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

H. pylori Treatment Algorithm

Bismuth quadruple therapy for 14 days is the first-line treatment for H. pylori infection in North America, consisting of a high-dose PPI twice daily, bismuth subsalicylate 262 mg (2 tablets) four times daily, metronidazole 500 mg three to four times daily (total 1.5-2 g/day), and tetracycline HCl 500 mg four times daily. 1, 2

First-Line Treatment Selection

Preferred Regimen: Bismuth Quadruple Therapy (14 days)

• PPI component: Use esomeprazole or rabeprazole 40 mg twice daily (taken 30 minutes before meals on an empty stomach) to increase cure rates by 8-12% compared to standard PPIs 1, 3
• Bismuth component: Bismuth subsalicylate 262 mg (2 tablets) four times daily, 30 minutes before meals 1
• Metronidazole component: 500 mg three to four times daily (total daily dose 1.5-2 g) 1
• Tetracycline component: Tetracycline HCl 500 mg four times daily—never substitute doxycycline, which is ineffective despite being a tetracycline derivative 3
• This regimen achieves 80-90% eradication rates even in areas with high clarithromycin and metronidazole resistance 1, 2
• Bismuth has no described bacterial resistance, and tetracycline resistance remains rare (<5%) 1

Alternative First-Line When Bismuth Unavailable: Concomitant Non-Bismuth Quadruple Therapy (14 days)

• PPI (esomeprazole or rabeprazole 40 mg) twice daily + amoxicillin 1000 mg twice daily + clarithromycin 500 mg twice daily + metronidazole 500 mg twice daily 1, 3
• Only use this regimen if local clarithromycin resistance is <15%—most regions in North America now exceed this threshold 1
• This regimen administers all antibiotics simultaneously to prevent resistance development during treatment 1

Alternative First-Line: Rifabutin Triple Therapy (14 days)

• Rifabutin 150 mg twice daily + amoxicillin 1000 mg twice daily + high-dose PPI twice daily 1, 2
• Rifabutin resistance is extremely rare, making this an effective alternative 1
• Reserve for patients without penicillin allergy 1

Critical Optimization Factors

• 14-day duration is mandatory—improves eradication by approximately 5% compared to 7-10 day regimens 1, 4
• High-dose PPI twice daily (not standard once-daily dosing) increases efficacy by 6-12% 1
• Take PPI 30 minutes before meals on an empty stomach without concomitant antacids 1
• Take amoxicillin at the start of meals to minimize gastrointestinal intolerance 5

Second-Line Treatment After First-Line Failure

If Bismuth Quadruple Therapy Was NOT Used First-Line

• Use optimized bismuth quadruple therapy for 14 days (as described above) 1, 2

If Bismuth Quadruple Therapy Failed or Was Used First-Line

• 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, 2
• Only use if patient has no prior fluoroquinolone exposure (for any indication)—cross-resistance is universal within the fluoroquinolone family 1
• Levofloxacin resistance rates are rising (11-30% primary, 19-30% secondary) 1

Alternative Second-Line: Rifabutin Triple Therapy

• If not used first-line and patient has no penicillin allergy 1, 2

Third-Line and Rescue Therapies

After Two Failed Eradication Attempts

• Antibiotic susceptibility testing should guide further treatment whenever possible 1, 4, 2
• Confirm patient adherence before proceeding—more than 10% of patients are poor compliers 1

Empiric Third-Line Options (if susceptibility testing unavailable)

• Rifabutin triple therapy for 14 days (if not previously used): Rifabutin 150 mg twice daily + amoxicillin 1000 mg twice daily + high-dose 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 (double standard dose) twice daily 1, 2

Antibiotic Selection Principles

Never Repeat These Antibiotics After Failure

• Clarithromycin: Resistance develops rapidly after exposure; eradication rates drop from 90% to 20% with resistant strains 1
• Levofloxacin: Fluoroquinolone resistance develops quickly after any fluoroquinolone exposure 1

Safe to Re-Use After Failure

• Amoxicillin: Resistance remains extremely rare (<5%) 1, 5
• Tetracycline: Resistance remains rare (<5%) 1
• Bismuth: No described bacterial resistance 1
• Metronidazole with bismuth: Bismuth's synergistic effect overcomes in vitro metronidazole resistance 1

Confirmation of Eradication

• Test all patients for eradication success at least 4 weeks after completion of therapy using urea breath test or validated monoclonal stool antigen test 1, 2
• Patient must be off PPIs/PCABs for 2 weeks before testing 1
• Never use serology to confirm eradication—antibodies persist long after successful treatment 1

Special Populations

Patients with Penicillin Allergy

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

Patients with Renal Impairment

• GFR 10-30 mL/min: Amoxicillin 500 mg or 250 mg every 12 hours 5
• GFR <10 mL/min: Amoxicillin 500 mg or 250 mg every 24 hours 5
• Hemodialysis: Amoxicillin 500 mg or 250 mg every 24 hours, with additional dose during and at end of dialysis 5
• Do NOT use amoxicillin 875 mg dose if GFR <30 mL/min 5

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, though evidence for increasing eradication rates is limited 1, 4
• Probiotics should not be considered primary treatment 1

Patient Factors Affecting Success

• Smoking increases eradication failure risk (odds ratio 1.95) 1
• High BMI/obesity increases failure risk due to lower drug concentrations at gastric mucosal level 1
• Poor compliance (>10% of patients) leads to much lower eradication rates 1

Common Pitfalls to Avoid

• Never use PPI-clarithromycin triple therapy without susceptibility testing when regional clarithromycin resistance exceeds 15-20%—most North American regions now exceed this threshold 1
• Never assume low clarithromycin resistance without local surveillance data—resistance has increased globally from 9% in 1998 to >20% in most regions 1
• Never use standard-dose PPI once daily—always use twice-daily high-dose dosing 1
• Never use doxycycline as a tetracycline substitute—it is ineffective for H. pylori despite being a tetracycline derivative 3
• Never use levofloxacin empirically as first-line therapy due to rapidly rising fluoroquinolone resistance rates 1
• Never repeat clarithromycin if patient has prior macrolide exposure for any indication—cross-resistance is universal 1