What is the recommended first‑line bismuth‑based quadruple regimen (proton‑pump inhibitor, bismuth, tetracycline, and metronidazole) with dosing and duration for an adult with Helicobacter pylori infection and no known drug allergies?

Bismuth-Based Quadruple Therapy for H. pylori Eradication

The recommended first-line bismuth quadruple regimen consists of a proton pump inhibitor (PPI) twice daily, bismuth subsalicylate 262 mg (two tablets) four times daily, tetracycline 500 mg four times daily, and metronidazole 500 mg three to four times daily for 14 days. 1, 2

Complete Regimen Components and Dosing

PPI Component:

• Esomeprazole 40 mg or rabeprazole 40 mg twice daily are strongly preferred over standard-dose PPIs, as they increase cure rates by 8–12% 1
• Standard-dose alternatives (if high-dose unavailable): esomeprazole 20 mg, lansoprazole 30 mg, omeprazole 20 mg, or rabeprazole 20 mg twice daily 1, 2
• Avoid pantoprazole because 40 mg provides acid suppression equivalent to only 9 mg omeprazole, leading to inferior outcomes 1
• Take PPI 30 minutes before meals on an empty stomach, without concomitant antacids 1, 2

Bismuth Component:

• Bismuth subsalicylate 262 mg: two tablets four times daily (30 minutes before meals and at bedtime) 1, 2
• Alternative: bismuth subcitrate 120 mg four times daily 1, 2

Tetracycline Component:

• Tetracycline 500 mg four times daily 1, 2
• Do not substitute doxycycline for tetracycline, as it yields significantly inferior eradication rates 1, 2

Metronidazole Component:

• Metronidazole 500 mg three to four times daily (total daily dose 1.5–2 g) 1, 2
• Take 30 minutes after meals 1

Treatment Duration

The mandatory duration is 14 days to maximize eradication success 1, 2. This represents the consensus recommendation from the American Gastroenterological Association, Toronto Consensus, and Maastricht V/Florence guidelines 1. While the American College of Gastroenterology considers 10–14 days acceptable 2, and some studies show non-inferiority of 10-day regimens 3, 4, extending treatment from 7 to 14 days improves eradication by approximately 5% 1.

Efficacy and Resistance Considerations

This regimen achieves 80–90% eradication rates even in regions with high dual resistance to clarithromycin and metronidazole 1. The key advantages include:

• No bacterial resistance to bismuth has been described 1
• Bismuth's synergistic effect overcomes metronidazole resistance in vitro, preserving efficacy against resistant strains 1, 2
• Tetracycline resistance remains rare (1–5%) 1
• The regimen is especially recommended when clarithromycin resistance exceeds 15% 1, 2

Studies demonstrate eradication rates of 93–96% per protocol and 89–93% intention-to-treat 3, 5, 4, with rescue therapy after failed clarithromycin-based regimens showing 94–95% success 5.

Clinical Context and Indications

Bismuth quadruple therapy is the preferred first-line treatment in most clinical scenarios, particularly:

• Areas with clarithromycin resistance >15% 1, 2
• Patients with penicillin allergy (first-choice regimen because it contains tetracycline rather than amoxicillin) 1, 2
• Second-line therapy after clarithromycin-based triple therapy failure 1, 2

Critical Optimization Factors

• Complete the full 14-day course to maximize eradication rates 1, 2
• High-dose PPI twice daily is mandatory; standard once-daily dosing significantly reduces efficacy 1
• Never shorten therapy below 14 days 1
• Avoid concomitant use of H2-receptor antagonists or other antacids 2

Common Pitfalls to Avoid

• Do not substitute doxycycline for tetracycline 1, 2
• Do not use pantoprazole due to markedly lower acid-suppression potency 1
• Never repeat clarithromycin if it was in a failed prior regimen, as resistance develops rapidly 1
• After two failed eradication attempts with confirmed adherence, antibiotic susceptibility testing should guide further treatment 1, 2

Adverse Effects and Tolerability

Side effects are generally mild and include fatigue, discomfort, and gastrointestinal symptoms 3. Diarrhea occurs in 21–41% of patients during the first week due to gut microbiota disruption 1. The 10-day regimen shows lower adverse effect incidence (22.6%) compared to 14 days (28.5%) 4, though the 14-day duration remains the guideline-endorsed standard for optimal efficacy 1.

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 persist long after successful treatment 1.