What is the recommended first‑line 14‑day regimen for Helicobacter pylori eradication, and what alternative regimens should be used for patients with bismuth intolerance, metronidazole allergy, penicillin allergy, or who are pregnant or lactating?

Recommended First-Line 14-Day Regimen for H. pylori Eradication

Bismuth quadruple therapy for 14 days is the recommended first-line treatment, consisting of a high-dose proton pump inhibitor (PPI) twice daily, bismuth subsalicylate 262 mg four times daily, metronidazole 500 mg three to four times daily, and tetracycline 500 mg four times daily. 1, 2

First-Line Regimen Details

Standard bismuth quadruple therapy achieves 80–90% eradication rates even in regions with high clarithromycin and metronidazole resistance, making it the preferred initial approach. 1, 2

Specific Dosing Protocol

• PPI component: Esomeprazole or rabeprazole 40 mg twice daily is strongly preferred over other PPIs, as it increases cure rates by 8–12% compared to standard-dose PPIs 1, 2, 3
• Bismuth: Bismuth subsalicylate 262 mg (two tablets) four times daily, taken 30 minutes before meals and at bedtime 1, 2
• Metronidazole: 500 mg three to four times daily (total 1.5–2 g daily), taken 30 minutes after meals 1, 2, 3
• Tetracycline: 500 mg four times daily 1, 2, 3
• Duration: 14 days is mandatory, improving eradication by approximately 5% compared to 7–10 day regimens 1, 2, 4

Critical Administration Details

• Take PPI 30 minutes before meals on an empty stomach, without concomitant antacids 1, 2
• Never use pantoprazole 40 mg, as it provides acid suppression equivalent to only 9 mg omeprazole and yields inferior outcomes 1
• Do not substitute doxycycline for tetracycline, as multiple studies demonstrate significantly inferior eradication rates 1, 3

Alternative First-Line Regimens for Specific Situations

When Bismuth is Unavailable

Concomitant non-bismuth quadruple therapy for 14 days may be used only when bismuth is unavailable and local clarithromycin resistance is documented below 15%. 1, 2

• Regimen: High-dose PPI twice daily + amoxicillin 1000 mg twice daily + clarithromycin 500 mg twice daily + metronidazole 500 mg twice daily 1, 4
• This regimen administers all antibiotics simultaneously, preventing resistance development during treatment 1

In Regions with Documented Low Clarithromycin Resistance (<15%)

Clarithromycin-based triple therapy may be considered only in areas with documented clarithromycin resistance below 15% and no prior macrolide exposure. 1, 2

• Regimen: Esomeprazole or rabeprazole 40 mg twice daily + clarithromycin 500 mg twice daily + amoxicillin 1000 mg twice daily for 14 days 1
• Never assume low clarithromycin resistance without local surveillance data, as most regions now exceed 15–20% resistance 1

Alternative Regimens for Special Populations

Bismuth Intolerance

If bismuth is not tolerated, concomitant non-bismuth quadruple therapy (PPI + amoxicillin + clarithromycin + metronidazole) for 14 days is the alternative, but only in regions with clarithromycin resistance <15%. 1, 2

• If clarithromycin resistance is ≥15% and bismuth cannot be used, consider levofloxacin triple therapy as first-line only if local levofloxacin resistance is documented <15% 1
• Levofloxacin regimen: Esomeprazole or rabeprazole 40 mg twice daily + amoxicillin 1000 mg twice daily + levofloxacin 500 mg once daily for 14 days 1

Metronidazole Allergy

For patients with metronidazole allergy, use PPI-based triple therapy with clarithromycin and amoxicillin for 14 days, but only in regions with clarithromycin resistance <15%. 1

• Regimen: Esomeprazole or rabeprazole 40 mg twice daily + clarithromycin 500 mg twice daily + amoxicillin 1000 mg twice daily 1
• If clarithromycin resistance is ≥15%, consider levofloxacin triple therapy (PPI + amoxicillin + levofloxacin) for 14 days 1

Penicillin Allergy

Bismuth quadruple therapy is the first-choice regimen for patients with penicillin allergy, as it contains tetracycline instead of amoxicillin. 1, 2

• Consider penicillin allergy testing to rule out true anaphylaxis, as most reported allergies are not true allergies and amoxicillin resistance remains rare (<5%) 1, 2
• If confirmed penicillin allergy and bismuth is unavailable, use PPI + clarithromycin + metronidazole for 14 days, but only where clarithromycin resistance is <15% 1, 2

Pregnancy and Lactation

Defer H. pylori eradication until after pregnancy and breastfeeding is complete. 2

• Tetracycline is contraindicated in pregnancy due to effects on fetal bone and tooth development 2
• Clarithromycin is FDA pregnancy category C 2
• If treatment is absolutely necessary during pregnancy, amoxicillin-based regimens may be considered, but this is not standard practice 2

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, 2

• Discontinue PPI at least 2 weeks before testing 1, 2
• Never use serology to confirm eradication, as antibodies persist long after successful treatment 1

Critical Pitfalls to Avoid

• Never use once-daily PPI dosing—this is a major cause of treatment failure 1, 2
• Never shorten therapy below 14 days—this reduces eradication success by approximately 5% 1, 2, 4
• Never use levofloxacin empirically as first-line therapy—reserve it for second-line treatment to prevent resistance development 1
• Never repeat clarithromycin if it was in a failed regimen—resistance develops rapidly after exposure, dropping eradication rates from 90% to 20% 1
• Avoid pantoprazole due to inferior acid-suppression potency 1