What is the recommended first‑line therapy for Helicobacter pylori infection in an adult patient without drug allergies, pregnancy, or severe comorbidities, considering local clarithromycin resistance?

H. pylori Treatment: First-Line Therapy Recommendation

Bismuth quadruple therapy for 14 days is the definitive first-line treatment for H. pylori infection in adults without drug allergies, pregnancy, or severe comorbidities, achieving 80–90% eradication rates regardless of local clarithromycin resistance. 1, 2, 3

Recommended First-Line Regimen

The standard bismuth quadruple therapy consists of:

• High-dose PPI (esomeprazole or rabeprazole 40 mg) twice daily – taken 30 minutes before meals on an empty stomach 1, 2, 3
• Bismuth subsalicylate 262 mg (two tablets) four times daily 1, 2, 3
• Metronidazole 500 mg three to four times daily (total 1.5–2 g/day) 1, 2, 3
• Tetracycline 500 mg four times daily 1, 2, 3
• Duration: 14 days (mandatory) 1, 2, 3, 4

Esomeprazole or rabeprazole 40 mg twice daily is strongly preferred over other PPIs because it increases cure rates by 8–12% compared to standard-dose PPIs. 1, 2, 3

Why Bismuth Quadruple Therapy Is First-Line

Clarithromycin resistance now exceeds 15–20% across North America and most of Europe, reducing traditional triple therapy success rates to approximately 70%—well below the 80% minimum target. 1, 2, 3 When clarithromycin-resistant strains are present, triple therapy eradication rates plummet from 90% to 20%. 1, 3

Bismuth quadruple therapy achieves 80–90% eradication even in regions with high dual resistance to clarithromycin and metronidazole because:

• No bacterial resistance to bismuth has been described 1, 2, 3
• Bismuth's synergistic effect overcomes metronidazole resistance in vitro 5, 1, 2
• The regimen uses WHO "Access" antibiotics (tetracycline, metronidazole) rather than "Watch" agents (clarithromycin, levofloxacin), supporting antimicrobial stewardship 1, 3

Alternative First-Line Options (Restricted Use)

If bismuth is unavailable AND local clarithromycin resistance is documented <15%:

• Concomitant non-bismuth quadruple therapy: High-dose PPI twice daily + amoxicillin 1000 mg twice daily + clarithromycin 500 mg twice daily + metronidazole 500 mg twice daily for 14 days 1, 2, 3, 4

Clarithromycin-based triple therapy (PPI + clarithromycin 500 mg twice daily + amoxicillin 1000 mg twice daily for 14 days) should only be used when:

• Local clarithromycin resistance is documented <15% 5, 1, 2, 3
• The patient has no prior macrolide exposure for any indication 1, 2, 3

Critical Optimization Factors

Treatment duration of 14 days is mandatory—extending therapy from 7 to 14 days improves eradication success by approximately 5%. 5, 1, 2, 3, 4 The Toronto Consensus, Maastricht V/Florence, and American College of Gastroenterology all endorse 14 days as the standard. 1, 3, 4

High-dose PPI twice daily is non-negotiable; once-daily dosing is a major cause of treatment failure. 1, 2, 3 Standard twice-daily PPI dosing increases cure rates by 6–10% compared to once-daily regimens. 1

Avoid pantoprazole 40 mg—its acid-suppression potency is equivalent to only ~9 mg omeprazole, yielding inferior outcomes. 1, 2, 3

Higher metronidazole doses (1.5–2 g daily in divided doses) improve eradication even against resistant strains when combined with bismuth. 1, 2, 3

Second-Line Treatment After First-Line Failure

If bismuth quadruple therapy fails, levofloxacin triple therapy is the recommended second-line option:

• High-dose PPI (esomeprazole or rabeprazole 40 mg) twice daily 1, 2, 3
• Amoxicillin 1000 mg twice daily 1, 2, 3
• Levofloxacin 500 mg once daily 1, 2, 3
• Duration: 14 days 1, 2, 3

This regimen should only be used if the patient has no prior fluoroquinolone exposure for any indication, as levofloxacin resistance rates are rising (primary 11–30%, secondary 19–30%). 1, 2, 3 Levofloxacin should never be used empirically as first-line therapy. 1, 2, 3

If clarithromycin-based triple therapy fails, retreat with bismuth quadruple therapy for 14 days. 1, 2, 3

Third-Line and Rescue Strategies

After two documented eradication failures with confirmed patient adherence, antibiotic susceptibility testing should guide further treatment. 5, 1, 2, 3, 4

Rescue options include:

• Rifabutin triple therapy: Rifabutin 150 mg twice daily + amoxicillin 1000 mg twice daily + high-dose PPI twice daily for 14 days (rifabutin resistance is rare) 1, 2, 3, 4
• High-dose dual therapy: Amoxicillin 2–3 g daily in 3–4 divided doses + high-dose PPI twice daily for 14 days 1, 2, 3

Confirmation of Eradication

Verify eradication ≥4 weeks after completing therapy using a urea breath test or validated monoclonal stool antigen test. 1, 2, 3 Discontinue PPI ≥2 weeks before testing. 1, 2, 3

Never use serology to confirm eradication—antibodies persist long after successful treatment. 1, 3

Common Pitfalls to Avoid

• Never use once-daily PPI dosing 1, 2, 3
• Never shorten therapy below 14 days 1, 2, 3, 4
• Never repeat clarithromycin or levofloxacin after a failed regimen—resistance develops rapidly after exposure 1, 2, 3
• Do not assume low clarithromycin resistance without local surveillance data; most regions now have high resistance rates 1, 2, 3
• Metronidazole can be reused with bismuth due to synergistic effects; amoxicillin and tetracycline can be reused because resistance remains rare (<5%) 1, 2, 3

Special Populations

Penicillin allergy: Bismuth quadruple therapy is the first choice because it contains tetracycline instead of amoxicillin. 1, 2, 3 Consider penicillin-allergy testing to rule out true anaphylaxis, as most reported allergies are not true allergies. 1, 3

If confirmed penicillin allergy and bismuth is unavailable: Use PPI + clarithromycin 500 mg twice daily + metronidazole 500 mg twice daily for 14 days, but only where clarithromycin resistance is documented <15%. 1, 2, 3