What is the recommended first‑line regimen for Helicobacter pylori eradication in a patient without macrolide allergy and with local clarithromycin resistance ≤15%, and what alternative regimens should be used if resistance is higher, there is a macrolide allergy, or the patient cannot tolerate amoxicillin or tetracycline?

First-Line Treatment for Helicobacter pylori Eradication

Bismuth quadruple therapy for 14 days is the definitive first-line treatment for H. pylori eradication, regardless of local clarithromycin resistance patterns, achieving 80–90% eradication rates even in regions with high antibiotic resistance. 1, 2, 3

Recommended First-Line Regimen

The standard bismuth quadruple therapy consists of:

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred; increases cure rates by 8–12% compared to other PPIs) 1, 2, 3
• Bismuth subsalicylate 262 mg (2 tablets) four times daily 1, 3
• Metronidazole 500 mg three to four times daily (total 1.5–2 g/day) 1, 2, 3
• Tetracycline 500 mg four times daily 1, 2, 3
• Duration: 14 days mandatory (improves eradication by ~5% compared to shorter regimens) 1, 2, 3, 4

Take PPI 30 minutes before meals on an empty stomach, without concomitant antacids. 1, 3

Why Bismuth Quadruple Therapy Is First-Line

Clarithromycin resistance now exceeds 15–20% across North America and most of Europe, reducing traditional triple therapy success rates to only ~70%—well below the 80% minimum target. 1, 3 When clarithromycin-resistant strains are present, triple therapy eradication drops from ~90% to ~20%. 1, 3

Bismuth quadruple therapy is not affected by clarithromycin resistance and achieves 80–90% eradication even against dual clarithromycin-metronidazole resistant strains, because bismuth's synergistic effect overcomes metronidazole resistance. 1, 2, 3 No bacterial resistance to bismuth has been described. 1

Alternative First-Line Regimens (Restricted Use)

If Bismuth Is Unavailable

Concomitant non-bismuth quadruple therapy for 14 days:

• 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

This regimen should only be used when bismuth is unavailable AND local clarithromycin resistance is documented <15%. 1, 2, 3

If Local Clarithromycin Resistance Is Documented <15%

Clarithromycin-based triple therapy for 14 days:

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

This regimen is restricted to areas with documented clarithromycin resistance <15% AND patients with no prior macrolide exposure for any indication. 1, 2, 3

Special Populations

Macrolide (Clarithromycin) Allergy

Use bismuth quadruple therapy as described above—it contains no macrolides. 1, 2, 3

Penicillin (Amoxicillin) Allergy

Bismuth quadruple therapy is the first choice because it contains tetracycline instead of amoxicillin. 1, 2, 3

In the absence of anaphylaxis history, consider penicillin allergy testing to delist the allergy and enable amoxicillin use, as true amoxicillin resistance remains extremely rare (<5%). 5, 2

If confirmed penicillin allergy and bismuth is unavailable: Use PPI + clarithromycin + metronidazole for 14 days, only where clarithromycin resistance is <15%. 3

Tetracycline Intolerance or Contraindication

If the patient cannot tolerate tetracycline:

Option 1 (preferred): Rifabutin triple therapy for 14 days 1, 2

• Rifabutin 150 mg twice daily
• Amoxicillin 1000 mg twice daily (or metronidazole 500 mg twice daily if penicillin allergy)
• High-dose PPI twice daily

Rifabutin resistance is rare, making this an effective alternative. 1, 2

Option 2: Concomitant non-bismuth quadruple therapy (as above), only if clarithromycin resistance <15%. 1, 2

Second-Line Treatment After First-Line Failure

After bismuth quadruple therapy fails, use levofloxacin triple therapy for 14 days (provided no prior fluoroquinolone exposure): 5, 1, 2, 3

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

Never use levofloxacin empirically as first-line therapy due to rapidly rising fluoroquinolone resistance rates (primary 11–30%, secondary 19–30%). 1, 2

After clarithromycin-based triple therapy fails, use bismuth quadruple therapy for 14 days. 5, 1, 2, 3

Third-Line and Rescue Therapies

After two failed eradication attempts with confirmed patient adherence, antibiotic susceptibility testing should guide further treatment. 5, 1, 2, 3

Rescue options include:

• Rifabutin triple therapy (rifabutin 150 mg BID, amoxicillin 1 g BID, high-dose PPI BID) for 14 days 5, 1, 2
• High-dose dual therapy (amoxicillin 2–3 g daily in 3–4 divided doses, high-dose PPI BID) for 14 days 5, 1, 3

Critical Optimization Factors

High-dose PPI twice daily is mandatory; once-daily dosing is a major cause of treatment failure. 1, 2, 3

Esomeprazole or rabeprazole 40 mg twice daily increases cure rates by 8–12% compared to other PPIs at standard doses. 1, 2, 3

Avoid pantoprazole—40 mg provides acid suppression equivalent to only ~9 mg omeprazole and yields inferior outcomes. 1, 3

Treatment duration of 14 days is mandatory for all regimens; shorter durations reduce eradication by ~5%. 5, 1, 2, 3, 4

Higher metronidazole doses (1.5–2 g daily in divided doses) improve eradication rates even against resistant strains when combined with bismuth. 5, 2

Amoxicillin should be dosed at least 2 g daily divided TID or QID to avoid low trough levels. 5

Confirmation of Eradication

Verify eradication ≥4 weeks after therapy using urea breath test or validated monoclonal stool antigen test; discontinue PPI ≥2 weeks before testing. 1, 2, 3

Never use serology to confirm eradication—antibodies persist after successful treatment. 1, 3

Common Pitfalls to Avoid

Never assume low clarithromycin resistance without local surveillance data—most regions now have high resistance rates. 1, 2, 3

Never repeat clarithromycin or levofloxacin after a failed regimen—resistance develops rapidly after exposure. 5, 1, 2, 3

Never use once-daily PPI dosing. 1, 2, 3

Never shorten therapy below 14 days. 5, 1, 2, 3, 4

Avoid repeating antibiotics to which the patient has been previously exposed, especially clarithromycin and levofloxacin. 5, 1

Metronidazole can be reused with bismuth due to synergistic effects; amoxicillin and tetracycline can be reused because resistance remains rare. 5, 1