What is the first-line treatment for a patient with a confirmed diagnosis of H pylori (Helicobacter pylori) infection?

H. pylori Treatment

First-Line Treatment Recommendation

Bismuth quadruple therapy for 14 days is the definitive first-line treatment for H. pylori infection, achieving 80-90% eradication rates even in areas with high antibiotic resistance. 1

Bismuth Quadruple Therapy Regimen

The preferred regimen consists of: 1, 2

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred, taken 30 minutes before meals)
• 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)

Why Bismuth Quadruple Therapy is Superior

• No bacterial resistance to bismuth has ever been described 1, 2
• Tetracycline resistance remains rare (1-5%) 1, 2
• Bismuth's synergistic effect overcomes metronidazole resistance, even when present in vitro 1, 2
• Not affected by clarithromycin resistance, which now exceeds 15-20% in most of North America and Europe 1, 3
• Achieves 80-90% eradication even with dual clarithromycin-metronidazole resistance 1

Alternative First-Line Option (Limited Use)

Triple therapy may only be considered in areas with documented clarithromycin resistance below 15%, which is increasingly rare. 1, 3

If local resistance data confirms <15% clarithromycin resistance: 1

• Esomeprazole or rabeprazole 40 mg twice daily
• Clarithromycin 500 mg twice daily
• Amoxicillin 1000 mg twice daily
• Duration: 14 days

Critical caveat: Most regions now have clarithromycin resistance exceeding 15-20%, making this regimen unacceptable without local surveillance data. 1, 3

When Bismuth is Unavailable

Concomitant non-bismuth quadruple therapy is the recommended alternative: 1

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

This regimen administers all antibiotics simultaneously, preventing resistance development during treatment. 1

Critical Optimization Factors

PPI Selection and Dosing

High-dose PPI twice daily is mandatory—standard once-daily dosing is inadequate and significantly reduces treatment efficacy. 1, 3, 2

• Esomeprazole or rabeprazole 40 mg twice daily increases cure rates by 8-12% compared to other PPIs 1, 3
• Take 30 minutes before meals on an empty stomach 1
• Do not use concomitant antacids (including H2-receptor antagonists) 1

Treatment Duration

14 days is mandatory for all regimens—extending from 7 to 14 days improves eradication by approximately 5%. 1, 3, 2

Patient Compliance

• Diarrhea occurs in 21-41% of patients during the first week due to gut microbiota disruption 1
• Consider adjunctive probiotics to reduce diarrhea and improve compliance 1, 3
• Poor compliance accounts for >10% of treatment failures 2

Second-Line Treatment After First-Line Failure

If Bismuth Quadruple Therapy Fails

Levofloxacin triple therapy for 14 days (if no prior fluoroquinolone exposure): 1, 3, 2

• High-dose PPI (esomeprazole or rabeprazole 40 mg) twice daily
• Amoxicillin 1000 mg twice daily
• Levofloxacin 500 mg once daily (or 250 mg twice daily)

Critical warning: Levofloxacin resistance rates are 11-30% (primary) and 19-30% (secondary). 1 Never use if patient has had prior fluoroquinolone exposure for any indication. 1

If Triple Therapy Fails

Switch to bismuth quadruple therapy for 14 days (if not previously used). 1, 3

Key Principle: Never Repeat Failed Antibiotics

Never re-use clarithromycin or levofloxacin if they were in a failed regimen—resistance develops rapidly after exposure, with eradication rates dropping from 90% to 20% with resistant strains. 1

However: 1

• Metronidazole can be re-used with bismuth due to synergistic effects
• Amoxicillin and tetracycline can be re-used because resistance remains rare (<5%)

Third-Line and Rescue Therapies

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

If susceptibility testing is unavailable: 1

Rifabutin Triple Therapy (14 days)

• Rifabutin 150 mg twice daily
• Amoxicillin 1000 mg twice daily
• High-dose PPI twice daily

Rifabutin resistance is rare, making this effective after multiple failures. 1

High-Dose Dual Therapy (14 days)

• Amoxicillin 2-3 grams daily in 3-4 split doses
• High-dose PPI (double standard dose) twice daily

This is an alternative rescue option when other therapies have been exhausted. 1

Confirmation of Eradication

Test for eradication success at least 4 weeks after completing therapy using urea breath test or monoclonal stool antigen test. 1, 3, 2

• Discontinue PPI at least 2 weeks before testing to avoid false-negative results 1, 3, 2
• Never use serology to confirm eradication—antibodies persist long after successful treatment 1

Special Populations

Penicillin Allergy

Bismuth quadruple therapy is the first choice, as it contains tetracycline, not amoxicillin. 1

Consider penicillin allergy testing to delist the allergy and enable amoxicillin use, as most patients who report penicillin allergy are found not to have a true allergy. 1

Patients with Prior NSAID Use or Peptic Ulcer History

H. pylori eradication is mandatory before starting NSAID treatment in patients with peptic ulcer history. 2

Bleeding Peptic Ulcer

Start H. pylori eradication treatment immediately when oral feeding is reintroduced—delaying treatment leads to reduced compliance or loss to follow-up. 1, 2

Eradication reduces rebleeding rate from 26% to near zero. 1

Gastric MALT Lymphoma

H. pylori eradication is first-line treatment, achieving cure rates of 60-80% in early-stage cases. 1

Common Pitfalls and How to Avoid Them

Pitfall 1: Using Standard-Dose PPI Once Daily

Solution: Always use high-dose PPI (esomeprazole or rabeprazole 40 mg) twice daily. 1, 3

Pitfall 2: Assuming Low Clarithromycin Resistance Without Data

Solution: Assume high clarithromycin resistance (>15-20%) and use bismuth quadruple therapy unless local surveillance data confirms otherwise. 1, 3

Pitfall 3: Using 7-10 Day Treatment Courses

Solution: Always prescribe 14 days—shorter durations reduce eradication by approximately 5%. 1, 3, 2

Pitfall 4: Repeating Clarithromycin After First-Line Failure

Solution: Never re-use clarithromycin or levofloxacin if they were in a failed regimen. 1

Pitfall 5: Using Levofloxacin as First-Line Therapy

Solution: Reserve levofloxacin for second-line therapy only—using it first-line accelerates resistance and eliminates a valuable rescue option. 1

Pitfall 6: Testing for Eradication Too Early or While on PPI

Solution: Wait at least 4 weeks after therapy completion and discontinue PPI at least 2 weeks before testing. 1, 3, 2

Patient Factors Affecting Success

• Smoking increases eradication failure risk (odds ratio 1.95) 2
• High BMI reduces drug concentrations at the gastric mucosal level 2
• Poor compliance accounts for >10% of failures—proactively address adherence 2