What is the recommended first-line treatment for H pylori (Helicobacter pylori) infection?

H. pylori Treatment

Bismuth quadruple therapy for 14 days is the recommended first-line treatment for H. pylori infection, consisting of a high-dose PPI twice daily, bismuth subsalicylate, metronidazole, and tetracycline. 1, 2

First-Line Treatment Regimen

Bismuth quadruple therapy achieves 80-90% eradication rates even in areas with high clarithromycin and metronidazole resistance, making it superior to traditional triple therapy. 1, 2

Specific Dosing for Bismuth Quadruple Therapy:

• PPI (esomeprazole or rabeprazole preferred): 40 mg twice daily, taken 30 minutes before meals 1, 3
• 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: 500 mg four times daily 1
• Duration: 14 days (mandatory—improves eradication by ~5% compared to shorter regimens) 1, 3, 2

Why Bismuth Quadruple Therapy is Preferred:

• No bacterial resistance to bismuth has ever been described 1, 2
• Effective even against strains with dual resistance to clarithromycin and metronidazole 1
• Uses antibiotics from the WHO "Access group" (tetracycline, metronidazole) rather than "Watch group" (clarithromycin, levofloxacin), supporting antimicrobial stewardship 1
• Clarithromycin resistance now exceeds 15-20% in most of North America and Europe, making traditional triple therapy achieve only 70% eradication rates 1, 2

Alternative First-Line Option (When Bismuth Unavailable)

Concomitant non-bismuth quadruple therapy for 14 days is the recommended alternative when bismuth is not available: 1, 2

• PPI: Twice daily (high-dose)
• Amoxicillin: 1000 mg twice daily 1, 4
• Clarithromycin: 500 mg twice daily
• Metronidazole: 500 mg twice daily

This regimen should only be used in areas with documented clarithromycin resistance below 15%, and even then, bismuth quadruple therapy remains superior. 1

Critical Optimization Factors

PPI Selection and Dosing:

• High-dose PPI twice daily is mandatory—standard once-daily dosing is inadequate 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, without concomitant antacids 1

Treatment Duration:

• 14 days is mandatory for all regimens—improves eradication by approximately 5% compared to 7-10 day regimens 1, 3, 2

Adjunctive Therapy:

• Consider probiotics to reduce antibiotic-associated diarrhea (occurs in 21-41% of patients), though evidence for improving eradication rates is limited 1, 3, 2

Second-Line Treatment After First-Line Failure

After bismuth quadruple therapy failure, levofloxacin-based triple therapy for 14 days is recommended (if no prior fluoroquinolone exposure): 1, 2

• PPI: Twice daily (high-dose)
• Amoxicillin: 1000 mg twice daily 4
• Levofloxacin: 500 mg once daily or 250 mg twice daily

Critical caveat: Levofloxacin resistance rates are rising (11-30% primary, 19-30% secondary), and the FDA recommends fluoroquinolones be used as a last choice due to serious side effects 1

If clarithromycin-based therapy was used first-line and failed, use bismuth quadruple therapy as second-line. 3, 2

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 Unavailable:

Rifabutin-based triple therapy for 14 days: 1, 2

• Rifabutin: 150 mg twice daily
• Amoxicillin: 1000 mg twice daily 4
• PPI: Twice daily (high-dose)
• Rifabutin resistance is extremely rare 1

High-dose dual amoxicillin-PPI therapy for 14 days (alternative rescue option): 1

• Amoxicillin: 2-3 grams daily in 3-4 split doses 4
• PPI: Double standard dose, twice daily

Verification of Eradication

Confirm eradication with urea breath test or monoclonal stool antigen test at least 4 weeks after completion of therapy and at least 2 weeks after PPI discontinuation. 1, 3, 2

Never use serology to confirm eradication—antibodies persist long after successful treatment. 1, 2

Critical Pitfalls to Avoid

• Never repeat antibiotics that failed previously, especially clarithromycin and levofloxacin—resistance develops rapidly after exposure 1, 2
• Never assume low clarithromycin resistance without local surveillance data—most regions now have high resistance rates 1
• Avoid concomitant, sequential, or hybrid therapies as first-line—they include unnecessary antibiotics that contribute to global antibiotic resistance without therapeutic benefit 1
• Never use standard-dose PPI once daily—always use twice-daily high-dose dosing 1, 3, 2
• Do not use levofloxacin empirically as first-line therapy due to rapidly rising fluoroquinolone resistance rates 1

Special Populations

Penicillin Allergy:

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

Patient Factors Affecting Success:

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