What is the recommended first‑line triple therapy for Helicobacter pylori eradication in an adult without macrolide allergy in a region with ≤15% clarithromycin resistance?

H. pylori Triple Therapy in Low Clarithromycin Resistance Regions

In regions with documented clarithromycin resistance below 15%, the recommended first-line triple therapy is a high-dose PPI (esomeprazole or rabeprazole 40 mg) twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1000 mg twice daily for 14 days. 1, 2

Regimen Components and Dosing

• High-dose PPI twice daily is mandatory—esomeprazole or rabeprazole 40 mg twice daily increases cure rates by 8–12% compared to standard-dose PPIs 1, 2
• Clarithromycin 500 mg twice daily combined with amoxicillin 1000 mg twice daily forms the antibiotic backbone 1, 3
• All PPIs should be taken 30 minutes before meals on an empty stomach, without concomitant antacids 1
• Treatment duration must be 14 days—this improves eradication success by approximately 5% compared to 7–10 day regimens 1, 2, 4

Critical Prerequisite: Confirm Low Resistance

• This regimen should ONLY be used when local clarithromycin resistance is documented to be <15% 1, 2, 3
• In most of North America and Central, Western, and Southern Europe, clarithromycin resistance now exceeds 20%, making this regimen unacceptable without susceptibility testing 1
• When clarithromycin-resistant strains are present, eradication rates drop from 90% to approximately 20% 1

Alternative First-Line Options (Superior in Most Settings)

Even in low-resistance areas, bismuth quadruple therapy achieves superior 80–90% eradication rates and should be strongly considered as the preferred first-line option 1, 2, 4:

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred) 1
• Bismuth subsalicylate 262 mg (two tablets) four times daily 1
• Metronidazole 500 mg three to four times daily 1, 3
• Tetracycline 500 mg four times daily 1, 3
• Duration: 14 days 1, 4

Bismuth quadruple therapy is not affected by clarithromycin resistance and maintains efficacy even against dual clarithromycin-metronidazole resistant strains due to bismuth's synergistic effect 1, 2

Optimization Strategies for Triple Therapy

• Use long-acting clarithromycin formulations (clarithromycin MR 1000 mg once daily) if available, which can achieve 100% eradication at 14 days regardless of CYP2C19 genotype 5
• Avoid pantoprazole—its acid-suppression potency is markedly lower (40 mg pantoprazole ≈ 9 mg omeprazole equivalent) 1
• Never use once-daily PPI dosing—this is a major cause of treatment failure 1

Common Pitfalls to Avoid

• Never assume low clarithromycin resistance without local surveillance data—most regions now have high resistance rates 1, 2
• Avoid repeating clarithromycin if the patient has prior macrolide exposure for any indication—cross-resistance is universal within the macrolide family 1
• Do not shorten therapy below 14 days—7-day regimens are inadequate 1, 4
• Never use serology to confirm eradication—antibodies persist long after successful treatment 2, 3

Verification of Eradication

• Confirm eradication with urea breath test or monoclonal stool antigen test at least 4 weeks after completion of therapy 1, 2, 3
• Discontinue PPI at least 2 weeks before testing 1, 2

Second-Line Options After Triple Therapy Failure

• Bismuth quadruple therapy for 14 days (if not previously used) is the preferred second-line option 1, 2, 4
• Levofloxacin triple therapy (PPI twice daily + amoxicillin 1000 mg twice daily + levofloxacin 500 mg once daily for 14 days) is an alternative if no prior fluoroquinolone exposure 1, 2, 3
• Never repeat clarithromycin after failure—resistance develops rapidly after exposure 1, 4

Special Populations

• In patients with penicillin allergy, substitute metronidazole 500 mg twice daily for amoxicillin in the triple therapy regimen 1, 2
• Consider penicillin allergy testing to enable amoxicillin use, as most reported allergies are not true allergies 1