What is the recommended first-line treatment for Helicobacter (H.) pylori infection?

First-Line Treatment for H. pylori Infection

Bismuth quadruple therapy for 14 days is the recommended first-line treatment for H. pylori infection, consisting of a high-dose PPI twice daily, bismuth subsalicylate (262 mg four times daily), metronidazole (500 mg three to four times daily), and tetracycline (500 mg four times daily). 1, 2, 3

Why Bismuth Quadruple Therapy is Preferred

The shift away from traditional triple therapy (PPI + clarithromycin + amoxicillin) is driven by alarming increases in antibiotic resistance:

• Clarithromycin resistance now exceeds 15-20% in most of North America and Europe, making traditional triple therapy achieve only 70% eradication rates—well below the 80% minimum acceptable threshold 1, 2
• When H. pylori strains are clarithromycin-resistant, eradication rates drop from 90% to approximately 20% 1
• Bismuth quadruple therapy achieves 80-90% eradication rates even against strains with dual resistance to clarithromycin and metronidazole 1, 3
• Bacterial resistance to bismuth is extremely rare, and tetracycline resistance remains low at 1-5% globally 1

Specific Dosing Regimen

The complete bismuth quadruple therapy regimen consists of 1, 3:

• PPI (esomeprazole or rabeprazole 40 mg preferred) twice daily, taken 30 minutes before meals
• Bismuth subsalicylate 262 mg (2 tablets) four times daily
• Metronidazole 500 mg three to four times daily (total 1.5-2 g daily)
• Tetracycline 500 mg four times daily
• Duration: 14 days mandatory (not 7-10 days)

Critical Optimization Factors

High-Dose PPI is Mandatory

• Use high-dose PPI twice daily (not once daily), as this increases cure rates by 6-12% compared to standard dosing 1, 2, 3
• Esomeprazole or rabeprazole 40 mg twice daily are preferred over other PPIs, as they increase cure rates by an additional 8-12% 1, 3
• PPIs must be taken 30 minutes before meals on an empty stomach, without concomitant antacids 1

Treatment Duration Cannot Be Shortened

• 14-day duration is superior to 7-10 day regimens, improving eradication success by approximately 5% 1, 2, 3
• This extended duration is particularly important given rising resistance patterns 2

Alternative First-Line Option (When Bismuth Unavailable)

If bismuth is not available, concomitant non-bismuth quadruple therapy is the alternative 1, 2:

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

This regimen should only be used when bismuth quadruple therapy cannot be administered, as it includes clarithromycin and is affected by resistance patterns 1, 2

When Triple Therapy May Be Considered

Triple therapy (PPI + clarithromycin + amoxicillin) should only be used in areas with documented clarithromycin resistance below 15%, and even then, bismuth quadruple therapy remains superior 1, 2:

• This scenario is increasingly rare, as most regions now exceed this threshold 1
• If used, must be 14 days duration with high-dose PPI twice daily 2
• Never assume low resistance without local surveillance data 1

Common Pitfalls to Avoid

• Never use standard once-daily PPI dosing—this significantly reduces treatment efficacy 1, 2
• Avoid repeating antibiotics from prior failed attempts, especially clarithromycin and levofloxacin, where resistance develops rapidly after exposure 1, 2, 3
• Do not use 7-10 day regimens—14 days is mandatory for optimal outcomes 1, 2, 3
• Never use serology to confirm eradication, as antibodies persist long after successful treatment 2

Confirmation of Eradication

• Use urea breath test or monoclonal stool antigen test at least 4 weeks after completion of therapy 2, 3
• Discontinue PPI at least 2 weeks before testing to avoid false-negative results 2, 3

Special Populations

• In patients with penicillin allergy, bismuth quadruple therapy is the first choice, as it contains tetracycline rather than amoxicillin 1, 2
• In pediatric patients, treatment should only be conducted by pediatric gastroenterologists in specialist centers, and fluoroquinolones and tetracyclines should be avoided 3

Patient Factors Affecting Success

• Smoking increases eradication failure risk (odds ratio 1.95) 3
• High BMI/obesity increases failure risk due to lower drug concentrations at the gastric mucosal level 3
• Poor compliance accounts for more than 10% of treatment failures 1