Treatment Protocol for Helicobacter pylori Infection
First-Line Treatment: Bismuth Quadruple Therapy
Bismuth quadruple therapy for 14 days is the definitive first-line treatment for H. pylori infection, achieving 80–90% eradication rates regardless of local clarithromycin resistance patterns. 1, 2
Standard Regimen Components
- High-dose proton pump inhibitor (PPI) twice daily – esomeprazole or rabeprazole 40 mg twice daily is strongly preferred, as it increases cure rates by 8–12% compared to standard-dose PPIs 1, 2, 3
- Bismuth subsalicylate 262 mg (two tablets) four times daily or bismuth subcitrate 120 mg four times daily 1, 2
- Metronidazole 500 mg three to four times daily (total 1.5–2 g daily in divided doses) 1, 2, 3
- Tetracycline 500 mg four times daily 1, 2
- Duration: 14 days is mandatory – extending from 7 to 14 days improves eradication by approximately 5% 1, 2, 3
Administration Details
- Take PPI 30 minutes before meals on an empty stomach, without concomitant antacids 1, 3
- Take bismuth 30 minutes before meals and at bedtime 2
- Take metronidazole with food in divided doses and avoid alcohol due to disulfiram-like reactions 3
Why Bismuth Quadruple Therapy First-Line
- Clarithromycin resistance now exceeds 15–20% in most of North America and Europe, making traditional triple therapy achieve only ~70% eradication (dropping to ~20% with resistant strains) 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
- Bismuth's synergistic effect overcomes metronidazole resistance in vitro, preserving efficacy even against resistant strains 1, 2
Alternative First-Line Regimens (Restricted Use)
Concomitant Non-Bismuth Quadruple Therapy
Use only when bismuth is unavailable AND local clarithromycin resistance is documented <15%: 1, 2
- High-dose PPI (esomeprazole or rabeprazole 40 mg) twice daily 1
- Amoxicillin 1000 mg twice daily 1
- Clarithromycin 500 mg twice daily 1
- Metronidazole 500 mg twice daily 1
- Duration: 14 days 1
Clarithromycin-Based Triple Therapy
Use only in regions with documented clarithromycin resistance <15% AND no prior macrolide exposure: 1, 2, 3
- High-dose PPI (esomeprazole or rabeprazole 40 mg) twice daily 1, 3
- Clarithromycin 500 mg twice daily (500 mg is superior to 250 mg) 1, 4
- Amoxicillin 1000 mg twice daily 1, 3
- Duration: 14 days 1, 3
Critical caveat: Standard triple therapy should be abandoned when regional clarithromycin resistance exceeds 15–20%, as this threshold has been surpassed in most clinical settings 1, 2
Special Populations
Penicillin (Amoxicillin) Allergy
- Bismuth quadruple therapy is the first choice, as it contains tetracycline rather than amoxicillin 1, 2, 3
- Consider penicillin allergy testing after first-line failure, as true anaphylaxis is rare and most reported allergies are not genuine; amoxicillin resistance remains extremely rare (<5%) 2, 3
- If confirmed penicillin allergy and bismuth unavailable: Use PPI + clarithromycin 500 mg + metronidazole 500 mg twice daily for 14 days, only where clarithromycin resistance <15% 2, 5
Tetracycline Intolerance
- Preferred: Rifabutin-based triple therapy (rifabutin 150 mg twice daily + amoxicillin 1000 mg twice daily + high-dose PPI twice daily) for 14 days; rifabutin resistance is rare 2
- Alternative: Concomitant non-bismuth quadruple therapy (as above) only if clarithromycin resistance <15% 2
Second-Line Treatment After First-Line Failure
After Bismuth Quadruple Therapy Failure
Levofloxacin-based triple therapy for 14 days is the recommended second-line option, provided the patient has no prior fluoroquinolone exposure: 1, 2, 3
- High-dose PPI (esomeprazole or rabeprazole 40 mg) twice daily 1
- Amoxicillin 1000 mg twice daily 1
- Levofloxacin 500 mg once daily (or 250 mg twice daily) 1
- Duration: 14 days 1
Critical caveat: Levofloxacin resistance rates are 11–30% (primary) and 19–30% (secondary); do not use levofloxacin empirically as first-line therapy 1, 2, 3
After Clarithromycin-Based Triple Therapy Failure
- Bismuth quadruple therapy for 14 days (as detailed above) 1, 2
- Never repeat clarithromycin if it was in the failed regimen, as resistance develops rapidly and eradication rates drop from 90% to 20% with resistant strains 1, 2
Third-Line and Rescue Therapies
After two documented eradication failures with confirmed patient adherence, perform antibiotic susceptibility testing to guide further treatment whenever possible. 1, 2, 3
Rescue Options
- Rifabutin triple therapy: Rifabutin 150 mg twice daily + amoxicillin 1000 mg twice daily + high-dose PPI twice daily for 14 days 1, 2
- High-dose dual therapy: Amoxicillin 2–3 g daily in 3–4 divided doses + high-dose PPI (double standard dose) twice daily for 14 days 1, 2
Molecular testing for clarithromycin and levofloxacin resistance is available and can guide therapy selection earlier in the treatment algorithm 1, 3
Confirmation of Eradication
Test for eradication success at least 4 weeks after completion of therapy using urea breath test or validated monoclonal stool antigen test. 1, 2, 3
- Discontinue PPI at least 2 weeks before testing (preferably 7–14 days) to avoid false-negative results 1, 2
- Never use serology to confirm eradication, as antibodies persist long after successful treatment 1, 2
When Confirmation Is Mandatory
- Gastric ulcers 1
- Complicated or bleeding peptic ulcers 1
- Low-grade gastric MALT lymphoma 1
- After any treatment failure 1
Critical Optimization Factors
PPI Dosing
- High-dose PPI twice daily is mandatory; once-daily dosing is a major cause of treatment failure 1, 2, 3
- Esomeprazole or rabeprazole 40 mg twice daily is strongly preferred over other PPIs, increasing cure rates by 8–12% 1, 2, 3
- Avoid pantoprazole 40 mg, as its acid-suppression potency is equivalent to only ~9 mg omeprazole and yields inferior outcomes 1, 2
- Standard twice-daily doses for other PPIs: esomeprazole 20 mg, lansoprazole 30 mg, omeprazole 20 mg, rabeprazole 20 mg 1
Treatment Duration
- 14-day duration is mandatory for all regimens; shortening therapy reduces eradication by approximately 5% 1, 2, 3
- Toronto Consensus, Maastricht V/Florence, and American College of Gastroenterology all endorse 14 days as the standard of care 1, 2
Antibiotic Considerations
- Never repeat antibiotics that failed previously, especially clarithromycin and levofloxacin, where resistance develops rapidly after exposure 1, 2
- Metronidazole can be reused with bismuth due to synergistic effects 1, 2
- Amoxicillin and tetracycline can be reused because resistance remains rare 1, 2
- Avoid prior macrolide exposure (azithromycin, clarithromycin) as it predicts clarithromycin resistance; prior fluoroquinolone exposure predicts levofloxacin resistance 1
Common Pitfalls to Avoid
- Do not assume low clarithromycin resistance without local surveillance data; most regions now have high resistance rates 1, 2
- Never use once-daily PPI dosing for eradication; it significantly reduces treatment efficacy 1, 2, 3
- Do not shorten therapy below 14 days 1, 2, 3
- Avoid concomitant use of other antacids (H2-receptor antagonists) with PPIs during treatment, as this may interfere with PPI absorption 3
- Do not use levofloxacin empirically as first-line therapy, as this accelerates resistance development and eliminates a valuable rescue option 1, 2, 3
- Never use serology for test-of-cure, as antibodies persist after successful eradication 1, 2
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, potentially reducing efficacy 1
- Poor compliance is a leading cause of failure; provide clear written instructions and counsel on expected side effects 1
- Diarrhea occurs in 21–41% of patients during the first week due to gut microbiota disruption; consider adjunctive probiotics to reduce risk and improve compliance 1