What is the recommended first‑line regimen for Helicobacter pylori eradication in an adult without contraindications, including alternatives for bismuth or tetracycline intolerance, penicillin allergy, or treatment failure, and how should eradication be confirmed?

H. pylori Treatment: Evidence-Based Recommendations

First-Line Treatment Regimen

Bismuth quadruple therapy for 14 days is the definitive first-line treatment for H. pylori eradication in adults without contraindications, achieving 80–90% eradication rates even in regions with high clarithromycin and metronidazole resistance. 1

Standard Bismuth Quadruple Therapy Components

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred, as they increase cure rates by 8–12% compared to other PPIs) 1
• Bismuth subsalicylate 262 mg (2 tablets) four times daily or bismuth subcitrate 120 mg four times daily 1, 2
• Metronidazole 500 mg three to four times daily (total 1.5–2 g daily) 1
• Tetracycline 500 mg four times daily 1
• Duration: 14 days mandatory (improves eradication by ~5% compared to shorter regimens) 1

Administration Details

• Take PPI 30 minutes before meals on an empty stomach, without concomitant antacids 1
• Bismuth should be taken 30 minutes before meals and at bedtime 1
• Metronidazole should be taken 30 minutes after meals 1

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Alternative First-Line Regimen (When Bismuth Unavailable)

Concomitant non-bismuth quadruple therapy for 14 days is the recommended alternative when bismuth is not available, but should only be used in regions with documented clarithromycin resistance <15%. 1

Concomitant Therapy Components

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred) 1
• Amoxicillin 1000 mg twice daily 1
• Clarithromycin 500 mg twice daily 1
• Metronidazole 500 mg twice daily 1
• Duration: 14 days 1

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Special Populations & Modifications

Penicillin Allergy

Bismuth quadruple therapy is the first-choice regimen for patients with penicillin allergy, as it contains tetracycline rather than amoxicillin. 1

• Consider penicillin allergy testing after first-line failure, as most reported allergies are not true allergies 1
• If bismuth unavailable and clarithromycin resistance <15%: use PPI + clarithromycin + metronidazole for 14 days 1

Tetracycline Intolerance

If tetracycline cannot be used, amoxicillin-based bismuth quadruple therapy is the alternative: 1

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg) 1
• Bismuth subsalicylate 262 mg four times daily 1
• Metronidazole 500 mg three to four times daily 1
• Amoxicillin 1000 mg twice to three times daily (replacing tetracycline) 1
• Duration: 14 days 1

Bismuth Intolerance

Concomitant non-bismuth quadruple therapy (as detailed above) is the recommended alternative when bismuth cannot be tolerated. 1

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Second-Line Treatment After First-Line Failure

After Failed Clarithromycin-Based Therapy

Bismuth quadruple therapy for 14 days (if not previously used) is the definitive second-line option, achieving 80–90% eradication even against dual clarithromycin-metronidazole resistant strains. 1

After Failed Bismuth Quadruple Therapy

Levofloxacin triple therapy for 14 days (only if no prior fluoroquinolone exposure): 1

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg) 1
• Amoxicillin 1000 mg twice daily 1
• Levofloxacin 500 mg once daily 1

Critical caveat: Never use levofloxacin in patients with prior fluoroquinolone exposure for any indication (e.g., chronic bronchopneumopathy), as cross-resistance is universal. 1

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Third-Line & Rescue Therapies

After two failed eradication attempts with confirmed patient adherence, antibiotic susceptibility testing should guide further treatment whenever possible. 1, 3

Empiric Third-Line Options (When Susceptibility Testing Unavailable)

Rifabutin triple therapy for 14 days: 1

• Rifabutin 150 mg twice daily 1
• Amoxicillin 1000 mg twice daily 1
• High-dose PPI twice daily 1

High-dose dual therapy for 14 days (alternative rescue option): 1

• Amoxicillin 2–3 g daily in 3–4 divided doses 1
• High-dose PPI twice daily 1

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Confirmation of Eradication (Test-of-Cure)

All patients must undergo test-of-cure at least 4 weeks after completing therapy using urea breath test or validated monoclonal stool antigen test. 4

Critical Testing Requirements

• Discontinue PPIs at least 2 weeks (preferably 7–14 days) before testing to avoid false-negative results 4
• Discontinue antibiotics and bismuth for at least 4 weeks before testing 4
• Patient should fast for at least 6 hours before testing 4
• Never use serology for test-of-cure, as antibodies persist long after successful eradication 1, 4

Mandatory Test-of-Cure Populations

• All patients with gastric ulcer (requires endoscopic follow-up to ensure complete healing) 4
• All patients with complicated peptic ulcer disease or bleeding ulcers 4
• All patients with low-grade gastric MALT lymphoma 4
• All patients after treatment failure 4

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Critical Optimization Factors

PPI Selection & Dosing

• High-dose PPI twice daily is mandatory; standard once-daily dosing significantly reduces efficacy 1
• Esomeprazole or rabeprazole 40 mg twice daily are strongly preferred over other PPIs (8–12% higher cure rates) 1
• Avoid pantoprazole, as 40 mg provides acid-suppression equivalent to only ~9 mg omeprazole 1

Treatment Duration

• 14-day duration is mandatory for all regimens; extending from 7 to 14 days improves eradication by ~5% 1
• Toronto Consensus, Maastricht V/Florence, and American College of Gastroenterology all endorse 14 days as standard 1

Antibiotic Selection Principles

• Never repeat antibiotics that failed previously, especially clarithromycin and levofloxacin, where resistance develops rapidly after exposure 1
• Metronidazole can be reused with bismuth due to synergistic effects that overcome in vitro resistance 1
• Amoxicillin and tetracycline can be reused because resistance remains rare (<5%) 1
• Bismuth has no described resistance 1

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Common Pitfalls to Avoid

• Do not use clarithromycin-based triple therapy empirically when regional clarithromycin resistance exceeds 15% (now most of North America and Europe) 1
• Do not assume low clarithromycin resistance without local surveillance data—most regions now have high resistance rates 1
• Do not use levofloxacin as first-line therapy; this accelerates resistance development and eliminates a valuable rescue option 1
• Do not test for cure earlier than 4 weeks after treatment completion, as this yields false-negative results 4
• Do not use standard-dose PPI once daily; this is a major cause of treatment failure 1
• Do not shorten therapy below 14 days 1

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Patient Factors Affecting Success

• Smoking roughly doubles the odds of eradication failure (OR ~1.95); advise cessation during therapy 1
• High BMI/obesity may lower gastric mucosal drug concentrations, potentially reducing efficacy 1
• Poor compliance is a leading cause of failure; provide clear education on rationale, dosing, expected side effects (diarrhea in 21–41% during first week), and importance of completing the full 14-day course 1

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Management After Treatment Failure

After First Failure

• Select a completely different antibiotic regimen based on prior antibiotic exposure 1
• Review all prior antibiotic exposures (including for non-gastric infections) 1
• Avoid clarithromycin if any prior macrolide exposure; avoid levofloxacin if any prior fluoroquinolone exposure 1

After Two Failures

• Antibiotic susceptibility testing should guide further treatment whenever possible 1, 3
• Molecular testing for clarithromycin and levofloxacin resistance is available and can guide therapy selection 1
• Address compliance barriers before prescribing third-line therapy 1
• Consider rifabutin triple therapy or high-dose dual therapy as empiric third-line options 1