H. pylori Medical Management
First-Line Treatment Recommendation
Bismuth quadruple therapy for 14 days is the preferred first-line treatment for H. pylori infection in North America, achieving 80-90% eradication rates even in areas with high clarithromycin and metronidazole resistance. 1, 2
The regimen consists of:
- High-dose PPI twice daily (esomeprazole or rabeprazole 40 mg preferred, taken 30 minutes before meals) 1
- Bismuth subsalicylate 262 mg (2 tablets) four times daily 1
- Metronidazole 500 mg three to four times daily (total 1.5-2 g daily) 1
- Tetracycline 500 mg four times daily 1
This recommendation is based on the 2024 American College of Gastroenterology guideline, which represents the most recent and authoritative guidance for North American practice. 2
Why Bismuth Quadruple Therapy is Preferred
Resistance Profile Advantages
- No bacterial resistance to bismuth has been described 1
- Tetracycline resistance remains rare (<5%) 1
- Bismuth's synergistic effect overcomes metronidazole resistance even when in vitro resistance is present 1
- Not affected by clarithromycin resistance, which now exceeds 15-20% in most of North America and Europe 1, 2
Superior to Traditional Triple Therapy
Traditional PPI-clarithromycin-amoxicillin triple therapy should be abandoned in most clinical scenarios because clarithromycin resistance has increased globally from 9% in 1998 to over 20% in most regions, reducing eradication rates to only 70%—well below the 80% minimum target. 1 When H. pylori strains are clarithromycin-resistant, eradication rates drop from 90% to approximately 20%. 1
Alternative First-Line Options
When Bismuth is Unavailable
Concomitant non-bismuth quadruple therapy for 14 days is the recommended alternative: 1, 2
- PPI twice daily (esomeprazole or rabeprazole 40 mg preferred)
- Amoxicillin 1000 mg twice daily
- Clarithromycin 500 mg twice daily
- Metronidazole 500 mg twice daily
This regimen avoids the pitfall of sequential therapy by administering all antibiotics simultaneously, preventing resistance development during treatment. 1
For Patients Without Penicillin Allergy
Rifabutin triple therapy for 14 days is an acceptable alternative first-line option: 1, 2
- Rifabutin 150 mg twice daily
- Amoxicillin 1000 mg twice daily
- High-dose PPI twice daily
Rifabutin resistance remains rare, and amoxicillin resistance is extremely rare (<5%). 1
Critical Optimization Factors
Treatment Duration
14 days is mandatory—extending treatment from 7 to 14 days improves eradication success by approximately 5%. 1, 2 Never use shorter durations.
PPI Dosing
High-dose PPI twice daily is mandatory—standard once-daily dosing is inadequate. 1 Esomeprazole or rabeprazole 40 mg twice daily increases cure rates by 8-12% compared to other PPIs at standard doses. 1 The PPI should be taken 30 minutes before meals on an empty stomach, without concomitant use of other antacids. 1
Timing of Administration
Amoxicillin should be taken at the start of a meal to minimize gastrointestinal intolerance. 3
Second-Line Treatment After First-Line Failure
If Bismuth Quadruple Therapy Failed
Levofloxacin triple therapy for 14 days (if no prior fluoroquinolone exposure): 1, 2
- PPI twice daily (esomeprazole or rabeprazole 40 mg)
- Amoxicillin 1000 mg twice daily
- Levofloxacin 500 mg once daily (or 250 mg twice daily)
Critical caveat: Rising levofloxacin resistance rates (11-30% primary, 19-30% secondary) make this less reliable. 1 The FDA recommends fluoroquinolones be used as a last choice due to risk of serious side effects. 1
If Clarithromycin-Based Therapy Failed
Never repeat clarithromycin if it was in the failed regimen—resistance develops rapidly after exposure, and eradication rates drop from 90% to 20% with resistant strains. 1, 2 Use bismuth quadruple therapy for 14 days if not previously used. 1
Third-Line and Rescue Therapies
After Two Treatment Failures
Antibiotic susceptibility testing should guide further treatment whenever possible. 1, 2 This is the current standard recommendation after two failed eradication attempts.
Empiric Third-Line Options
If susceptibility testing is unavailable:
Rifabutin triple therapy for 14 days: 1, 2
- Rifabutin 150 mg twice daily
- Amoxicillin 1000 mg twice daily
- High-dose PPI twice daily
High-dose dual amoxicillin-PPI therapy for 14 days: 1, 2
- Amoxicillin 2-3 grams daily in 3-4 split doses
- High-dose PPI (double standard dose) twice daily
Special Populations
Patients with Penicillin Allergy
Bismuth quadruple therapy is the first choice because it contains tetracycline, not amoxicillin. 1 However, consider penicillin allergy testing to delist the allergy and enable amoxicillin use, as most patients who report penicillin allergy are found not to have a true allergy. 1
Pediatric Patients
Treatment should only be conducted by pediatricians in specialist centers. 1 First-line options include: 4
- PPI + amoxicillin + metronidazole for 14 days
- PPI + amoxicillin + clarithromycin for 14 days (with susceptibility testing)
- Bismuth + amoxicillin + metronidazole for 14 days
Fluoroquinolones cannot be used in children due to cartilage toxicity concerns, and tetracyclines are contraindicated due to effects on developing teeth and bones. 4
Confirmation of Eradication (Test of Cure)
Mandatory for All Patients
Test of cure is now standard of care for every patient. 5, 2
Recommended Testing Methods
- Urea breath test (sensitivity 94.7-97%, specificity 95-100%) 5
- Laboratory-based validated monoclonal stool antigen test (sensitivity and specificity >90%) 5
- Never use serology—antibodies persist long after successful treatment 1, 5
Timing of Testing
Test at least 4 weeks after completion of therapy to allow gastric mucosa recovery and avoid false-negative results. 5, 2 Discontinue PPIs at least 2 weeks before testing (preferably 7-14 days). 5
Special Scenarios Requiring Mandatory Confirmation
- Gastric ulcer patients: Require endoscopic follow-up to ensure complete healing 5
- Gastric MALT lymphoma patients: Require upper endoscopy with biopsy-based testing 5
- Complicated duodenal ulcer or bleeding ulcer patients: Continue PPI until eradication is confirmed 5
Common Pitfalls and How to Avoid Them
Never Repeat Failed Antibiotics
Avoid re-using clarithromycin and levofloxacin where resistance develops rapidly after exposure. 1, 2 Review all prior antibiotic exposures, including macrolides (azithromycin) for any indication, as cross-resistance is universal within the macrolide family. 1
Ensure Adequate Treatment Duration
Never use 7-10 day regimens—14 days is mandatory for all first-line and salvage therapies. 1, 2
Use High-Dose PPI Twice Daily
Standard once-daily PPI dosing is inadequate and significantly reduces treatment efficacy. 1 Always use twice-daily dosing, preferably with esomeprazole or rabeprazole 40 mg. 1
Address Compliance Issues
More than 10% of patients are poor compliers, leading to much lower eradication rates. 6 Explain the rationale, dosing, expected side effects, and importance of completing the full course before prescribing. 5
Patient Factors Affecting Success
- Smoking increases risk of eradication failure (odds ratio 1.95) 1
- High BMI increases risk of failure due to lower drug concentrations at the gastric mucosal level 1
- Diarrhea occurs in 21-41% of patients during the first week due to disruption of normal gut microbiota 1
Consider Adjunctive Probiotics
Probiotics can reduce antibiotic-associated diarrhea and improve patient compliance, though evidence for increasing eradication rates is limited. 1, 7 This should not replace optimization of the primary antibiotic regimen.
Antimicrobial Stewardship Considerations
Bismuth quadruple therapy 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 The American Gastroenterological Association explicitly recommends avoiding concomitant, sequential, or hybrid therapies as they include unnecessary antibiotics that contribute to global antibiotic resistance without therapeutic benefit. 1