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

H. pylori Eradication: Current Treatment Guidelines

First-Line Treatment Recommendation

Bismuth quadruple therapy for 14 days is the preferred first-line treatment for H. pylori infection, achieving 80-90% eradication rates even in areas with high clarithromycin and metronidazole resistance. 1, 2, 3

Standard Bismuth Quadruple Therapy Regimen

• PPI twice daily (esomeprazole or rabeprazole 40 mg preferred, or pantoprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg, dexlansoprazole 30 mg, or rabeprazole 20 mg) 1
• Bismuth subsalicylate 262 mg or bismuth subcitrate 120 mg four times daily 1
• Metronidazole 500 mg three to four times daily (total daily dose 1.5-2 g) 1, 2
• Tetracycline 500 mg four times daily 1, 2
• Duration: 14 days mandatory 1, 2, 3

The superiority of bismuth quadruple therapy stems from the fact that no bacterial resistance to bismuth has been described, and tetracycline resistance remains rare (<5%) 1. Additionally, bismuth's synergistic effect overcomes metronidazole resistance even when in vitro resistance is present 1, 2.

Critical Optimization Factors

• PPI must be taken twice daily, 30 minutes before meals on an empty stomach, without concomitant antacids 1, 3
• High-dose PPI (esomeprazole or rabeprazole 40 mg twice daily) increases cure rates by 8-12% compared to standard PPIs 1, 2
• 14-day duration is superior to 7-10 day regimens, improving eradication by approximately 5% 1, 2, 3

Alternative First-Line Option When Bismuth is Unavailable

Concomitant non-bismuth quadruple therapy for 14 days is the recommended alternative when bismuth is not available 1, 2, 3:

• PPI twice daily + amoxicillin 1000 mg twice daily + clarithromycin 500 mg twice daily + metronidazole 500 mg twice daily 1, 2

This regimen avoids the pitfall of sequential therapy by administering all antibiotics simultaneously, preventing resistance development during treatment 2.

When Triple Therapy May Be Considered (Restricted Use)

Triple therapy should only be used in areas with documented clarithromycin resistance <15% 1, 2:

• PPI twice daily + clarithromycin 500 mg twice daily + amoxicillin 1000 mg twice daily for 14 days 2, 4

However, clarithromycin resistance now exceeds 15-20% in most of North America and Central, Western, and Southern Europe, making this option unacceptable in most regions 2. When H. pylori strains are clarithromycin-resistant, eradication rates drop from 90% to approximately 20% 2.

Second-Line Treatment After First-Line Failure

After Failed Clarithromycin-Based Therapy

Bismuth quadruple therapy for 14 days (if not previously used) 1, 3

After Failed Bismuth Quadruple Therapy

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

• PPI twice daily (esomeprazole or rabeprazole 40 mg preferred) + amoxicillin 1000 mg twice daily + levofloxacin 500 mg once daily (or 250 mg twice daily) 1, 2

Critical caveat: Levofloxacin resistance rates are rapidly increasing (11-30% primary, 19-30% secondary resistance globally) 1, 2. Never use levofloxacin empirically as first-line therapy, and avoid in patients with prior fluoroquinolone exposure for any indication 2.

Third-Line and Rescue Therapies

After Two Failed Eradication Attempts

Antibiotic susceptibility testing should guide further treatment whenever possible 1, 2, 3, 5, 6

Rifabutin Triple Therapy (Third-Line)

Rifabutin 150 mg twice daily (or 300 mg once daily) + amoxicillin 1000 mg twice daily + PPI twice daily for 14 days 1, 2, 3

Rifabutin resistance is rare, making it highly effective as rescue therapy after multiple failures 1, 2. However, it should be reserved for patients who have failed at least 2-3 prior regimens due to potential myelotoxicity 7.

High-Dose Dual Therapy (Rescue Option)

Amoxicillin 2-3 grams daily in 3-4 split doses + high-dose PPI (double standard dose) twice daily for 14 days 1, 2, 3

This is an alternative rescue therapy when other options have been exhausted 1, 3.

Special Populations

Patients with Penicillin Allergy

Bismuth quadruple therapy is the first choice, as it contains tetracycline instead of amoxicillin 1, 2, 3

Consider penicillin allergy testing to delist the allergy and enable amoxicillin use, as most patients who report penicillin allergy do not have true allergy 1, 2.

If bismuth is unavailable and penicillin allergy is confirmed, use PPI + clarithromycin + metronidazole for 14 days (only in areas with documented clarithromycin resistance <15%) 1.

Critical Antibiotic Reuse Rules

• Never reuse clarithromycin or levofloxacin after failure, as resistance develops rapidly after exposure 1, 2, 3
• Amoxicillin and tetracycline can be reused because resistance remains rare (<5%) 1, 2
• Metronidazole can be reused with bismuth because bismuth's synergistic effect overcomes in vitro resistance 1, 2

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 stopping PPIs 1, 2, 3

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

Common Pitfalls to Avoid

• Do not use standard-dose PPI once daily—always use twice-daily dosing to maximize efficacy 1, 2, 3
• Do not use treatment durations shorter than 14 days 1, 2, 3, 7
• Do not use concomitant, sequential, or hybrid therapies—they include unnecessary antibiotics that contribute to global antibiotic resistance without therapeutic benefit 2
• Do not assume low clarithromycin resistance without local surveillance data—most regions now have high resistance rates 2
• Do not use levofloxacin as first-line therapy—this accelerates resistance development and eliminates a valuable rescue option 2

Why Bismuth Quadruple Therapy is Preferred

The paradigm shift toward bismuth quadruple therapy as first-line treatment is driven by:

• Rising clarithromycin resistance (now exceeding 15-20% in most developed regions) 1, 2
• No bacterial resistance to bismuth 1, 2
• Rare tetracycline resistance (<5%) 1
• Effectiveness against dual-resistant strains (clarithromycin + metronidazole) 1, 2
• Use of WHO "Access group" antibiotics (tetracycline, metronidazole) rather than "Watch group" antibiotics (clarithromycin, levofloxacin) from an antimicrobial stewardship perspective 2

H. pylori treatment should be approached as an infectious disease with the goal of near-100% cure rates, not as a typical gastroenterological disease with modest success rates 2.