 7 94% Clarithromycin triple therapy 14 97% Sequential therapy 10 94% Sequential therapy 14 97% Fluoroquinolone triple 7 <80% Fluoroquinolone triple 10 <90% Fluoroquinolone triple 14 96%

Treatment Comparison – 2 - Susceptible Strains (PP) - Therapy Days Success PPI metronidazole triple 7 94% PPI metronidazole triple 14 97% PPI bismuth tetra metro 7 91% PPI bismuth tetra metro 10 93% PPI bismuth tetra metro 14 >95% PPI + amoxicillin 7 10% PPI + amoxicillin 10 20% PPI + amoxicillin 14 50%

Treatment Comparison - With Resistant Strains (PP) - Therapy Days Success Clarithromycin triple therapy 7 <20% Clarithromycin triple therapy 14 <50% Sequential therapy (dual) 10 <20% Sequential therapy (dual) 14 <20% Fluoroquinolone triple 7 <20% Fluoroquinolone triple 10 <20% Fluoroquinolone triple 14 <50%

Effect of Clari Resistance 7 day Triple PPI + Amox + Clari (94%) + PPI + Amox (10%)

7 Day Clari-Triple Rx PP 100 80 Treatment Success (%) 60 40 20 94% 80 Susceptible 60 Treatment Success (%) 40 20 10% Clari Res Triple Rx Dual (PPI +A)

Useful History Details of the prior regimen How many times attempted? Type and dose and antibiotics? Type and dose of PPI? Any adjuvant (e.g., probiotics)? How many times attempted? Any drug allergies or inabilities to take one or more drugs?

Predict Success for an Individual Patient Prior antibiotic use Previously treated for H. pylori Predict Resistance Treatment outcome (per protocol) All Suscept Clari Resistant Metro Resistant Dual Resistant Regimen 94% 7 day Clari Triple 97% 14 day Clari Triple 95% 10 day Sequential 98+% 14 day Sequential 97+% 14 day Concomitant

Predict Success for an Individual Patient Prior antibiotic use Previously treated for H. pylori Predict Resistance Treatment outcome (per protocol) All Suscept Clari Resistant Metro Resistant Dual Resistant Regimen <20% 94% 7 day Clari Triple 97% <50% 14 day Clari Triple 95% 80% 10 day Sequential 98+% 88% 14 day Sequential 97+% 97% 14 day Concomitant/Hybrid

Predict Success for an Individual Patient Prior antibiotic use Previously treated for H. pylori Predict Resistance Treatment outcome (per protocol) All Suscept Clari Resistant Metro Resistant Dual Resistant Regimen <20% 94% 94% 7 day Clari Triple <50% 97% 97% 14 day Clari Triple 95% 80% 75% 10 day Sequential 98+% 88% 75% 14 day Sequential 97+% 97% 97% 14 day Concomitant

Predict Success for an Individual Patient Prior antibiotic use Previously treated for H. pylori Predict Resistance Treatment outcome (per protocol) All Suscept Clari Resistant Metro Resistant Dual Resistant Regimen <20% 94% 94% <20% 7 day Clari Triple 97% <50% 97% <50% 14 day Clari Triple 95% 80% 75% <20% 10 day Sequential 98+% 88% 75% <20% 14 day Sequential 97+% 97% 97% <50% 14 day Concomitant

Regimens Concomitant: b.i.d. for 14 days PPI (40 mg omeprazole or equivalent) Amoxicillin 1000 mg Clarithromcyin 500 mg Metronidazole 500 mg

Previously treated for H. pylori Bismuth Quadruple Rx Prior antibiotic use Previously treated for H. pylori Predict Resistance Treatment outcome (per protocol) All Suscep Clari Resistan Metro Resistan Dual Resistant Regimen 7 day bismuth quadruple 91% n/a 75% n/a 10 day bismuth quadruple 93% n/a 85% n/a n/a 95% n/a 14 day bismuth quadruple 99%

Previously treated for H. pylori Bismuth Quadruple Rx Prior antibiotic use Previously treated for H. pylori Predict Resistance Treatment outcome (per protocol) All Suscept Clari Resistant Metro Resistant Dual Resistant Regimen 7 day bismuth quadruple 91% 10 day bismuth quadruple 93% 14 day bismuth quadruple 99%

Previously treated for H. pylori Bismuth Quadruple Rx Prior antibiotic use Previously treated for H. pylori Predict Resistance Treatment outcome (per protocol) All Suscept Clari Resistant Metro Resistant Dual Resistant Regimen 7 day bismuth quadruple 91% n/a 75% n/a 10 day bismuth quadruple 93% n/a 85% n/a n/a 95% n/a 14 day bismuth quadruple 99%

Bismuth Quadruple Tetracycline is difficult to obtain Doxycycline is not a useful substitute! Helidac (other packaged product, not currently available Give for 14 days

+ a PPI

Recommended Empiric Regimens (14 days) Concomitant therapy Bismuth quadruple therapy Currently only Pylera available (give for 14 days) + PPI Do not use doxycycline PPI: always use 40 mg omeprazole or equivalent b.i.d.

Keys to Success Use what is effective locally Use it exactly (dose, duration, etc) Base therapy on measured susceptibility testing (Tailored therapy) Confirm cure in all cases

Initial Approach 2015 H. pylori infected History of antibiotic use? Previously treated for H. pylori? Treatment naive Treatment naive Prior treatment Failure Prior treatment Failure 14 day concomitant Rx 14 day bismuth quadruple Alternate best local Rx

Treatment Failures Antimicrobials not used before Fluoroquinolones Rifabutin PPI – Amoxicillin high dose

14 day Fluoroquinolone Amoxicillin 1 gram b.i.d. Levo 500 or Moxi 400 once a day PPI b.i.d. 14 days (7 and 10 day = poor results) Can not be used if a fluoroquinolone has been used in the past Best if based on culture and susceptibility testing Miehlke: Helicobacter 2011:16:420

Rifabutin Triple Rx Rifabutin 150 mg once daily (b.i.d.?) Amoxicillin 1.5 g t.i.d. Pantoprazole 80 mg t.i.d. (or equivalent) (Consider adding bismuth 2 tabs b.i.d.) All for 14 days * We need more studies and confirmation Borody: Aliment Pharmacol Ther 2006;23:481.

High Dose PPI-Amox PPI (eg, 40 mg esomeprazole) plus Amoxicillin 750 mg every 6 hours for 14 days.

Choice for a Population Depends on resistance patterns 14 day triple (only when all susceptible) 14 day concomitant 14 day bismuth quadruple (dual resistance) Should yield >90% eradication

Clari-Containing Regimens - Conclusions - High prevalence of clari AND met resistance (high dual resistance) No clari-containing regimen is useful when the is a high prevalence of dual resistance

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