How do I treat a confirmed Helicobacter pylori infection, including first-line therapy, alternatives for penicillin allergy or clarithromycin resistance, and follow-up testing?

Treatment of Confirmed Helicobacter pylori Infection

Bismuth quadruple therapy for 14 days is the definitive first-line treatment for confirmed H. pylori infection, achieving 80–90% eradication rates even in regions with high clarithromycin and metronidazole resistance. 1, 2

First-Line Treatment: Bismuth Quadruple Therapy

The recommended 14-day regimen consists of:

• Esomeprazole or rabeprazole 40 mg twice daily (preferred over other PPIs; increases cure rates by 8–12%) 3, 1, 2
• Bismuth subsalicylate 262 mg (two tablets) four times daily 1, 2
• Metronidazole 500 mg three to four times daily (total 1.5–2 g/day) 1, 2
• Tetracycline 500 mg four times daily 1, 2

Critical administration details:

• Take PPI 30 minutes before meals on an empty stomach, without concomitant antacids 1, 2
• Take bismuth 30 minutes before meals and at bedtime 2
• Take metronidazole 30 minutes after meals 2
• 14-day duration is mandatory—extending from 7 to 14 days improves eradication by approximately 5% 3, 1, 2

Why bismuth quadruple therapy is superior:

• Clarithromycin resistance now exceeds 15–20% across North America and Europe, reducing traditional triple-therapy cure rates to only ~70% 3, 1, 2
• Bismuth quadruple therapy is unaffected by clarithromycin resistance and achieves 80–90% eradication even with dual clarithromycin-metronidazole resistance 1, 2
• No bacterial resistance to bismuth has been described 1
• Uses WHO "Access" antibiotics (tetracycline, metronidazole) rather than "Watch" agents (clarithromycin, levofloxacin), supporting antimicrobial stewardship 2

Alternative First-Line Options (When Bismuth Unavailable)

Concomitant non-bismuth quadruple therapy for 14 days:

• Esomeprazole or rabeprazole 40 mg twice daily 1
• Amoxicillin 1000 mg twice daily 1
• Clarithromycin 500 mg twice daily 1
• Metronidazole 500 mg twice daily 1

This regimen should only be used when:

• Bismuth is genuinely unavailable 1
• Local clarithromycin resistance is documented <15% 1, 2
• Patient has no prior macrolide exposure 2

Penicillin Allergy Management

For confirmed penicillin allergy:

• Bismuth quadruple therapy is the preferred first choice because it contains tetracycline instead of amoxicillin 1, 2
• Consider penicillin allergy testing after first-line failure—most reported allergies are not true allergies, and amoxicillin resistance remains rare (<5%) 1, 2

If bismuth unavailable and confirmed penicillin allergy:

• PPI 40 mg twice daily + clarithromycin 500 mg twice daily + metronidazole 500 mg twice daily for 14 days 1
• Only use where clarithromycin resistance is documented <15% 1

Second-Line Treatment After First-Line Failure

After bismuth quadruple therapy fails:

• Levofloxacin triple therapy for 14 days (only if no prior fluoroquinolone exposure): 3, 1, 2
  • Esomeprazole or rabeprazole 40 mg twice daily 1
  • Amoxicillin 1000 mg twice daily 1
  • Levofloxacin 500 mg once daily 1

After clarithromycin-based triple therapy fails:

• Bismuth quadruple therapy for 14 days (if not previously used) 1, 2
• Alternative: Levofloxacin triple therapy (if no prior fluoroquinolone exposure) 1

Critical pitfall: Never repeat clarithromycin or levofloxacin if they were in the failed regimen—resistance develops rapidly after exposure, dropping eradication rates from ~90% to ~20% 1, 2

Third-Line and Rescue Therapies

After two documented treatment failures with confirmed patient adherence:

• Obtain antibiotic susceptibility testing (culture-based or molecular) to guide further therapy 3, 1, 2
• Culture is available from Mayo Clinic, ARUP, Labcorp, Quest Diagnostics, and Microbiology Specialists 3
• Molecular testing (next-generation sequencing) is available from American Molecular Laboratories for susceptibility to amoxicillin, clarithromycin, levofloxacin, tetracycline, metronidazole, and rifabutin 3

Empiric third-line options when susceptibility testing unavailable:

Rifabutin triple therapy for 14 days:

• Rifabutin 150 mg twice daily 1, 2
• Amoxicillin 1000 mg twice daily 1, 2
• Esomeprazole or rabeprazole 40 mg twice daily 1, 2
• Rifabutin resistance is rare 1

High-dose dual therapy for 14 days:

• Amoxicillin 2–3 g daily divided into 3–4 doses 1, 2
• Esomeprazole or rabeprazole 40 mg twice daily 1, 2
• Offers simpler dosing schedule for elderly or complex patients 2

Confirmation of Eradication (Test-of-Cure)

Mandatory testing for:

• All patients with gastric ulcer 1
• Complicated or bleeding peptic ulcers 1
• Gastric MALT lymphoma 1
• After treatment failure 3, 1

Testing protocol:

• Perform urea breath test or validated monoclonal stool antigen test 3, 1, 2
• Wait ≥4 weeks after completing therapy 3, 1, 2
• Discontinue PPI ≥2 weeks before testing (preferably 7–14 days) 3, 1, 2
• Never use serology for confirmation—antibodies persist long after successful eradication 3, 1, 2

Critical Optimization Factors

High-dose PPI twice daily is mandatory:

• Standard once-daily PPI dosing is a major cause of treatment failure 1, 2
• Esomeprazole or rabeprazole 40 mg twice daily increases cure rates by 8–12% compared to other PPIs 3, 1, 2
• Avoid pantoprazole—40 mg provides acid suppression equivalent to only ~9 mg omeprazole, yielding inferior outcomes 1, 2

Patient factors affecting success:

• Smoking roughly doubles the odds of eradication failure (OR ~1.95)—advise cessation during therapy 1
• Elevated BMI/obesity may lower gastric mucosal drug concentrations, potentially reducing efficacy 1
• Poor compliance is a leading cause of failure—provide clear written instructions and counsel on expected side effects 1

Expected side effects:

• Diarrhea occurs in 21–41% of patients during the first week due to disruption of gut microbiota 1
• Consider adjunctive probiotics to reduce diarrhea risk and improve compliance 1
• Flatulence and diarrhea from H. pylori gastritis typically resolve after successful eradication 2

Common Pitfalls to Avoid

• Do not use once-daily PPI dosing—it significantly reduces treatment efficacy 1, 2
• Do not shorten therapy below 14 days—this reduces eradication success by ~5% 3, 1, 2
• Do not repeat antibiotics that failed previously, especially clarithromycin and levofloxacin 1, 2
• Do not assume low clarithromycin resistance without local surveillance data—most regions now have high resistance rates 1
• Do not use levofloxacin empirically as first-line therapy—reserve it for second-line use to prevent resistance development 1, 2
• Do not test for cure earlier than 4 weeks or without stopping PPIs for ≥2 weeks—yields false-negative results 1, 2
• Do not use clarithromycin-based triple therapy in areas where clarithromycin resistance exceeds 15%—efficacy drops to unacceptable levels 3, 1, 2

Special Clinical Scenarios

Bleeding peptic ulcer:

• Start eradication therapy immediately when oral feeding resumes—delaying reduces compliance and increases loss to follow-up 1
• Eradication reduces rebleeding rate from ~26% to near-zero 1

NSAID or aspirin users with prior peptic ulcer:

• Eradicate H. pylori before starting chronic NSAID therapy—reduces new ulcer risk by ~50% 1
• After successful eradication, long-term incidence of peptic ulcer bleeding is low even without gastroprotective treatment 1

Gastric MALT lymphoma:

• H. pylori eradication is first-line treatment, achieving cure in 60–80% of early-stage cases 1
• When t(11,18) translocation is present, eradication is usually ineffective and adjunctive treatments are needed 1

Gastric ulcer:

• Continue PPI therapy after eradication until endoscopic confirmation of healing 1
• Endoscopic surveillance is required to exclude malignancy 1