What is the recommended approach to diagnose and treat Helicobacter pylori infection, including first‑line therapy, alternatives for drug allergies, pregnancy, renal or hepatic impairment, and options for clarithromycin‑resistant strains?

H. pylori Infection: Diagnosis and Treatment

First-Line Treatment

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

The regimen consists of:

• High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred, as they increase cure rates by 8-12% compared to standard PPIs) 1
• Bismuth subsalicylate 262 mg (2 tablets) four times daily 1
• Metronidazole 500 mg three to four times daily 1
• Tetracycline 500 mg four times daily 1

Why 14 Days is Mandatory

Extending treatment from 7 to 14 days improves eradication success by approximately 5%, making shorter durations unacceptable. 1, 2

PPI Optimization

• Take PPI 30 minutes before meals on an empty stomach without concomitant antacids 1
• Standard once-daily PPI dosing is inadequate and significantly reduces efficacy 1
• Avoid pantoprazole (40 mg pantoprazole ≈ only 9 mg omeprazole equivalent) 1

Alternative First-Line When Bismuth Unavailable

Concomitant non-bismuth quadruple therapy for 14 days: PPI twice daily + amoxicillin 1000 mg twice daily + clarithromycin 500 mg twice daily + metronidazole 500 mg twice daily—but only in regions with clarithromycin resistance <15%. 1

Clarithromycin Triple Therapy: Severely Restricted

Standard triple therapy (PPI + clarithromycin + amoxicillin) should be abandoned when regional clarithromycin resistance exceeds 15-20%, which now includes most of North America and Central, Western, and Southern Europe. 1 When clarithromycin-resistant strains are present, eradication rates plummet from 90% to approximately 20%. 1

Second-Line Treatment After First-Line Failure

After Clarithromycin-Based Triple Therapy Fails

Bismuth quadruple therapy for 14 days (if not previously used) is the preferred second-line option, achieving 80-90% eradication even with dual resistance. 1

After Bismuth Quadruple Therapy Fails

Levofloxacin triple therapy for 14 days—but only if the patient has had no prior fluoroquinolone exposure for any indication (including respiratory infections). 1 The regimen consists of:

• High-dose PPI (esomeprazole or rabeprazole 40 mg) twice daily 1
• Amoxicillin 1000 mg twice daily 1
• Levofloxacin 500 mg once daily 1

Critical caveat: Levofloxacin resistance rates are rapidly increasing (11-30% primary, 19-30% secondary resistance globally), making empiric use increasingly problematic. 1

Third-Line and Rescue Therapies

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

Empiric Third-Line Options When Susceptibility Testing Unavailable

Rifabutin triple therapy for 14 days: 1

• Rifabutin 150 mg twice daily
• Amoxicillin 1000 mg twice daily
• High-dose PPI twice daily

High-dose dual therapy for 14 days (alternative rescue option): 1

• Amoxicillin 2-3 grams daily in 3-4 divided doses
• High-dose PPI twice daily

Special Populations

Penicillin Allergy

Bismuth quadruple therapy is the first-choice regimen because it contains tetracycline rather than amoxicillin. 1 However, consider penicillin allergy testing after first-line failure, as most reported allergies are not true allergies. 1

Pregnancy

H. pylori eradication should generally be deferred until after pregnancy due to lack of safety data for most regimens. 4 If treatment is absolutely necessary, amoxicillin-based regimens are preferred over tetracycline (contraindicated) and metronidazole (avoid in first trimester). 4

Renal Impairment

• Tetracycline is contraindicated in severe renal impairment 4
• Dose-adjust metronidazole and levofloxacin based on creatinine clearance 4
• PPIs and bismuth generally do not require adjustment 4

Hepatic Impairment

• Use caution with metronidazole and clarithromycin in severe hepatic dysfunction 4
• PPIs may require dose reduction in severe cirrhosis 4

Critical Antibiotic Resistance Principles

Never repeat antibiotics that failed previously, especially clarithromycin and levofloxacin, where resistance develops rapidly after exposure. 1 However:

• Metronidazole can be reused with bismuth due to synergistic effects that overcome resistance 1
• Amoxicillin and tetracycline can be reused because resistance remains rare (<5%) 1
• Bismuth has no described resistance 1

Confirmation of Eradication

Test for eradication success at least 4 weeks after completing therapy using urea breath test or validated monoclonal stool antigen test. 1, 3

Discontinue PPI at least 2 weeks before testing to avoid false-negative results. 1, 3

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

Patient Factors Affecting Success

• Smoking roughly doubles the odds of eradication failure (OR ≈ 1.95); advise cessation during therapy 1, 3
• High BMI/obesity may lower gastric mucosal drug concentrations, reducing efficacy 1, 3
• Poor compliance accounts for >10% of failures; provide clear written instructions and counsel on expected side effects 1

Managing Side Effects

Diarrhea occurs in 21-41% of patients during the first week due to gut microbiota disruption. 1 Consider adjunctive probiotics to reduce diarrhea risk and improve compliance, though evidence for increasing eradication rates is limited. 1, 5

Common Pitfalls to Avoid

• Never use standard-dose PPI once daily—this is a major cause of treatment failure 1
• Never shorten therapy below 14 days 1, 2
• Never assume low clarithromycin resistance without local surveillance data—most regions now have high resistance 1
• Never use levofloxacin as first-line therapy—this accelerates resistance and eliminates a valuable rescue option 1
• Never test for cure earlier than 4 weeks or while on PPIs—this yields false-negative results 1