In an adult with confirmed Helicobacter pylori infection, what is the recommended first‑line regimen, and what alternative regimens should be used if clarithromycin resistance is high or the patient is pregnant, breastfeeding, penicillin‑allergic, or immunocompromised?

First-Line and Alternative Regimens for H. pylori Eradication

First-Line Regimen: Bismuth Quadruple Therapy

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

Standard Regimen Components

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred; increases cure rates by 8–12% compared to other PPIs) 1, 2
• Bismuth subsalicylate 262 mg (two tablets) four times daily or bismuth subcitrate 120 mg four times daily 1, 3
• Metronidazole 500 mg three to four times daily (total 1.5–2 g/day) 1, 3
• Tetracycline 500 mg four times daily 1, 3
• Duration: 14 days mandatory (improves eradication by ~5% versus shorter courses) 1, 2, 4

Administration Details

• Take PPI 30 minutes before meals on an empty stomach, without concomitant antacids 1, 2
• Bismuth should be taken 30 minutes before meals and at bedtime 1
• Metronidazole should be taken 30 minutes after meals 1

Why Bismuth Quadruple Therapy Is Preferred

• No bacterial resistance to bismuth has been described 1
• Bismuth's synergistic effect overcomes metronidazole resistance in vitro, maintaining efficacy even against resistant strains 1, 2
• Uses WHO "Access" antibiotics (tetracycline, metronidazole) rather than "Watch" agents (clarithromycin, levofloxacin), supporting antimicrobial stewardship 1, 2
• Clarithromycin resistance now exceeds 15–20% across North America and Europe, reducing traditional triple therapy cure rates to ~70% 1, 2

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Alternative First-Line Regimen When Bismuth Is Unavailable

Concomitant non-bismuth quadruple therapy for 14 days may be used only when bismuth is unavailable AND local clarithromycin resistance is documented <15%. 1, 2

Regimen Components

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred) 1
• Amoxicillin 1000 mg twice daily 1
• Clarithromycin 500 mg twice daily 1
• Metronidazole 500 mg twice daily 1
• Duration: 14 days 1, 4

This regimen avoids the pitfall of sequential therapy by administering all antibiotics simultaneously, preventing resistance development during treatment 1

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Clarithromycin-Based Triple Therapy (Highly Restricted)

Triple therapy (PPI + clarithromycin + amoxicillin) should only be used in areas with documented clarithromycin resistance <15% AND the patient has no prior macrolide exposure for any indication. 1, 2

Why This Regimen Is Restricted

• When H. pylori strains are clarithromycin-resistant, eradication rates drop from ~90% to ~20% 1
• Clarithromycin resistance has increased globally from 9% in 1998 to 17.6% in 2008–2009, and now exceeds 20% in most regions 1, 2
• Cross-resistance is universal within the macrolide family; prior macrolide use for any indication precludes clarithromycin use 1

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Special Populations

Penicillin Allergy

Bismuth quadruple therapy is the first-choice regimen because it contains tetracycline instead of amoxicillin. 1, 3, 2

• Consider penicillin allergy testing to rule out true anaphylaxis; most patients reporting penicillin allergy are not truly allergic 1
• Amoxicillin resistance remains extremely rare (<5%) 1, 2
• If confirmed penicillin allergy and bismuth is unavailable, use PPI + clarithromycin + metronidazole for 14 days only where clarithromycin resistance is <15% 3, 2

Pregnancy and Breastfeeding

Eradication therapy should be deferred until after pregnancy and breastfeeding. 2

• Tetracycline is contraindicated in pregnancy 2
• Clarithromycin is FDA category C 2

Immunocompromised Patients

Use the same first-line bismuth quadruple therapy regimen; no specific modifications are required based on immune status alone. 1, 3

• Ensure 14-day duration to maximize eradication success 1, 4
• Consider antibiotic susceptibility testing earlier (after first failure) in this population 1

Elderly Patients

Tetracycline is not contraindicated in elderly patients; age alone does not preclude bismuth quadruple therapy. 1

• Elderly individuals are a vulnerable population; balance eradication benefits against adverse-effect risk 1
• Shared decision-making is essential after multiple failures 1
• Four-times-daily dosing may be challenging; provide clear education on regimen rationale and dosing 1

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High Clarithromycin Resistance (≥15%)

In regions with clarithromycin resistance ≥15%, bismuth quadruple therapy is mandatory as first-line treatment; clarithromycin-based triple therapy should be abandoned. 1, 2, 5

• Standard triple therapy achieves only ~70% eradication in high-resistance areas, well below the 80% minimum target 1, 2
• If local resistance data is unavailable, assume high clarithromycin resistance and use bismuth quadruple therapy 1

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Critical Optimization Factors

PPI Dosing

• High-dose PPI twice daily is mandatory; once-daily dosing is a major cause of treatment failure 1, 2
• Esomeprazole or rabeprazole 40 mg twice daily is strongly preferred over other PPIs 1, 2
• Avoid pantoprazole; 40 mg provides acid suppression equivalent to only ~9 mg omeprazole, yielding inferior outcomes 1, 2

Treatment Duration

• 14 days is the evidence-based standard for all H. pylori regimens; endorsed by Toronto Consensus, Maastricht V/Florence, and American College of Gastroenterology 1, 2, 4
• Shortening therapy below 14 days reduces eradication success by ~5% 1, 2, 4

Antibiotic Reuse Rules

• Never reuse clarithromycin or levofloxacin after a failed regimen; resistance develops rapidly after exposure 1, 2
• Metronidazole can be reused with bismuth due to synergistic effects 1, 3
• Amoxicillin and tetracycline can be reused because resistance remains rare 1, 3

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Second-Line Treatment After First-Line Failure

After Clarithromycin-Based Triple Therapy Fails

Bismuth quadruple therapy for 14 days is the preferred second-line regimen. 1, 3, 4

• Never repeat clarithromycin; resistance develops rapidly and eradication rates drop from 90% to 20% with resistant strains 1

After Bismuth Quadruple Therapy Fails

Levofloxacin triple therapy for 14 days is the next option, provided the patient has no prior fluoroquinolone exposure for any indication. 1, 3, 2

Regimen Components

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred) 1, 3
• Amoxicillin 1000 mg twice daily 1, 3
• Levofloxacin 500 mg once daily (or 250 mg twice daily) 1, 3
• Duration: 14 days 1, 4

Levofloxacin Resistance Considerations

• Global levofloxacin resistance is rising (primary 11–30%, secondary 19–30%) 1, 2
• Never use levofloxacin empirically as first-line therapy; this accelerates resistance development 1, 2
• Cross-resistance exists within the fluoroquinolone family 1

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Third-Line and Rescue Therapies

After Two Failed Eradication Attempts

Antibiotic susceptibility testing should guide further treatment whenever possible. 1, 3, 2, 4

• Molecular testing for clarithromycin and levofloxacin resistance is available but less reliable than culture-based testing 1
• Stool-based molecular testing is an emerging option that avoids endoscopy 1

Rifabutin Triple Therapy (Third-Line)

Rifabutin triple therapy for 14 days is reserved for patients who have failed at least two prior regimens. 1, 3, 2

Regimen Components

• Rifabutin 150 mg twice daily (or 300 mg once daily) 1, 3
• Amoxicillin 1000 mg twice daily 1, 3
• High-dose PPI twice daily 1, 3
• Duration: 14 days 1, 4

Rifabutin resistance is rare, making it effective as rescue therapy 1, 2

High-Dose Dual Therapy (Rescue Option)

High-dose dual therapy for 14 days offers a simpler regimen after multiple failures. 1, 3, 2

Regimen Components

• Amoxicillin 2–3 g daily in 3–4 divided doses 1, 3
• High-dose PPI twice daily (double standard dose) 1, 3
• Duration: 14 days 1, 4

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Confirmation of Eradication

Verify eradication ≥4 weeks after therapy using a urea breath test or validated monoclonal stool antigen assay; discontinue PPI ≥2 weeks before testing. 1, 3, 2

• Never use serology to confirm eradication; antibodies persist long after successful treatment 1, 2

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Common Pitfalls to Avoid

• Do not use once-daily PPI dosing; it is a major cause of treatment failure 1, 2
• Do not shorten therapy below 14 days 1, 2, 4
• Do not repeat clarithromycin or levofloxacin after a failed regimen 1, 2
• Do not assume low clarithromycin resistance without local surveillance data 1, 2
• Avoid pantoprazole due to inferior acid-suppression potency 1, 2
• Do not use levofloxacin empirically as first-line therapy 1, 2
• Do not substitute doxycycline for tetracycline; it yields significantly inferior eradication rates 1