What is the recommended quadruple therapy regimen for a patient with Helicobacter pylori (H. pylori) infection, including dosage and duration?

Quadruple Therapy for H. pylori Infection

Recommended First-Line Regimen

Bismuth quadruple therapy for 14 days is the preferred first-line treatment for H. pylori infection, achieving 80-90% eradication rates even in areas with high antibiotic resistance. 1, 2

The regimen consists of:

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred, taken 30 minutes before meals on an empty stomach) 1, 2
• Bismuth subsalicylate 262 mg (2 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) 1, 2
• Tetracycline 500 mg four times daily 1, 2

Why This Regimen Works

Bismuth quadruple therapy overcomes the major challenge of antibiotic resistance that has rendered traditional triple therapy ineffective in most regions. 1 Clarithromycin resistance now exceeds 15-20% in most of North America and Europe, making standard triple therapy achieve only 70% eradication rates—well below the 80% minimum target. 1

Key advantages include:

• No bacterial resistance to bismuth has ever been described 1, 2
• Tetracycline resistance remains rare (<5%) 1, 2
• Bismuth's synergistic effect overcomes metronidazole resistance, making the regimen effective even against strains with dual resistance to clarithromycin and metronidazole 1, 2
• 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 1

Critical Optimization Factors

The 14-day duration is mandatory—not optional—as it improves eradication by approximately 5% compared to 7-10 day regimens. 1, 2 Recent U.S. data from Kaiser Permanente Northern California (26,669 initial treatments) confirms that 14-day bismuth quadruple therapy (PBMT-14) achieved 88.3% eradication rates without substantial decline in effectiveness over time. 3

High-dose PPI twice daily is non-negotiable. 1, 2 Esomeprazole or rabeprazole 40 mg twice daily increases cure rates by 8-12% compared to standard PPIs or standard dosing. 1, 2 Standard once-daily dosing is inadequate and significantly reduces treatment efficacy. 1

Alternative When Bismuth is Unavailable

Concomitant non-bismuth quadruple therapy is the recommended alternative when bismuth is not available, consisting of: 1, 2

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

This regimen achieved 89.8% eradication rates in the Kaiser Permanente study (PACM-14), the highest among all regimens tested. 3 However, it should only be used in areas with clarithromycin resistance <15%. 1, 2

Special Populations

For patients with penicillin allergy, bismuth quadruple therapy is the first choice, as it contains tetracycline, not amoxicillin. 1, 2 Consider penicillin allergy testing to delist the allergy and enable amoxicillin use, as most patients who report penicillin allergy are found not to have a true allergy. 1

After Treatment Failure

Never repeat antibiotics that failed previously, especially clarithromycin and levofloxacin, where resistance develops rapidly after exposure. 1, 2 The Kaiser Permanente study confirmed that repeat use of previously prescribed regimens was associated with significantly lower eradication rates (adjusted OR 0.51 for PBMT-14). 3

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

Second-line options after bismuth quadruple therapy failure include:

• Levofloxacin triple therapy (if no prior fluoroquinolone exposure): PPI twice daily + amoxicillin 1000 mg twice daily + levofloxacin 500 mg once daily for 14 days 1, 2
• Rifabutin triple therapy: rifabutin 150 mg twice daily + amoxicillin 1000 mg twice daily + PPI twice daily for 14 days 1, 4

Confirmation of Eradication

Test of cure is mandatory for all patients. 2, 5 Use urea breath test (sensitivity 94.7-97%, specificity 95-100%) or validated monoclonal stool antigen test (sensitivity and specificity >90%). 5

Testing must be performed at least 4 weeks after completion of therapy, with PPIs discontinued at least 2 weeks before testing. 2, 5 Testing before 4 weeks will yield false-negative results due to temporary bacterial suppression rather than true eradication. 5

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

Patient Factors Affecting Success

Smoking increases the risk of eradication failure (odds ratio 1.95 for smokers versus non-smokers). 1, 2

High BMI increases risk of failure due to lower drug concentrations at the gastric mucosal level. 1, 2

Poor compliance accounts for >10% of treatment failures. 1, 2 Address adherence barriers before prescribing, including explaining the rationale, dosing, expected side effects, and importance of completing the full course. 5

Prior macrolide or metronidazole use significantly reduces eradication rates. 3 The Kaiser Permanente study showed that prior macrolide use reduced PACM-14 effectiveness (adjusted OR 0.68), and prior metronidazole use reduced PBMT-14 effectiveness (adjusted OR 0.61). 3 Review antibiotic history thoroughly before selecting a regimen. 3

Common Pitfalls to Avoid

• Do not use standard-dose PPI once daily—always use high-dose twice-daily dosing 1, 2
• Do not shorten treatment duration to 7-10 days—14 days is mandatory 1, 2
• Do not take PPI with food or other antacids—must be taken 30 minutes before meals on an empty stomach 1, 2
• Do not assume low clarithromycin resistance without local surveillance data—most regions now have high resistance rates 1
• Do not test for eradication before 4 weeks—will yield unreliable results 5
• Do not continue PPI within 2 weeks of testing—will cause false-negative results 5