What is the first‑line Helicobacter pylori eradication regimen for an adult with no known drug allergies?

H. pylori Eradication Protocol

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

First-Line Regimen: Bismuth Quadruple Therapy (14 days)

The recommended regimen consists of:

• Esomeprazole or rabeprazole 40 mg twice daily (preferred over other PPIs; increases cure rates by 8–12%) 1, 2
• Bismuth subsalicylate 262 mg (two tablets) four times daily 1, 3
• Metronidazole 500 mg three to four times daily (total 1.5–2 g/day) 1, 3, 2
• Tetracycline 500 mg four times daily 1, 3, 2

Critical Administration Details

• Take PPI 30 minutes before meals on an empty stomach, without concomitant antacids 1, 2
• Take bismuth 30 minutes before meals and at bedtime 1
• Take metronidazole 30 minutes after meals 1
• 14-day duration is mandatory—extending from 7 to 14 days improves eradication by approximately 5% 4, 1, 2, 5

Why This Regimen Is Superior

• Clarithromycin resistance now exceeds 15–20% across North America and Europe, reducing traditional triple therapy success to only ~70% 1, 2
• Bismuth quadruple therapy is unaffected by clarithromycin resistance and achieves 80–90% eradication even against dual clarithromycin-metronidazole resistant strains 1, 2
• No bacterial resistance to bismuth has been described, and tetracycline resistance remains rare (<5%) 1, 2
• Uses WHO "Access" antibiotics (tetracycline, metronidazole) rather than "Watch" agents (clarithromycin, levofloxacin), supporting antimicrobial stewardship 2

Alternative First-Line Option (Only When Bismuth Unavailable)

Concomitant non-bismuth quadruple therapy for 14 days:

• Esomeprazole or rabeprazole 40 mg twice daily 1, 2
• Amoxicillin 1000 mg twice daily 1, 2
• Clarithromycin 500 mg twice daily 1, 2
• Metronidazole 500 mg twice daily 1, 2

This regimen should only be used when bismuth is unavailable AND local clarithromycin resistance is documented <15% 1, 2

Second-Line Treatment (After First-Line Failure)

If Bismuth Quadruple Therapy Fails

Levofloxacin triple therapy for 14 days (only if no prior fluoroquinolone exposure):

• Esomeprazole or rabeprazole 40 mg twice daily 1, 3
• Amoxicillin 1000 mg twice daily 1, 3
• Levofloxacin 500 mg once daily 1, 3

Do not use levofloxacin if the patient has received any fluoroquinolone for any indication (e.g., respiratory infections, UTIs), as cross-resistance is universal 1

If Clarithromycin-Based Therapy Fails

Switch to bismuth quadruple therapy for 14 days (regimen above) 1, 3, 2

Never repeat clarithromycin—resistance drops eradication rates from ~90% to ~20% with resistant strains 1, 2

Third-Line and Rescue Therapies

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

Empiric Third-Line Options (If Susceptibility Testing Unavailable)

Rifabutin triple therapy for 14 days:

• Esomeprazole or rabeprazole 40 mg twice daily 1, 3
• Amoxicillin 1000 mg twice daily 1, 3
• Rifabutin 150 mg twice daily 1, 3

High-dose dual therapy for 14 days (simpler regimen for elderly or complex patients):

• Esomeprazole or rabeprazole 40 mg twice daily 1, 3
• Amoxicillin 2–3 grams daily divided into 3–4 doses 1, 3

Confirmation of Eradication (Test-of-Cure)

Perform urea breath test or monoclonal stool antigen test:

• At least 4 weeks after completing therapy 1, 3, 2
• At least 2 weeks after discontinuing PPI 1, 3, 2

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

Patient Factors That Reduce Success

• Smoking roughly doubles the odds of treatment failure (OR 1.95)—advise cessation during therapy 4, 1
• Elevated BMI/obesity may lower gastric mucosal drug concentrations 4, 1
• Poor compliance is a leading cause of failure—provide clear written instructions and stress completing the full 14-day course 1

Expected Side Effects

• Diarrhea occurs in 21–41% of patients during the first week due to disruption of gut microbiota—this does not indicate treatment failure 1
• Consider adjunctive probiotics to reduce diarrhea risk and improve compliance 1

Critical Pitfalls to Avoid

• Never use once-daily PPI dosing—this is a major cause of treatment failure 1, 2
• Never use pantoprazole 40 mg—it provides acid suppression equivalent to only ~9 mg omeprazole and yields inferior outcomes 1, 2
• Never shorten therapy below 14 days—this reduces eradication by ~5% 4, 1, 2, 5
• Never repeat clarithromycin or levofloxacin if they were in a failed regimen 1, 2
• Never assume low clarithromycin resistance without local surveillance data—most regions now exceed 15–20% resistance 1, 2
• Do not use clarithromycin-based triple therapy empirically—it should be restricted to areas with documented clarithromycin resistance <15% 4, 1, 2

Special Populations

Penicillin Allergy

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

Consider penicillin allergy testing after first-line failure—most reported allergies are not true allergies, and amoxicillin resistance remains rare (<5%) 1, 2