Quadruple Therapy for Helicobacter pylori
Recommended Regimen
Bismuth quadruple therapy for 14 days is the preferred first-line treatment for H. pylori infection, consisting of a proton pump inhibitor (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
This regimen achieves 80-90% eradication rates even against metronidazole-resistant strains due to the synergistic effect of bismuth with other antibiotics. 1
Why Quadruple Therapy is Preferred
Antibiotic Resistance Considerations
Clarithromycin resistance now exceeds 15-20% in most regions of North America and Europe, making traditional triple therapy unacceptably ineffective with eradication rates dropping to approximately 20% versus 90% with susceptible strains. 1, 3
Bismuth quadruple therapy is not affected by clarithromycin resistance and metronidazole resistance in vitro does not significantly affect outcomes because bismuth's synergistic effect overcomes this resistance. 4, 1
No bacterial resistance to bismuth has been described, and tetracycline resistance remains rare in Europe and most regions. 4, 2
Specific Dosing Details
Standard Bismuth Quadruple Therapy Components
PPI (high-dose): Esomeprazole 40 mg or rabeprazole 20 mg twice daily, taken 30 minutes before meals on an empty stomach 1, 2
Bismuth: Bismuth subcitrate 120-140 mg three to four times daily OR bismuth subsalicylate 262 mg four times daily 1, 2
Metronidazole: 500 mg three to four times daily (total daily dose 1.5-2 g) 1, 2
Tetracycline: Tetracycline hydrochloride 500 mg four times daily 1, 2
Critical Optimization Factors
Treatment duration of 14 days is mandatory rather than 7-10 days, as this improves eradication success by approximately 5%. 1, 3
High-dose PPI twice daily is essential—standard once-daily dosing is inadequate and reduces efficacy by 6-10%. 1, 3
Higher doses of metronidazole (1.5-2 g daily) improve eradication rates even with resistant strains when combined with bismuth. 1
Alternative When Bismuth is Unavailable
If bismuth is not available, concomitant non-bismuth quadruple therapy is the recommended alternative: PPI twice daily + amoxicillin 1000 mg twice daily + clarithromycin 500 mg twice daily + metronidazole 500 mg twice daily for 14 days. 1, 3
This regimen avoids the pitfall of sequential therapy by administering all antibiotics simultaneously, preventing the development of resistance during treatment. 1
Second-Line Treatment After Quadruple Therapy Failure
Levofloxacin-containing triple therapy (PPI twice daily + amoxicillin 1000 mg twice daily + levofloxacin 500 mg once daily or 250 mg twice daily) for 14 days is recommended as second-line treatment. 4, 1, 3
Rising levofloxacin resistance rates (11-30% primary, 19-30% secondary) should be taken into account—do not use levofloxacin empirically as first-line therapy. 1
After two failed eradication attempts, antibiotic susceptibility testing should guide further treatment whenever possible. 4, 1, 3
Special Populations
Patients with Penicillin Allergy
Bismuth quadruple therapy is the first choice in patients with penicillin allergy, as it contains tetracycline, not amoxicillin. 4, 1
Alternatively, PPI-clarithromycin-metronidazole combination may be prescribed in areas of low clarithromycin resistance. 4
Important Contraindications
Never substitute doxycycline for tetracycline—multiple studies demonstrate significantly inferior results. 2
Avoid repeating antibiotics previously used, especially clarithromycin and levofloxacin, where resistance develops rapidly after exposure. 1
Common Pitfalls and Caveats
Compliance and Side Effects
Bismuth quadruple therapy is considered one of the least tolerable regimens due to side effects, though compliance rates remain satisfactory. 4, 2
Diarrhea occurs in 21-41% of patients during the first week due to disruption of normal gut microbiota—consider adjunctive probiotics to reduce this risk. 1, 5
Patient Factors Affecting Success
Smoking increases risk of eradication failure with an odds ratio of 1.95 for smokers versus non-smokers. 1
High BMI, especially in obese patients, increases risk of failure due to lower drug concentrations at the gastric mucosal level. 1
Poor compliance (>10% of patients) leads to much lower eradication rates—emphasize the importance of completing the full 14-day course. 1