Bismuth Quadruple Therapy for Helicobacter pylori Eradication
The recommended first-line bismuth quadruple therapy consists of a high-dose proton-pump inhibitor (PPI) twice daily, bismuth subsalicylate 262 mg (or bismuth subcitrate 120 mg) four times daily, metronidazole 500 mg three to four times daily, and tetracycline 500 mg four times daily for 14 days, achieving 80–90% eradication rates even in areas with high clarithromycin and metronidazole resistance. 1
Specific Dosing Regimen
The complete 14-day regimen includes:
PPI (high-dose): Esomeprazole or rabeprazole 40 mg twice daily is strongly preferred over standard-dose PPIs, as it increases cure rates by 8–12% 1. Standard alternatives include omeprazole 20 mg, lansoprazole 30 mg, or rabeprazole 20 mg twice daily 1. Avoid pantoprazole due to markedly inferior acid-suppression potency (40 mg pantoprazole ≈ 9 mg omeprazole equivalent) 1.
Bismuth subsalicylate: 262 mg (two tablets) four times daily, taken 30 minutes before meals and at bedtime 1. Alternatively, bismuth subcitrate 120 mg four times daily 1.
Metronidazole: 500 mg three to four times daily (total 1.5–2 g daily in divided doses) 1. Higher doses (1.5–2 g daily) improve eradication even against resistant strains when combined with bismuth 1.
Tetracycline: 500 mg four times daily 1. Do not substitute doxycycline, as it yields significantly inferior eradication rates 1.
Treatment Duration
Fourteen days is mandatory and endorsed by the American College of Gastroenterology, Toronto Consensus, and Maastricht V/Florence guidelines 1. Extending therapy from 7–10 days to 14 days improves eradication by approximately 5% 1. While 10 days may be acceptable for bismuth quadruple therapy when local data demonstrate equivalence, 14 days remains the preferred standard 1.
Administration Instructions
- PPI timing: Take 30 minutes before meals on an empty stomach, without concomitant antacids 1.
- Bismuth timing: Take 30 minutes before meals and at bedtime 1.
- Tetracycline with fluids: Swallow with a full glass of water (8 ounces); adequate fluid intake, particularly at bedtime, reduces esophageal irritation risk 2.
- Complete all doses: Each dose includes 3 capsules (bismuth + metronidazole + tetracycline) taken 4 times daily 2. If more than 4 doses are missed, contact the prescribing physician 2.
Efficacy and Resistance Profile
Bismuth quadruple therapy achieves 80–90% eradication rates even with dual resistance to clarithromycin and metronidazole 1. Bismuth exerts a synergistic effect that overcomes metronidazole resistance in vitro, preserving regimen efficacy against resistant strains 1. The regimen is especially recommended when clarithromycin resistance exceeds 15% 1. No bacterial resistance to bismuth has been described, and tetracycline resistance remains rare (<5%) 1.
When Clarithromycin Resistance Is Likely
Bismuth quadruple therapy is the definitive first-line choice when:
- Regional clarithromycin resistance exceeds 15–20% 1
- The patient has prior macrolide exposure for any indication (cross-resistance is universal within the macrolide family) 1
- Standard triple therapy has failed 3, 4
Never use clarithromycin-based triple therapy empirically when clarithromycin resistance is documented or suspected, as eradication rates drop from 90% to 20% with resistant strains 1.
After Standard Triple-Therapy Failure
Bismuth quadruple therapy is the preferred second-line option after clarithromycin-based triple therapy fails 4. The American Gastroenterological Association, Toronto Consensus, and Maastricht V/Florence guidelines all recommend bismuth quadruple therapy as second-line treatment after clarithromycin-based failures 4. Never reuse clarithromycin if it was in the failed regimen, as resistance develops rapidly after exposure 4. Metronidazole can be reused with bismuth due to synergistic effects 4.
Alternative When Bismuth Is Unavailable
Concomitant (non-bismuth) quadruple therapy for 14 days may be used only in regions with clarithromycin resistance <15% 1:
- PPI twice daily (esomeprazole or rabeprazole 40 mg preferred)
- Amoxicillin 1000 mg twice daily
- Clarithromycin 500 mg twice daily
- Metronidazole 500 mg twice daily
This regimen avoids the pitfall of sequential therapy by administering all antibiotics simultaneously, preventing resistance development during treatment 1.
Special Populations
In patients with penicillin allergy, bismuth quadruple therapy is the first-choice regimen because it contains tetracycline rather than amoxicillin 1. Consider penicillin allergy testing after first-line failure, as most patients who report penicillin allergy do not have a true allergy 3, 4.
Tetracycline is not contraindicated in elderly patients; age alone does not preclude its use 1. However, the four-times-daily dosing may be challenging for some elderly individuals 1.
Critical Pitfalls to Avoid
- Never shorten therapy below 14 days 1
- Never use standard-dose PPI once daily—twice-daily high-dose PPI is mandatory 1
- Never substitute pantoprazole due to inferior acid suppression 1
- Do not substitute doxycycline for tetracycline 1
- Do not repeat clarithromycin or levofloxacin if they were in a failed regimen 4
- Do not continue empirical therapy after two failures—antibiotic susceptibility testing becomes essential 4, 5
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. Discontinue PPI at least 2 weeks before testing 1. Never use serology to confirm eradication, as antibodies may persist long after successful treatment 1.
Expected Adverse Events
Diarrhea occurs in 21–41% of patients during the first week due to gut microbiota disruption 1. Temporary and harmless darkening of the tongue and/or black stool is common and reversible within several days after treatment stops 2. Stool darkening should not be confused with melena 2. Consider adjunctive probiotics to reduce diarrhea risk and improve compliance 1.