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

H. pylori Treatment

Bismuth quadruple therapy for 14 days is the preferred first-line treatment for H. pylori infection, consisting of a high-dose PPI twice daily, bismuth subsalicylate, metronidazole, and tetracycline. 1, 2, 3

First-Line Treatment Regimen

The optimal bismuth quadruple therapy regimen includes:

• Esomeprazole or rabeprazole 40 mg twice daily (taken 30 minutes before meals on an empty stomach) 1, 3
• Bismuth subsalicylate 262 mg (2 tablets) four times daily 1, 3
• Metronidazole 500 mg three to four times daily (total 1.5-2 g daily) 1, 3
• Tetracycline 500 mg four times daily 1, 3
• Duration: 14 days mandatory 1, 2, 3

This regimen achieves 80-90% eradication rates even in areas with high clarithromycin and metronidazole resistance. 1, 3 No bacterial resistance to bismuth has been described, and tetracycline resistance remains rare at 1-5%. 1, 3

Why Bismuth Quadruple Therapy is Superior

• 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 target. 1, 2
• Bismuth's synergistic effect overcomes metronidazole resistance even when present in vitro, allowing effective treatment despite resistance patterns. 1, 3
• The regimen 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

Alternative First-Line Option (When Bismuth Unavailable)

Concomitant non-bismuth quadruple therapy for 14 days:

• PPI (esomeprazole or rabeprazole 40 mg) 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

This regimen administers all antibiotics simultaneously, preventing the development of resistance during treatment. 1 However, it should only be used when bismuth is truly unavailable, as it includes clarithromycin which contributes to global antibiotic resistance. 1

Critical Optimization Factors

High-dose PPI dosing is mandatory for treatment success:

• Esomeprazole or rabeprazole 40 mg twice daily increases cure rates by 8-12% compared to other PPIs and standard doses. 1, 2, 3
• Standard once-daily PPI dosing is inadequate and significantly reduces treatment efficacy. 1, 2
• PPIs must be taken 30 minutes before meals on an empty stomach, without concomitant antacids. 1, 3

Treatment duration of 14 days is superior to shorter regimens:

• Extending treatment from 7 to 14 days improves eradication success by approximately 5%. 1, 2, 3

Second-Line Treatment After First-Line Failure

After bismuth quadruple therapy failure, use levofloxacin triple therapy for 14 days (if no prior fluoroquinolone exposure):

• PPI (esomeprazole or rabeprazole 40 mg) twice daily 1, 2, 3
• Amoxicillin 1000 mg twice daily 1, 2, 3
• Levofloxacin 500 mg once daily or 250 mg twice daily 1, 2, 3

Critical caveat: Never use levofloxacin empirically as first-line therapy due to rapidly rising fluoroquinolone resistance rates (11-30% primary, 19-30% secondary). 1 The FDA recommends fluoroquinolones be used as a last choice due to risk of serious side effects. 1

Third-Line and Rescue Therapies

After two failed eradication attempts with confirmed patient compliance, antibiotic susceptibility testing should guide further treatment. 1, 2, 3

Rifabutin-based triple therapy for 14 days:

• Rifabutin 150 mg twice daily 1, 2
• Amoxicillin 1000 mg twice daily 1, 2
• PPI (esomeprazole or rabeprazole 40 mg) twice daily 1, 2

Rifabutin resistance is rare, making this an effective rescue option after multiple treatment failures. 1, 2

High-dose dual amoxicillin-PPI therapy for 14 days (alternative rescue option):

• Amoxicillin 2-3 grams daily in 3-4 split doses 1
• PPI (esomeprazole or rabeprazole 40 mg) twice daily 1

Verification of Eradication

Confirm eradication with urea breath test or monoclonal stool antigen test:

• Test at least 4 weeks after completion of therapy 1, 2, 3
• Discontinue PPI at least 2 weeks before testing to avoid false-negative results 1, 2, 3
• Never use serology to confirm eradication—antibodies may persist long after successful treatment 1, 2

Special Populations

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 amoxicillin resistance remains rare (<5%). 1

Pediatric patients:

• First-line options include PPI + amoxicillin + clarithromycin, PPI + amoxicillin + metronidazole, or bismuth + amoxicillin + metronidazole. 1
• Fluoroquinolones and tetracyclines cannot be used in children, limiting treatment options. 1, 2
• Treatment should only be conducted by pediatricians in specialist centers. 1

Common Pitfalls and How to Avoid Them

Never repeat antibiotics that failed previously:

• Avoid re-using clarithromycin and levofloxacin where resistance develops rapidly after exposure. 1, 2
• Metronidazole can be re-used with bismuth because bismuth's synergistic effect overcomes in vitro resistance. 1
• Amoxicillin and tetracycline can be re-used because resistance to these agents remains rare. 1

Patient factors affecting success:

• Smoking increases risk of eradication failure (odds ratio 1.95). 1, 3
• High BMI reduces drug concentrations at the gastric mucosal level. 1, 3
• Poor compliance accounts for more than 10% of treatment failures—proactive measures to improve adherence are essential. 3

Avoid concomitant, sequential, or hybrid therapies as first-line options:

• These regimens include unnecessary antibiotics that contribute to global antibiotic resistance without therapeutic benefit. 1

Adjunctive Therapies

Probiotics can reduce side effects but do not significantly increase eradication rates:

• Consider adjunctive probiotics to reduce antibiotic-associated diarrhea (occurs in 21-41% of patients during first week). 1, 2
• Evidence for increasing eradication rates is limited—probiotics should not be considered primary treatment. 1, 2

Special Clinical Scenarios

Bleeding peptic ulcer:

• Start H. pylori eradication treatment immediately when oral feeding is reintroduced to prevent reduced compliance or loss to follow-up. 3

Before starting NSAID therapy:

• H. pylori eradication is mandatory in patients with peptic ulcer history, as it prevents peptic ulcer bleeding. 3

Gastric MALT lymphoma:

• H. pylori eradication is first-line treatment, with cure rates of 60-80% in early-stage cases. 1