What is the recommended first‑line therapy for an otherwise healthy adult with confirmed Helicobacter pylori infection?

H. pylori Treatment in Adults

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

Recommended First-Line Regimen (14 Days)

The optimal regimen consists of:

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

Critical Administration Details

• Take PPI 30 minutes before meals on an empty stomach; avoid concomitant antacids 1
• 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% 1, 2

Why Bismuth Quadruple Therapy Is First-Line

Clarithromycin resistance now exceeds 15–20% across North America and Europe, reducing traditional triple therapy success to only 70% 1, 2. In contrast:

• Bismuth quadruple therapy maintains 80–90% eradication even against strains resistant to both clarithromycin and metronidazole 1, 3
• No bacterial resistance to bismuth has been reported, and tetracycline resistance remains rare (<5%) 1
• The regimen uses WHO "Access" antibiotics (tetracycline, metronidazole) rather than "Watch" agents (clarithromycin, levofloxacin), supporting antimicrobial stewardship 1
• Bismuth's synergistic effect overcomes metronidazole resistance in vitro 1, 2

Alternative First-Line Option (When Bismuth Unavailable)

Concomitant non-bismuth quadruple therapy for 14 days may be used only if bismuth is unavailable and local clarithromycin resistance is documented to be <15% 1:

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

However, recent high-quality evidence shows this regimen achieved only 85.9% eradication in intention-to-treat analysis, inferior to bismuth quadruple therapy's 90.4% 3. A 10-day course is insufficient; 14 days is required 4, 3.

Second-Line Therapy After First-Line Failure

If bismuth quadruple therapy fails:

• Levofloxacin triple therapy for 14 days (PPI 40 mg twice daily + amoxicillin 1000 mg twice daily + levofloxacin 500 mg once daily) is recommended only if the patient has had no prior fluoroquinolone exposure 1, 5
• Never repeat clarithromycin if it was in the failed regimen—eradication rates drop from ~90% to ~20% with resistant strains 1, 5

If clarithromycin-based therapy fails:

• Switch to bismuth quadruple therapy for 14 days 6, 1, 5

Third-Line and Rescue Strategies

After two documented treatment failures with confirmed adherence, obtain antibiotic susceptibility testing to guide therapy 6, 1, 5. Empiric third-line options when testing is unavailable:

• Rifabutin triple therapy (PPI 40 mg twice daily + amoxicillin 1000 mg twice daily + rifabutin 150 mg twice daily) for 14 days 1, 2
• High-dose dual therapy (PPI 40 mg twice daily + amoxicillin 2–3 g daily divided into 3–4 doses) for 14 days, useful in elderly or complex patients 1, 5

Confirmation of Eradication (Test-of-Cure)

Perform urea breath test or monoclonal stool antigen test:

• At least 4 weeks after completing therapy 1, 5, 2
• At least 2 weeks after stopping the PPI 1, 5, 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 1, 2
• Elevated BMI/obesity may lower gastric mucosal drug concentrations 1, 2
• Poor compliance is a leading cause of failure; provide clear written instructions emphasizing the full 14-day course 1, 2

Expected Side Effects

• Diarrhea occurs in 21–41% of patients during the first week due to gut microbiota disruption; this does not indicate treatment failure 1, 2
• Adjunctive probiotics may be considered to reduce diarrhea risk and improve compliance 2

Critical Pitfalls to Avoid

• Never use once-daily PPI dosing—it is a major cause of treatment failure 1, 2
• Avoid pantoprazole 40 mg—its acid-suppression effect equals only ~9 mg omeprazole, yielding inferior outcomes 1, 2
• Do not shorten therapy below 14 days—this reduces eradication by ~5% 1, 2, 3
• Never repeat clarithromycin or levofloxacin if they were part of a failed regimen 1, 5
• Do not use clarithromycin-based triple therapy empirically unless local surveillance confirms resistance <15%; most regions now exceed 15–20% resistance 1, 2

Special Populations – Penicillin Allergy

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