First-Line Treatment for Uncomplicated H. pylori Infection
Bismuth quadruple therapy for 14 days is the definitive first-line treatment for uncomplicated H. pylori infection in adults without known drug allergies, consisting of a high-dose PPI twice daily, bismuth subsalicylate, metronidazole, and tetracycline. 1, 2, 3
Recommended Regimen Components
The standard bismuth quadruple therapy regimen includes:
- High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred, taken 30 minutes before meals) 1, 2
- Bismuth subsalicylate 262 mg (two tablets) four times daily 1
- Metronidazole 500 mg three to four times daily (total 1.5-2 g daily) 1, 2
- Tetracycline 500 mg four times daily 1, 2, 3
- Duration: 14 days mandatory 1, 2, 4, 3
Why Bismuth Quadruple Therapy Is Preferred
This regimen achieves 80-90% eradication rates even in areas with high clarithromycin and metronidazole resistance, which now exceeds 15-20% in most of North America and Europe 1, 2. Clarithromycin resistance has increased globally from 9% in 1998 to 17.6% in 2008-2009, making traditional triple therapy achieve only 70% eradication rates in many regions 1, 2.
Bismuth has no described bacterial resistance, and its synergistic effect with other antibiotics overcomes metronidazole resistance in vitro 1, 2. This makes bismuth quadruple therapy effective even against strains with dual resistance to clarithromycin and metronidazole 1.
Critical Optimization Factors
High-dose PPI dosing is mandatory because it increases eradication efficacy by 6-10% compared to standard dosing 1, 2. Esomeprazole or rabeprazole 40 mg twice daily increases cure rates by an additional 8-12% compared to other PPIs 1, 2.
The 14-day duration improves eradication success by approximately 5% compared to 7-10 day regimens 1, 2, 4. All major guidelines (Toronto Consensus, Maastricht V/Florence, American College of Gastroenterology) mandate 14 days as the standard of care 1, 4, 3.
Alternative First-Line Option (Restricted Use)
Concomitant non-bismuth quadruple therapy may be considered only when bismuth is unavailable AND local clarithromycin resistance is documented below 15%:
- 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
However, this regimen should NOT be used empirically in most North American settings where clarithromycin resistance exceeds 15% 1, 2.
Verification of Eradication
Confirm eradication with urea breath test or monoclonal stool antigen test at least 4 weeks after completion of therapy and at least 2 weeks after PPI discontinuation 5, 1, 2, 3. Never use serology to confirm eradication, as antibodies persist long after successful treatment 5, 2.
Common Pitfalls to Avoid
Never use standard once-daily PPI dosing—this is a major cause of treatment failure 1. Always use twice-daily dosing 1, 2.
Avoid pantoprazole because 40 mg provides acid-suppression equivalent to only 9 mg of omeprazole, leading to inferior outcomes 1.
Do not shorten therapy below 14 days, as this reduces eradication success 1, 2, 4.
Never substitute doxycycline for tetracycline, as it yields significantly inferior eradication rates 1.
Special Population: Penicillin Allergy
Bismuth quadruple therapy is the ideal first choice for patients with penicillin allergy because it contains tetracycline rather than amoxicillin 1, 6. However, consider penicillin allergy testing after treatment failure, as most patients who report penicillin allergy are found not to have a true allergy 1.