What is the recommended quadruple therapy regimen for the treatment of Helicobacter pylori (H. pylori)?

Quadruple Therapy for H. pylori

Bismuth quadruple therapy for 14 days is the preferred first-line treatment for H. pylori infection, consisting of a PPI twice daily, bismuth subsalicylate (262 mg) or bismuth subcitrate (120 mg) four times daily, metronidazole 500 mg three to four times daily, and tetracycline 500 mg four times daily. 1, 2

First-Line Quadruple Therapy Regimens

Bismuth Quadruple Therapy (Preferred)

• PPI: Standard dose twice daily, taken 30 minutes before meals on an empty stomach 2
• Bismuth: Subsalicylate 262 mg or subcitrate 120 mg four times daily 2
• Metronidazole: 500 mg three to four times daily (total daily dose 1.5-2 g) 2
• Tetracycline: 500 mg four times daily 1, 2
• Duration: 14 days mandatory 1, 2

This regimen achieves 80-90% eradication rates even in areas with high dual resistance to clarithromycin and metronidazole because bismuth's synergistic effect overcomes in vitro metronidazole resistance, and no bacterial resistance to bismuth has been described. 1, 2

Concomitant Non-Bismuth Quadruple Therapy (Alternative When Bismuth Unavailable)

• PPI: 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
• Duration: 14 days (10-14 days acceptable if 10 days proven locally effective) 1

This regimen is appropriate in areas of high clarithromycin resistance where bismuth is not available, as administering all antibiotics simultaneously prevents resistance development during treatment. 2

Critical Optimization Factors

PPI Selection and Dosing

• High-dose PPI twice daily is mandatory—standard once-daily dosing is inadequate and significantly reduces efficacy by 6-10%. 2, 3
• Esomeprazole or rabeprazole 40 mg twice daily may increase cure rates by 8-12% compared to other PPIs. 2
• Take 30 minutes before meals on an empty stomach without concomitant antacids. 2

Treatment Duration

• 14 days is superior to 7-10 day regimens, improving eradication success by approximately 5%. 1, 2, 3
• All three major consensus groups (Toronto, Maastricht V/Florence, ACG) agree that 14 days maximizes first-attempt success. 1

Rationale for Bismuth Quadruple Therapy as First-Line

Antibiotic Stewardship Advantage

• Uses antibiotics from the WHO "Access group" (tetracycline and metronidazole) rather than the "Watch group" (clarithromycin, levofloxacin), making it preferable from an antimicrobial stewardship perspective. 2
• Avoids clarithromycin, which now has resistance rates exceeding 15-20% in most of North America and Central, Western, and Southern Europe. 2, 3

Resistance Profile

• Bismuth: No described resistance 2
• Tetracycline: Resistance remains rare (1-5%) 2
• Metronidazole: Can be used despite in vitro resistance (23-56% primary resistance) because bismuth overcomes this resistance in vivo 2
• Amoxicillin: Resistance remains rare (1-5%) 2

When Clarithromycin Resistance Matters

• When H. pylori strains are clarithromycin-resistant, eradication rates with triple therapy drop from 90% to approximately 20%. 2
• Standard triple therapy should be abandoned when regional clarithromycin resistance exceeds 15-20%. 2, 3

Special Populations

Penicillin Allergy

• Bismuth quadruple therapy is the first choice, as it contains tetracycline, not amoxicillin. 2

Pediatric Patients

• Treatment should only be conducted by pediatricians in specialist centers. 2
• First-line options include PPI + amoxicillin + clarithromycin, PPI + amoxicillin + metronidazole, or bismuth + amoxicillin + metronidazole. 2

Second-Line Treatment After First-Line Failure

If Bismuth Quadruple Therapy Fails

• Levofloxacin triple therapy for 14 days (if no prior fluoroquinolone exposure): PPI twice daily + amoxicillin 1000 mg twice daily + levofloxacin 500 mg once daily or 250 mg twice daily 1, 2, 3
• Rising levofloxacin resistance rates (11-30% primary, 19-30% secondary) limit its use—do not use empirically as first-line. 2

If Clarithromycin-Based Therapy Fails

• Bismuth quadruple therapy for 14 days (if not previously used) 2, 3

Critical Principle

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

Third-Line and Rescue Therapies

After Two Failed Attempts

• Antibiotic susceptibility testing should guide further treatment whenever possible. 2, 3, 4
• Address compliance issues, as more than 10% of patients are poor compliers. 2

Rescue Options

• Rifabutin triple therapy for 14 days: Rifabutin 150 mg twice daily + amoxicillin 1000 mg twice daily + PPI twice daily 1, 2
• High-dose dual amoxicillin-PPI therapy for 14 days: Amoxicillin 2-3 grams daily in 3-4 split doses + high-dose PPI twice daily 1, 2

Verification of Eradication

• Confirm eradication with urea breath test or monoclonal stool antigen test at least 4 weeks after completion of therapy and at least 2 weeks after PPI discontinuation. 2, 3
• Never use serology to confirm eradication—antibodies may persist long after successful treatment. 2, 3

Common Pitfalls and How to Avoid Them

Inadequate PPI Dosing

• Standard once-daily PPI dosing is the most common error—always use twice-daily dosing. 2, 3

Insufficient Treatment Duration

• Stopping at 7-10 days instead of 14 days reduces success by approximately 5%. 1, 2, 3

Repeating Failed Antibiotics

• Clarithromycin and levofloxacin develop resistance rapidly—never reuse after failure. 2
• Metronidazole, amoxicillin, and tetracycline can be reused because resistance remains rare or is overcome by bismuth. 2

Assuming Low Clarithromycin Resistance

• Never assume low clarithromycin resistance without local surveillance data—most regions now have high resistance rates. 2

Prior Macrolide Exposure

• Avoid clarithromycin if the patient has prior macrolide exposure for any indication, as cross-resistance is universal within the macrolide family. 2

Patient Factors Affecting Success

• Smoking: Increases risk of eradication failure (odds ratio 1.95) 2
• High BMI: Leads to lower drug concentrations at the gastric mucosal level, increasing failure risk 2
• Poor compliance: Accounts for more than 10% of failures 2

Adjunctive Therapies

• Probiotics can be used to reduce antibiotic-associated diarrhea (occurs in 21-41% of patients during the first week) and improve compliance, though evidence for increasing eradication rates is limited. 2, 3, 4
• Focus on optimizing the primary antibiotic regimen rather than relying on adjunctive therapies. 2