What is the recommended first‑line therapy for a typical adult with confirmed Helicobacter pylori infection, taking into account clarithromycin resistance, penicillin allergy, and pregnancy considerations?

H. pylori Treatment: First-Line Therapy Recommendations

Bismuth quadruple therapy for 14 days is the definitive first-line treatment for H. pylori infection in most clinical scenarios, achieving 80–90% eradication rates even in regions with high clarithromycin and metronidazole resistance. 1, 2

First-Line Treatment: Bismuth Quadruple Therapy

The standard regimen consists of:

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred)
• Bismuth subsalicylate 262 mg (2 tablets) four times daily
• Metronidazole 500 mg three to four times daily (total 1.5–2 g daily)
• Tetracycline 500 mg four times daily
• Duration: 14 days mandatory 1, 2, 3

This regimen is preferred because bacterial resistance to bismuth is essentially nonexistent, and bismuth's synergistic effect overcomes metronidazole resistance even when strains test resistant in vitro. 1, 2 The 14-day duration improves eradication by approximately 5% compared to shorter courses. 1, 4, 2

Why Bismuth Quadruple Therapy Is Superior

Clarithromycin resistance now exceeds 15–20% in most of North America and Central, Western, and Southern Europe, rendering traditional triple therapy unacceptably ineffective (achieving only ~70% eradication versus the 80% minimum target). 1, 4 When H. pylori strains are clarithromycin-resistant, eradication rates with triple therapy plummet from 90% to approximately 20%. 1

Bismuth quadruple therapy circumvents this problem entirely by using antibiotics from the WHO "Access group" (tetracycline and metronidazole) rather than the "Watch group" (clarithromycin, levofloxacin), making it preferable from both an efficacy and antimicrobial stewardship perspective. 1

Alternative First-Line: Concomitant Non-Bismuth Quadruple Therapy

If bismuth is unavailable, use concomitant non-bismuth quadruple therapy for 14 days:

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred)
• Amoxicillin 1000 mg twice daily
• Clarithromycin 500 mg twice daily
• Metronidazole 500 mg twice daily 1, 2, 3

This regimen should only be used when:

• Bismuth preparations are genuinely unavailable
• Local clarithromycin resistance is documented to be <15% 1, 2

The advantage over sequential therapy is that all antibiotics are administered simultaneously, preventing resistance development during treatment. 1

Restricted Option: Clarithromycin Triple Therapy

Triple therapy (PPI + clarithromycin 500 mg twice daily + amoxicillin 1000 mg twice daily for 14 days) should only be used when:

• Local surveillance data confirms clarithromycin resistance <15%
• No prior macrolide exposure for any indication 1, 4, 3

Never use this regimen empirically without documented low local resistance. 1, 4

Critical Optimization Factors for All Regimens

PPI Selection and Dosing

High-dose PPI twice daily is mandatory—standard once-daily dosing is inadequate and a major cause of treatment failure. 1, 2 Esomeprazole or rabeprazole 40 mg twice daily increases cure rates by an additional 8–12% compared to other PPIs at standard doses. 1, 2

Avoid pantoprazole: 40 mg provides acid-suppression equivalent to only ~9 mg omeprazole, leading to inferior outcomes. 1

Timing: Take PPI 30 minutes before meals on an empty stomach, without concomitant antacids. 1, 2

Treatment Duration

14 days is the evidence-based standard for all H. pylori regimens. 1, 4, 2, 3 The Toronto Consensus, Maastricht V/Florence, and American College of Gastroenterology all mandate this duration. 1, 3 Shorter courses reduce eradication success by approximately 5%. 1, 4, 2

Special Populations

Penicillin Allergy

Bismuth quadruple therapy is the first-choice regimen because it contains tetracycline rather than amoxicillin. 5, 1, 2, 6

Consider penicillin allergy testing to delist the allergy and enable amoxicillin use, as true anaphylaxis is rare and amoxicillin resistance remains extremely rare (<5%). 1, 2 If confirmed allergy and bismuth unavailable, use PPI + clarithromycin 500 mg twice daily + metronidazole 500 mg twice daily for 14 days (only in areas with clarithromycin resistance <15%). 5, 6

Pregnancy

Defer H. pylori eradication until after pregnancy and breastfeeding. Tetracycline is contraindicated in pregnancy, and clarithromycin is FDA pregnancy category C. 5 If treatment is absolutely necessary (e.g., bleeding ulcer), amoxicillin-based regimens are relatively safer, but consultation with maternal-fetal medicine is essential.

Clarithromycin Resistance Documented

Use bismuth quadruple therapy as described above—it is specifically designed to overcome clarithromycin resistance. 1, 2 Never re-use clarithromycin if it was in a failed regimen; resistance develops rapidly after exposure. 1, 2

Second-Line Treatment After First-Line Failure

If bismuth quadruple therapy fails, use levofloxacin triple therapy for 14 days:

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg)
• Amoxicillin 1000 mg twice daily
• Levofloxacin 500 mg once daily 5, 1, 4, 2

Critical caveat: Levofloxacin resistance is rising rapidly (11–30% primary, 19–30% secondary resistance globally). 1 Never use levofloxacin in patients with prior fluoroquinolone exposure for any indication (e.g., chronic bronchopneumopathy). 5, 1

If clarithromycin-based triple therapy fails, use bismuth quadruple therapy (if not previously used) or levofloxacin triple therapy. 5, 4, 2

Third-Line and Rescue Therapies

After two failed eradication attempts with confirmed patient adherence, antibiotic susceptibility testing should guide further treatment. 5, 1, 4, 2

Rescue options include:

• Rifabutin triple therapy: Rifabutin 150 mg twice daily + amoxicillin 1000 mg twice daily + high-dose PPI twice daily for 14 days. 1, 2 Rifabutin resistance is rare, making this highly effective after multiple failures. 1
• High-dose dual therapy: Amoxicillin 2–3 g daily in 3–4 divided doses + high-dose PPI twice daily for 14 days. 1, 2 This offers a simpler dosing schedule for patients struggling with complex regimens.

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, 4, 2 Discontinue PPI at least 2 weeks before testing. 1, 4, 2 Never use serology to confirm eradication—antibodies persist long after successful treatment. 1, 4

Common Pitfalls to Avoid

• Never use once-daily PPI dosing—it is a major cause of treatment failure 1, 2
• Never shorten therapy below 14 days 1, 4, 2, 3
• Never repeat clarithromycin or levofloxacin if they were in a failed regimen—resistance develops rapidly after exposure 1, 2
• Never assume low clarithromycin resistance without local surveillance data—most regions now have high resistance 1, 4
• Avoid pantoprazole due to inferior acid-suppression potency 1
• Do not use levofloxacin empirically as first-line therapy—this accelerates resistance and eliminates a valuable rescue option 1, 2