How should a confirmed Helicobacter pylori infection in an adult be managed, including first‑line therapy, considerations for clarithromycin resistance, penicillin allergy, pregnancy, and post‑treatment eradication testing?

Management of Helicobacter pylori Infection

First-Line Treatment

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

The regimen consists of:

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred; increases cure rates by 8–12% compared to standard PPIs) 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) 3, 1
• Tetracycline 500 mg four times daily 1, 2

All components must be taken for the full 14 days—extending from 7 to 14 days improves eradication by approximately 5%. 3, 4

PPI Administration Details

• Take 30 minutes before meals on an empty stomach 3, 1
• Twice-daily dosing is mandatory; once-daily dosing significantly reduces efficacy 3, 1
• Avoid pantoprazole (40 mg pantoprazole ≈ only 9 mg omeprazole equivalent) 1

Why Bismuth Quadruple Therapy First?

• No bacterial resistance to bismuth has been described 1
• Bismuth's synergistic effect overcomes metronidazole resistance in vitro 3, 1
• Not affected by clarithromycin resistance, which now exceeds 15–20% in most of North America and Europe 1, 2
• Uses antibiotics from the WHO "Access group" (tetracycline, metronidazole) rather than "Watch group" (clarithromycin, levofloxacin), supporting antimicrobial stewardship 1

Considerations for Clarithromycin Resistance

Standard triple therapy (PPI + clarithromycin + amoxicillin) should be abandoned when regional clarithromycin resistance exceeds 15–20%, as eradication rates drop from ~90% with susceptible strains to ~20% with resistant strains. 1, 2

Triple therapy may only be considered when:

• Local clarithromycin resistance is documented < 15% 1, 2, 4
• Patient has no prior macrolide exposure (for any indication) 1
• 14-day duration is used (not 7 days) 1, 4

If triple therapy is used, the regimen is:

• Esomeprazole or rabeprazole 40 mg twice daily + clarithromycin 500 mg twice daily + amoxicillin 1000 mg twice daily for 14 days 1

Critical pitfall: Never assume low clarithromycin resistance without local surveillance data—most regions now have high resistance. 1

Management of Penicillin Allergy

Bismuth quadruple therapy is the first-choice regimen in patients with penicillin allergy, as it contains tetracycline rather than amoxicillin. 1, 2, 5

However, consider penicillin allergy testing to delist the allergy, as true anaphylaxis to penicillin is rare despite prevalent chart documentation. 3 This enables use of amoxicillin-containing regimens, which are valuable for refractory infection. 3

Alternative if Bismuth Unavailable

If bismuth is unavailable and clarithromycin resistance is < 15%:

• PPI twice daily + clarithromycin 500 mg twice daily + metronidazole 500 mg twice daily for 14 days 1, 5

Management During Pregnancy

The provided evidence does not contain specific pregnancy-related recommendations for H. pylori treatment. In clinical practice, treatment is typically deferred until after delivery unless there is active bleeding, as tetracycline is contraindicated and clarithromycin/metronidazole carry pregnancy concerns.

Post-Treatment Eradication Testing

All patients must undergo test-of-cure at least 4 weeks after completing therapy using urea breath test or validated monoclonal stool antigen test. 1, 2, 4

Discontinue PPIs at least 2 weeks (preferably 7–14 days) before testing to avoid false-negative results. 1, 2

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

Mandatory Test-of-Cure Scenarios

• Gastric ulcer 1
• Complicated or bleeding peptic ulcer 1
• Gastric MALT lymphoma 1
• After treatment failure 1

Second-Line Treatment After First-Line Failure

After Clarithromycin-Based Triple Therapy Fails

Bismuth quadruple therapy for 14 days (if not previously used) 1, 4, 5

After Bismuth Quadruple Therapy Fails

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

• Esomeprazole or rabeprazole 40 mg twice daily + amoxicillin 1000 mg twice daily + levofloxacin 500 mg once daily for 14 days 1, 4, 5

Critical caveat: Levofloxacin resistance rates are 11–30% (primary) and 19–30% (secondary); never use levofloxacin as first-line therapy. 1

Never repeat antibiotics that failed previously, especially clarithromycin and levofloxacin, where resistance develops rapidly after exposure. 1, 2

Third-Line and Rescue Therapies

After two failed eradication attempts with confirmed patient adherence, antibiotic susceptibility testing should guide further treatment. 1, 2, 4

Empiric Third-Line Options (if susceptibility testing unavailable)

Rifabutin triple therapy (14 days):

• Rifabutin 150 mg twice daily + amoxicillin 1000 mg twice daily + high-dose PPI twice daily 1, 4
• Reserve for third-line or later; rifabutin resistance is rare 1

High-dose dual therapy (14 days):

• Amoxicillin 2–3 g daily divided into 3–4 doses + high-dose PPI twice daily 3, 1
• Dividing amoxicillin into at least three daily doses avoids low trough levels 3

Optimizing Treatment Success

Amoxicillin Dosing

Divide 2–3 g amoxicillin into at least three doses daily (not twice daily) to avoid low trough levels and improve efficacy. 3

Metronidazole Dosing

Higher doses of metronidazole (1.5–2 g/day range) significantly improve eradication rates. 3

• Take in divided doses (TID to QID) with food to reduce GI side effects 3
• Avoid alcohol during treatment due to disulfiram-like reaction 3

Acid Suppression Optimization

Inadequate acid suppression undermines eradication through multiple mechanisms. 3

• Higher dosing, greater frequency (TID or QID PPI), and more potent PPIs (esomeprazole, rabeprazole) may benefit refractory cases 3
• Intragastric pH affects amoxicillin efficacy and half-life 3

Common Pitfalls to Avoid

• Never use once-daily PPI dosing—twice daily is mandatory 3, 1
• Never shorten therapy below 14 days 1, 2, 4
• Never test for eradication while taking PPIs—wait ≥ 2 weeks after stopping 1, 2
• Never repeat the same failed regimen—guarantees failure and accelerates resistance 1
• Never use concomitant, sequential, or hybrid therapies—they include unnecessary antibiotics contributing to global resistance 1

Patient Factors Affecting Success

• Smoking roughly doubles the odds of eradication failure (OR ≈ 1.95); advise cessation during therapy 1
• High BMI/obesity may lower gastric mucosal drug concentrations 1
• Poor compliance is a leading cause of failure; provide clear written instructions and counsel on expected side effects 2
• Diarrhea occurs in 21–41% of patients during the first week due to gut microbiota disruption; this does not indicate treatment failure 1

Shared Decision-Making After Multiple Failures

After multiple failed eradication attempts, weigh potential benefits against adverse effects and inconvenience, particularly in individuals not at identifiably higher risk of complications (e.g., no gastric cancer family history, no peptic ulcer disease). 3 This is especially important in the elderly, those with frailty, and those with antibiotic intolerance. 3