Quadruple Therapy for H. pylori
Bismuth quadruple therapy for 14 days is the standard first-line regimen, consisting of a high-dose PPI twice daily, bismuth subsalicylate (or subcitrate), metronidazole, and tetracycline. 1, 2, 3
Standard Regimen Components
The complete 14-day regimen includes:
PPI (high-dose): Esomeprazole or rabeprazole 40 mg twice daily is strongly preferred, as it increases cure rates by 8–12% compared to standard-dose PPIs 1, 3. Alternative standard doses include omeprazole 20 mg, lansoprazole 30 mg, or rabeprazole 20 mg twice daily 1. Avoid pantoprazole due to significantly lower potency 1.
Bismuth subsalicylate: 262 mg (two tablets) four times daily, or bismuth subcitrate 120 mg four times daily 1, 3
Metronidazole: 500 mg three to four times daily (total 1.5–2 g daily) 1, 3
Critical Optimization Factors
Treatment duration of 14 days is mandatory, as it improves eradication success by approximately 5% compared to 7–10 day regimens 1, 2, 3, 4. This regimen achieves 80–90% eradication rates even against strains with dual resistance to clarithromycin and metronidazole 1, 3.
Administration timing matters:
- Take PPI 30 minutes before meals on an empty stomach, without concomitant antacids 1, 3
- Take bismuth 30 minutes before meals and at bedtime 1
- Take metronidazole with food to reduce gastrointestinal side effects 3
Why This Regimen Is Preferred
Bismuth quadruple therapy is recommended as first-line because:
- Clarithromycin resistance now exceeds 15–20% in most of North America and Europe, making traditional triple therapy achieve only 70% eradication rates 1, 2, 3
- Bacterial resistance to bismuth is extremely rare 1, 2
- Bismuth's synergistic effect overcomes metronidazole resistance in vitro 1, 3
- The regimen uses antibiotics from the WHO "Access group" (tetracycline, metronidazole) rather than the "Watch group" (clarithromycin, levofloxacin), supporting antimicrobial stewardship 1
Alternative First-Line Option
Concomitant non-bismuth quadruple therapy may be used when bismuth is unavailable, consisting of:
- High-dose PPI twice daily
- Amoxicillin 1000 mg twice daily
- Clarithromycin 500 mg twice daily
- Metronidazole 500 mg twice daily
- Duration: 14 days 1, 2, 3
This alternative should only be used in regions with documented clarithromycin resistance <15% 1, 2, 3. It avoids the pitfall of sequential therapy by administering all antibiotics simultaneously, preventing resistance development during treatment 1.
Common Pitfalls to Avoid
- Never use standard-dose PPI once daily—this is a major cause of treatment failure 1, 3
- Do not shorten therapy below 14 days, as this reduces eradication rates 1, 2, 3, 4
- Avoid substituting doxycycline for tetracycline, as it yields significantly inferior results 1
- Do not reduce bismuth dosing below the standard ~300 mg four times daily 3
- Never repeat antibiotics that failed previously, especially clarithromycin or levofloxacin, where resistance develops rapidly after exposure 1, 2, 3
Special Populations
For patients with penicillin allergy, bismuth quadruple therapy is the first choice since it contains tetracycline rather than amoxicillin 1, 3. Consider penicillin allergy testing after first-line failure, as most reported allergies are not true allergies 1, 3.
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 for test-of-cure, as antibodies persist long after successful eradication 1, 2.