What is the recommended antibiotic regimen for Helicobacter pylori (H. pylori) treatment?

H. Pylori Antibiotic Treatment

Bismuth quadruple therapy for 14 days is the preferred first-line treatment for H. pylori infection, consisting of a PPI twice daily, bismuth subsalicylate, metronidazole, and tetracycline. This regimen achieves 80-90% eradication rates even in areas with high clarithromycin and metronidazole resistance 1, 2.

First-Line Treatment Regimen

The recommended bismuth quadruple therapy includes:

• Proton pump inhibitor (preferably esomeprazole or rabeprazole 40 mg) twice daily, taken 30 minutes before meals 1
• Bismuth subsalicylate 262 mg (2 tablets) four times daily 1
• Metronidazole 500 mg three to four times daily (total 1.5-2 g daily) 1
• Tetracycline HCl 500 mg four times daily 3
• Duration: 14 days mandatory 1, 2

Critical point: Do NOT use doxycycline as a substitute for tetracycline—doxycycline is ineffective for H. pylori despite being a tetracycline derivative 3.

Alternative First-Line Option When Bismuth Unavailable

Concomitant non-bismuth quadruple therapy for 14 days:

• PPI (esomeprazole or rabeprazole 40 mg) twice daily 1
• Amoxicillin 1000 mg twice daily 1, 4
• Clarithromycin 500 mg twice daily 1
• Metronidazole 500 mg twice daily 1

This regimen should only be used in areas with clarithromycin resistance <15%, which is now rare in most of North America 1.

Why Bismuth Quadruple Therapy is Preferred

• No bacterial resistance to bismuth exists 1
• Effective against clarithromycin-resistant strains (resistance now exceeds 15-20% in most regions) 1
• Overcomes metronidazole resistance through bismuth's synergistic effect 1
• Uses "Access group" antibiotics (tetracycline, metronidazole) rather than "Watch group" antibiotics (clarithromycin, levofloxacin), supporting antimicrobial stewardship 1

Second-Line Treatment After First-Line Failure

If bismuth quadruple therapy fails:

• Levofloxacin triple therapy for 14 days: PPI twice daily + amoxicillin 1000 mg twice daily + levofloxacin 500 mg once daily (or 250 mg twice daily) 1, 5, 2
• Only use if patient has no prior fluoroquinolone exposure 1

If clarithromycin-based therapy fails:

• Bismuth quadruple therapy for 14 days (if not previously used) 1, 2

Third-Line and Rescue Therapies

After two failed eradication attempts:

• Antibiotic susceptibility testing should guide further treatment 1, 6, 2

Empiric rescue options when susceptibility testing unavailable:

• Rifabutin triple therapy for 14 days: rifabutin 150 mg twice daily + amoxicillin 1000 mg twice daily + PPI twice daily 1, 2
• High-dose dual amoxicillin-PPI therapy for 14 days: amoxicillin 2-3 grams daily in 3-4 divided doses + high-dose PPI twice daily 1

Critical Optimization Factors

To maximize eradication success:

• Use high-dose PPI twice daily (not standard once-daily dosing)—this increases cure rates by 6-12% 1
• Esomeprazole or rabeprazole 40 mg twice daily are preferred over other PPIs 1
• 14-day duration is mandatory—improves eradication by approximately 5% compared to 7-10 day regimens 1, 6
• Take PPI 30 minutes before meals on an empty stomach, without concomitant antacids 1
• Never repeat antibiotics previously used, especially clarithromycin and levofloxacin, as resistance develops rapidly 1

Special Populations

Patients with penicillin allergy:

• Bismuth quadruple therapy is the first choice (contains tetracycline, not amoxicillin) 1
• Consider penicillin allergy testing to enable amoxicillin use, as true penicillin allergy is often overreported and amoxicillin resistance remains rare (<5%) 1

Patients with renal impairment:

• GFR 10-30 mL/min: amoxicillin 500 mg or 250 mg every 12 hours 4
• GFR <10 mL/min: amoxicillin 500 mg or 250 mg every 24 hours 4
• Do NOT use 875 mg amoxicillin dose if GFR <30 mL/min 4

Confirmation of Eradication

Test-of-cure is mandatory:

• Urea breath test or monoclonal stool antigen test at least 4 weeks after completion of therapy 1, 6
• Discontinue PPI at least 2 weeks before testing 1
• Never use serology to confirm eradication—antibodies persist long after successful treatment 1

Common Pitfalls to Avoid

• Do not assume low clarithromycin resistance without local surveillance data—most regions now have high resistance rates (>15-20%) 1
• Do not use standard triple therapy (PPI + clarithromycin + amoxicillin) as first-line when clarithromycin resistance exceeds 15%, as eradication rates drop from 90% to 20% with resistant strains 1
• Do not use levofloxacin empirically as first-line therapy due to rapidly rising fluoroquinolone resistance rates (11-30% primary, 19-30% secondary) 1
• Do not use doxycycline instead of tetracycline HCl 3

Managing Side Effects

• Diarrhea occurs in 21-41% of patients during the first week due to gut microbiota disruption 1
• Consider adjunctive probiotics to reduce diarrhea risk and improve compliance 1, 6
• Patient factors affecting success: smoking (OR 1.95 for failure), high BMI (lower drug concentrations), and poor compliance (>10% of patients) 1