What is the standard first‑line Helicobacter pylori eradication triple therapy for an adult without known drug allergies?

H. pylori Eradication Triple Therapy

Standard first-line triple therapy consists of a high-dose proton pump inhibitor (PPI) twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1000 mg twice daily for 14 days—but this regimen should only be used in regions where clarithromycin resistance is documented to be below 15%, which excludes most of North America and Europe. 1, 2

Why Triple Therapy Is No Longer Preferred in Most Regions

• Clarithromycin resistance now exceeds 15–20% across most of North America and Central, Western, and Southern Europe, causing eradication rates to fall to approximately 70%—well below the 80% minimum acceptable threshold. 1, 2
• When H. pylori strains are clarithromycin-resistant, eradication rates drop from 90% to roughly 20%, making empiric triple therapy unacceptable without local susceptibility data. 1
• The World Health Organization has identified H. pylori as one of only 12 bacterial species requiring urgent investment in new antibiotic development due to high clarithromycin resistance rates. 1

Current First-Line Recommendation: Bismuth Quadruple Therapy

Bismuth quadruple therapy for 14 days is now the preferred first-line regimen for most clinical scenarios, achieving 80–90% eradication rates even in areas with high clarithromycin and metronidazole resistance. 1, 3, 2

Regimen Components:

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred; increases cure rates by 8–12% compared to standard-dose PPIs) 1, 3
• Bismuth subsalicylate 262 mg (2 tablets) four times daily 1
• Metronidazole 500 mg three to four times daily (total 1.5–2 g/day) 1, 3
• Tetracycline 500 mg four times daily 1, 3
• Duration: 14 days mandatory (improves eradication by approximately 5% compared to 7–10 day regimens) 1, 3, 2

Why Bismuth Quadruple Therapy Works:

• Bismuth has no described bacterial resistance, making it effective even against dual clarithromycin-metronidazole resistant strains. 1, 3
• Bismuth's synergistic effect overcomes metronidazole resistance in vitro, preserving regimen efficacy. 1, 3
• The regimen uses antibiotics from the WHO "Access group" (tetracycline, metronidazole) rather than the "Watch group" (clarithromycin, levofloxacin), making it preferable from an antimicrobial stewardship perspective. 1

When Triple Therapy May Still Be Considered

Triple therapy remains an option only in regions with documented clarithromycin resistance below 15% and in patients without prior macrolide exposure for any indication. 1, 2

Standard Triple Therapy Regimen:

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred) 1, 2
• Clarithromycin 500 mg twice daily (500 mg dose is superior to 250 mg, achieving 89.5% vs. 83.3% eradication by per-protocol analysis) 4
• Amoxicillin 1000 mg twice daily 1, 2, 5
• Duration: 14 days 1, 2, 6

Alternative Triple Therapy (Penicillin Allergy):

• High-dose PPI twice daily 1
• Clarithromycin 500 mg twice daily 1
• Metronidazole 500 mg twice daily 1
• Duration: 14 days 1

Critical Optimization Factors for Any Regimen

PPI Dosing:

• High-dose PPI twice daily is mandatory—standard once-daily dosing significantly reduces treatment efficacy by 6–10%. 1, 3, 2
• Esomeprazole or rabeprazole 40 mg twice daily are strongly preferred over other PPIs because they increase cure rates by an additional 8–12%. 1, 3
• Avoid pantoprazole—40 mg provides acid-suppression equivalent to only 9 mg of omeprazole. 1
• Take PPI 30 minutes before meals on an empty stomach without concomitant antacids. 1, 3

Treatment Duration:

• 14-day duration is mandatory for all regimens—extending from 7 to 14 days improves eradication success by approximately 5%. 1, 3, 2, 6

Amoxicillin Dosing:

• Although 1000 mg twice daily is standard, dividing amoxicillin into at least three doses daily avoids low trough levels and improves efficacy because amoxicillin has time-dependent bactericidal activity. 7, 3
• Adequate intragastric pH (achieved with high-dose PPI) directly affects amoxicillin efficacy and half-life. 7, 3

Alternative First-Line Option: Concomitant Non-Bismuth Quadruple Therapy

When bismuth is unavailable and regional clarithromycin resistance is documented below 15%, concomitant quadruple therapy may be used. 1, 2

Regimen:

• High-dose PPI twice daily 1, 2
• Amoxicillin 1000 mg twice daily 1, 2
• Clarithromycin 500 mg twice daily 1, 2
• Metronidazole 500 mg twice daily 1, 2
• Duration: 14 days 1, 2

This regimen administers all antibiotics simultaneously (avoiding the pitfall of sequential therapy, which can promote resistance development during treatment). 1

Critical Pitfalls to Avoid

• Never use triple therapy empirically in regions where clarithromycin resistance exceeds 15%—most of North America and Europe now fall into this category. 1, 2
• Never assume low clarithromycin resistance without local surveillance data—contact your hospital microbiology laboratory or regional public health department for local resistance patterns. 1
• Never use standard-dose PPI once daily—this is a major cause of treatment failure. 1, 3
• Never shorten treatment duration below 14 days—this reduces eradication success by approximately 5%. 1, 3, 2
• Avoid repeating clarithromycin if the patient has prior macrolide exposure (for any indication, including respiratory infections)—cross-resistance is universal within the macrolide family. 1, 2

Confirmation of Eradication

• Test-of-cure is mandatory using urea breath test or monoclonal stool antigen test at least 4 weeks after completing therapy. 1, 3, 2
• Discontinue PPI at least 2 weeks (preferably 7–14 days) before testing to avoid false-negative results. 1, 3, 2
• Never use serology for test-of-cure—antibodies persist long after successful eradication. 1, 3, 2

Special Populations

Penicillin Allergy:

• Bismuth quadruple therapy is the first choice because it contains tetracycline, not amoxicillin. 1, 3
• Consider penicillin allergy testing after first-line failure—true anaphylaxis to penicillin is rare despite prevalent chart documentation, and testing can enable amoxicillin use. 7, 3

Elderly or Frail Patients:

• After multiple failed eradication attempts, weigh the benefits of continued treatment against adverse effects and inconvenience, particularly in patients not at identifiably higher risk of complications (gastric cancer, peptic ulcer disease). 7, 3
• A shared decision-making approach is appropriate in these scenarios. 7, 3