What is the recommended quadruple therapy regimen for an adult patient with Helicobacter pylori (H. pylori) infection?

Quadruple Therapy for H. pylori

Bismuth quadruple therapy for 14 days is the recommended first-line treatment for H. pylori infection, consisting of a proton pump inhibitor (PPI) twice daily, bismuth subsalicylate or bismuth subcitrate four times daily, metronidazole 500 mg three to four times daily, and tetracycline 500 mg four times daily. 1, 2, 3

Bismuth Quadruple Therapy Components

The standard regimen includes four medications taken concurrently: 1, 2

• PPI (high-dose): Twice daily dosing is mandatory—use esomeprazole or rabeprazole 40 mg twice daily for optimal results, as high-dose PPIs increase eradication rates by 8-12% compared to standard PPIs 2, 3
• Bismuth: Subsalicylate 262 mg four times daily OR bismuth subcitrate 120 mg four times daily 2, 4
• Metronidazole: 500 mg three to four times daily 1, 2
• Tetracycline: 500 mg four times daily 1, 2
• Duration: 14 days is superior to 10 days, improving eradication by approximately 5% 1, 2, 4

Why Bismuth Quadruple Therapy is Preferred

This regimen achieves 80-90% eradication rates even in areas with high clarithromycin and metronidazole resistance. 2, 3, 4 The key advantages include:

• No bacterial resistance to bismuth has been described 2, 4
• Tetracycline resistance remains rare (<5%) 2
• Bismuth's synergistic effect overcomes metronidazole resistance in vitro, making the regimen effective even against resistant strains 2, 4
• Avoids clarithromycin, which has high resistance rates (>15%) in most regions 1

Alternative: Concomitant Non-Bismuth Quadruple Therapy

When bismuth is unavailable, concomitant non-bismuth quadruple therapy is the recommended alternative: 1, 2, 3

• PPI twice daily 1
• Amoxicillin 1000 mg twice daily 1
• Clarithromycin 500 mg twice daily 1
• Metronidazole 500 mg twice daily 1
• Duration: 14 days 1, 3

Critical caveat: This regimen should only be used in areas with documented clarithromycin resistance <15%, as clarithromycin resistance develops rapidly after exposure. 2, 4

Critical Optimization Factors

To maximize eradication success: 2, 3

• Take PPIs 30 minutes before meals on an empty stomach without concomitant use of other antacids 4
• Never shorten treatment duration below 14 days—this single factor improves success by ~5% 1, 2, 4
• Ensure patient compliance by addressing adherence barriers before prescribing, as poor compliance accounts for >10% of treatment failures 2
• Counsel patients about smoking cessation, as smoking increases eradication failure risk with an odds ratio of 1.95 2

Common Pitfalls to Avoid

• Never use clarithromycin-based triple therapy (PPI + amoxicillin + clarithromycin) as first-line unless local clarithromycin resistance is documented <15% 1, 4
• Never repeat antibiotics that failed previously, especially clarithromycin or levofloxacin, where resistance develops rapidly after exposure 2, 4
• Do not reduce bismuth dosing—the standard ~300 mg four times daily is critical for achieving 80-90% eradication rates 4

Confirmation of Eradication

Test of cure is mandatory for all patients: 2, 3, 4

• Use urea breath test or validated monoclonal stool antigen test at least 4 weeks after completion of therapy 1, 2, 3
• Discontinue PPIs at least 2 weeks before testing 2, 4
• Never use serology to confirm eradication 1, 4

Special Populations

For patients with penicillin allergy: Bismuth quadruple therapy is the first choice, as it contains tetracycline, not amoxicillin. 1, 2, 3