What is the recommended first‑line treatment for Helicobacter pylori infection in an adult patient without known drug allergies or prior therapy?

Treatment for H. pylori Infection

Bismuth quadruple therapy for 14 days is the recommended first-line treatment for H. pylori infection in adults without known drug allergies or prior therapy, achieving 80–90% eradication rates even in regions with high clarithromycin resistance. 1, 2

First-Line Regimen: Bismuth Quadruple Therapy

The standard 14-day regimen consists of:

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred) 1, 2
• Bismuth subsalicylate 262 mg four times daily 1, 2
• Metronidazole 500 mg three to four times daily (total 1.5–2 g/day) 1, 2
• Tetracycline 500 mg four times daily 1, 2

Why This Regimen Is Superior

Bismuth quadruple therapy overcomes the critical problem of rising antibiotic resistance. Clarithromycin resistance now exceeds 15–20% across North America and Europe, reducing traditional triple therapy success rates to only ~70%—well below the 80% minimum target. 1, 2 When H. pylori strains are clarithromycin-resistant, triple therapy eradication plummets from ~90% to ~20%. 1 In contrast, bismuth quadruple therapy maintains 80–90% efficacy even against strains with dual clarithromycin-metronidazole resistance because bismuth's synergistic effect overcomes metronidazole resistance in vitro. 1, 2

Critical Optimization Factors

PPI dosing is mandatory for success:

• Use esomeprazole or rabeprazole 40 mg twice daily—this increases cure rates by 8–12% compared to standard-dose PPIs 1, 2
• Take PPI 30 minutes before meals on an empty stomach, without concomitant antacids 1, 2
• Never use once-daily PPI dosing—this is a major cause of treatment failure 1, 2
• Avoid pantoprazole (40 mg provides acid suppression equivalent to only ~9 mg omeprazole) 1, 2

Treatment duration:

• 14 days is mandatory—extending from 7 to 14 days improves eradication by approximately 5% 1, 2, 3
• All major guidelines (Toronto Consensus, Maastricht V/Florence, American College of Gastroenterology) mandate this duration 1, 2, 3

Alternative First-Line Options (Restricted Use)

Clarithromycin-Based Triple Therapy

Only use when:

• Local clarithromycin resistance is documented <15% AND 1, 2, 4
• Patient has no prior macrolide exposure 1, 2

Regimen (14 days):

• Esomeprazole or rabeprazole 40 mg twice daily 1
• Clarithromycin 500 mg twice daily 1
• Amoxicillin 1000 mg twice daily 1

Concomitant Non-Bismuth Quadruple Therapy

Only when bismuth is unavailable AND clarithromycin resistance <15%: 1, 2

Regimen (14 days):

• High-dose PPI twice daily 1
• Amoxicillin 1000 mg twice daily 1
• Clarithromycin 500 mg twice daily 1
• Metronidazole 500 mg twice daily 1

Second-Line Treatment After First-Line Failure

After Clarithromycin-Based Triple Therapy Fails

Use bismuth quadruple therapy for 14 days (as described above) 1, 2, 3

After Bismuth Quadruple Therapy Fails

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

• Esomeprazole or rabeprazole 40 mg twice daily 1
• Amoxicillin 1000 mg twice daily 1
• Levofloxacin 500 mg once daily 1

Critical caveat: Levofloxacin resistance is rising globally (primary 11–30%, secondary 19–30%), so never use it empirically as first-line therapy. 1, 2 Cross-resistance exists within the fluoroquinolone family—never use levofloxacin in patients with prior fluoroquinolone exposure for any indication. 1

Third-Line and Rescue Therapies

After two documented treatment failures with confirmed adherence, obtain antibiotic susceptibility testing to guide further therapy. 1, 2, 3, 5

Empiric third-line options when susceptibility testing is unavailable:

Rifabutin Triple Therapy (14 days)

• Rifabutin 150 mg twice daily 1, 2
• Amoxicillin 1000 mg twice daily 1, 2
• High-dose PPI twice daily 1, 2

Rifabutin resistance is rare, making this effective after multiple failures. 1, 2

High-Dose Dual Therapy (14 days)

• Amoxicillin 2–3 g daily divided into 3–4 doses 1, 2
• High-dose PPI twice daily 1, 2

This offers a simpler regimen for patients struggling with adherence. 1, 2

Special Populations

Penicillin Allergy

Bismuth quadruple therapy is the first choice because it contains tetracycline instead of amoxicillin. 1, 2 Consider formal penicillin allergy testing after first-line failure, as most reported allergies are not true allergies and amoxicillin resistance remains rare (<5%). 1, 2

If confirmed penicillin allergy and bismuth unavailable, use PPI + clarithromycin + metronidazole for 14 days only where clarithromycin resistance is <15%. 2

Confirmation of Eradication

Test for eradication success at least 4 weeks after completing therapy using: 1, 2, 4

• Urea breath test (preferred) 1, 2
• Validated monoclonal stool antigen test 1, 2

Discontinue PPI at least 2 weeks before testing to avoid false-negative results. 1, 2, 4

Never use serology for confirmation—antibodies persist long after successful eradication. 1, 2

Common Pitfalls to Avoid

• Never repeat clarithromycin or levofloxacin if they were in a failed regimen—resistance develops rapidly after exposure 1, 2
• Never use standard-dose PPI once daily—this markedly increases failure risk 1, 2
• Never shorten therapy below 14 days—this reduces eradication by ~5% 1, 2, 3
• Never assume low clarithromycin resistance without local surveillance data—most regions now have high resistance 1, 2
• Never use levofloxacin as first-line therapy—this accelerates resistance and eliminates a valuable rescue option 1, 2

Patient Factors Affecting Success

Counsel patients on:

• Smoking roughly doubles the odds of treatment failure (OR ~1.95)—advise cessation during therapy 1
• Diarrhea occurs in 21–41% of patients during the first week due to gut microbiota disruption—this does not indicate treatment failure 1
• Elevated BMI/obesity may lower gastric mucosal drug concentrations, potentially reducing efficacy 1
• Completing the full 14-day course is essential—poor compliance is a leading cause of failure 1, 2

Antimicrobial Stewardship Advantage

Bismuth quadruple therapy uses WHO "Access" antibiotics (tetracycline, metronidazole) rather than "Watch" agents (clarithromycin, levofloxacin), supporting antimicrobial stewardship principles while maintaining superior efficacy. 2