What is the preferred first‑line regimen for Helicobacter pylori eradication in an adult patient with no known drug allergies, no prior Helicobacter pylori therapy, and no contraindications?

H. pylori Treatment

First-Line Regimen

Bismuth quadruple therapy for 14 days is the preferred first-line treatment for H. pylori eradication in adults with no prior therapy or drug allergies. 1, 2, 3

This regimen consists of:

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred; increases cure rates by 8-12% over standard PPIs) 1, 2
• Bismuth subsalicylate 262 mg (2 tablets) four times daily 1, 2
• Metronidazole 500 mg three to four times daily 1, 2, 3
• Tetracycline 500 mg four times daily 1, 2, 3

Why Bismuth Quadruple Therapy First-Line

• Achieves 80-90% eradication rates even in areas with high clarithromycin and metronidazole resistance 1, 2, 4
• Bacterial resistance to bismuth is extremely rare, making this regimen effective against resistant strains 1, 2
• Clarithromycin resistance now exceeds 15-20% in most of North America and Europe, rendering traditional triple therapy unacceptably ineffective (achieving only ~70% eradication) 1, 2
• Bismuth's synergistic effect overcomes metronidazole resistance in vitro, maintaining efficacy even with dual resistance 1, 2, 4

Critical Optimization Factors

• 14-day duration is mandatory—extending from 7 to 14 days improves eradication by approximately 5% 1, 2, 3, 5
• Take PPI 30 minutes before meals on an empty stomach without concomitant antacids 1, 2
• Esomeprazole or rabeprazole 40 mg twice daily is strongly preferred over other PPIs for superior acid suppression 1, 2
• Never use standard-dose PPI once daily—this is a major cause of treatment failure 1, 2

Alternative First-Line Option (Restricted Use)

Concomitant non-bismuth quadruple therapy may be used only when bismuth is unavailable and local clarithromycin resistance is documented below 15%: 1, 2, 5

• High-dose PPI twice daily
• Amoxicillin 1000 mg twice daily
• Clarithromycin 500 mg twice daily
• Metronidazole 500 mg twice daily
• Duration: 14 days

Do not use clarithromycin-based triple therapy as first-line treatment because clarithromycin resistance exceeds 15% in most regions, dropping eradication rates from 90% to approximately 20% with resistant strains. 1, 2

Second-Line Treatment After First-Line Failure

After bismuth quadruple therapy fails, use levofloxacin triple therapy (provided no prior fluoroquinolone exposure): 1, 2, 3, 5

• High-dose PPI (esomeprazole or rabeprazole 40 mg) twice daily
• Amoxicillin 1000 mg twice daily
• Levofloxacin 500 mg once daily
• Duration: 14 days

If clarithromycin-based therapy was used first-line and failed, switch to bismuth quadruple therapy as described above. 1, 2, 5

Critical Pitfall

Never repeat antibiotics that failed previously, especially clarithromycin or levofloxacin—resistance develops rapidly after exposure and guarantees treatment failure. 1, 2, 5

Third-Line and Rescue Therapies

After two failed eradication attempts with confirmed patient adherence, obtain antibiotic susceptibility testing to guide further treatment whenever possible. 1, 2, 3, 5

Empiric third-line options when susceptibility testing is unavailable:

• Rifabutin triple therapy: rifabutin 150 mg twice daily + amoxicillin 1000 mg twice daily + high-dose PPI twice daily for 14 days 1, 2, 5
• High-dose dual therapy: amoxicillin 2-3 g daily in 3-4 divided doses + high-dose PPI twice daily for 14 days 1, 2

Confirmation of Eradication

Test for eradication success at least 4 weeks after completing therapy using urea breath test or validated monoclonal stool antigen test. 1, 2, 3

• Discontinue PPI at least 2 weeks before testing to avoid false-negative results 1, 2, 3
• Never use serology to confirm eradication—antibodies persist long after successful treatment 1, 2, 3

Common Pitfalls to Avoid

• Inadequate PPI dosing significantly reduces efficacy—always use high-dose (twice daily) PPI, preferably esomeprazole or rabeprazole 40 mg 1, 2
• Shortening treatment duration below 14 days reduces eradication success by approximately 5% 1, 2, 3, 5
• Using pantoprazole—its potency is markedly lower (40 mg pantoprazole ≈ 9 mg omeprazole equivalent) 2
• Assuming low clarithromycin resistance without local surveillance data—most regions now have high resistance rates 1, 2
• Testing for cure earlier than 4 weeks or while still on PPIs yields false-negative results 1, 2

Special Populations

In patients with penicillin allergy, bismuth quadruple therapy is the first choice because it contains tetracycline rather than amoxicillin. 1, 2 Consider penicillin allergy testing after first-line failure, as most reported allergies are not true allergies. 2

In children, avoid fluoroquinolones and tetracyclines, limiting treatment options. 1, 3

Patient Factors Affecting Success

• Smoking roughly doubles the odds of eradication failure (OR ≈ 1.95)—advise cessation during therapy 1, 2
• High BMI/obesity may lower gastric mucosal drug concentrations, potentially reducing efficacy 1, 2
• Poor compliance is a leading cause of failure—provide clear written instructions and counsel on expected side effects (diarrhea occurs in 21-41% of patients during the first week) 2