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

H. pylori Treatment

Bismuth quadruple therapy for 14 days is the recommended first-line treatment for H. pylori infection in most clinical settings, consisting of a PPI twice daily, bismuth subsalicylate (~300mg four times daily), metronidazole 500mg three times daily, and tetracycline 500mg four times daily. 1, 2, 3

First-Line Treatment Selection

The choice of first-line therapy depends critically on local clarithromycin resistance patterns, though bismuth quadruple therapy is increasingly preferred as the universal first-line option:

Bismuth Quadruple Therapy (Preferred)

• Bismuth quadruple therapy achieves 80-90% eradication rates even against metronidazole-resistant strains due to bismuth's synergistic effect with other antibiotics. 2, 3
• This regimen is particularly valuable because bacterial resistance to bismuth is extremely rare, making it effective even in areas with high antibiotic resistance. 1, 3
• The standard regimen consists of: bismuth ~300mg four times daily, metronidazole 500mg three to four times daily, tetracycline 500mg four times daily, and PPI twice daily for 14 days. 1
• Higher doses of metronidazole (1.5-2g daily in divided doses) improve eradication rates even with resistant strains when combined with bismuth. 2

Alternative: Concomitant Non-Bismuth Quadruple Therapy

• When bismuth is unavailable, concomitant therapy is the preferred alternative: PPI twice daily, clarithromycin 500mg twice daily, amoxicillin 1g twice daily, and metronidazole 500mg twice daily for 14 days. 1, 2, 3
• This regimen avoids the pitfall of sequential therapy by administering all antibiotics simultaneously, preventing resistance development during treatment. 2

Clarithromycin-Based Triple Therapy (Limited Use)

• Triple therapy (PPI twice daily, clarithromycin 500mg twice daily, amoxicillin 1g twice daily for 14 days) should ONLY be used in areas with documented clarithromycin resistance <15%. 2, 3
• Standard triple therapy must be abandoned when regional clarithromycin resistance exceeds 15-20%, as eradication rates drop from 90% with susceptible strains to approximately 20% with resistant strains. 2
• Clarithromycin resistance has increased globally from 9% in 1998 to 17.6% in 2008-2009, now exceeding 20% in most of North America and Central, Western, and Southern Europe. 2, 4

Critical Treatment Optimization Factors

PPI Dosing

• High-dose PPI (twice daily) is mandatory and increases eradication efficacy by 6-10% compared to standard once-daily dosing. 4, 3
• Standard doses are: pantoprazole 40mg, lansoprazole 30mg, omeprazole 20mg, esomeprazole 20mg, dexlansoprazole 30mg, rabeprazole 20mg. 1
• PPIs should be taken 30 minutes before eating or drinking on an empty stomach, without concomitant use of other antacids. 1, 5
• Esomeprazole or rabeprazole 40mg twice daily may increase cure rates by an additional 8-12%. 2

Treatment Duration

• 14-day treatment duration is superior to 7-10 day regimens, improving eradication success by approximately 5%. 2, 4, 3
• This longer duration is recommended to maximize the probability of success on the first attempt. 2

Patient Adherence Factors

• Smoking increases the risk of eradication failure with an odds ratio of 1.95 for smokers versus non-smokers. 2
• High BMI, especially in obese patients, increases failure risk due to lower drug concentrations at the gastric mucosal level. 2
• More than 10% of patients are poor compliers, leading to significantly lower eradication rates. 2

Second-Line Treatment After First-Line Failure

After failure of clarithromycin-containing therapy, either bismuth quadruple therapy (if not previously used) or levofloxacin-containing triple therapy is recommended. 4, 3

Levofloxacin-Based Triple Therapy

• Regimen: PPI twice daily, amoxicillin 1000mg twice daily, levofloxacin 500mg once daily (or 250mg twice daily) for 14 days. 1, 2
• Do not use levofloxacin empirically as first-line therapy due to rapidly rising fluoroquinolone resistance rates (11-30% primary, 19-30% secondary resistance). 2
• The FDA recommends fluoroquinolones be used as a last choice due to risk of serious side effects. 2

Critical Principle: Avoid Antibiotic Repetition

• Never repeat antibiotics to which the patient has been previously exposed, especially clarithromycin and levofloxacin, where resistance develops rapidly after exposure. 2, 3
• Amoxicillin, tetracycline, and bismuth can be re-used because resistance to these agents remains rare (1-5%). 2
• Metronidazole can be re-used with bismuth because bismuth's synergistic effect overcomes in vitro resistance. 2

Third-Line and Rescue Therapies

After Two Failed Attempts

• After two failed therapies with confirmed patient adherence, H. pylori susceptibility testing should be performed to guide subsequent regimens. 1, 3
• Molecular testing for clarithromycin and levofloxacin resistance is available and can guide therapy selection earlier in the treatment algorithm. 2

Rifabutin-Based Triple Therapy

• Rifabutin triple therapy (rifabutin 150mg twice daily or 150-300mg once daily, amoxicillin 1g twice daily, PPI twice daily for 10-14 days) is highly effective as rescue therapy after multiple treatment failures. 1, 2
• Rifabutin and amoxicillin resistance are extremely rare, making this regimen reasonable to prescribe without prior sensitivity testing. 1
• Rifabutin should be reserved for patients who have failed previous eradication attempts with other antibiotics, not used as first-line therapy. 2

High-Dose Dual Therapy

• High-dose dual therapy (amoxicillin 2-3g daily in 3-4 split doses, high-dose PPI twice daily for 14 days) is an alternative rescue option when other therapies have been exhausted. 1, 2

Special Populations

Penicillin Allergy

• In patients with true penicillin allergy, bismuth quadruple therapy is the first choice, as it contains tetracycline rather than amoxicillin. 2
• Consider penicillin allergy testing to enable amoxicillin use, as amoxicillin resistance remains rare and it is a valuable antibiotic for H. pylori treatment. 2
• In triple therapy regimens, metronidazole can substitute for amoxicillin in penicillin-allergic patients. 2

Pediatric Patients

• Treatment of H. pylori infection in pediatric patients should only be conducted by pediatricians in specialist centers. 2
• Fluoroquinolones and tetracyclines should not be used in children, limiting treatment options. 3
• For neonates and infants aged 3 months or younger, the upper dose is 30mg/kg/day amoxicillin divided every 12 hours. 5

Renal Impairment

• Patients with glomerular filtration rate <30 mL/min should NOT receive the 875mg amoxicillin dose. 5
• For GFR 10-30 mL/min: amoxicillin 500mg or 250mg every 12 hours depending on infection severity. 5
• For GFR <10 mL/min: amoxicillin 500mg or 250mg every 24 hours, with additional doses during and after hemodialysis. 5

Verification of Eradication

• Confirm eradication with urea breath test or monoclonal stool antigen test at least 4 weeks after completion of therapy and at least 2 weeks after PPI discontinuation. 4, 3
• Serology should NOT be used to confirm eradication as antibodies may persist long after successful treatment. 4, 3

Adjunctive Therapies

• Probiotics can be used as adjunctive treatment to reduce antibiotic-associated diarrhea (which occurs in 21-41% of patients during the first week) and improve patient compliance. 2, 3
• However, probiotics are of unproven benefit for improving eradication rates and should be considered experimental for that purpose. 1

Common Pitfalls to Avoid

• Never assume low clarithromycin resistance without local surveillance data—most regions now have high resistance rates. 2
• Avoid repeating clarithromycin if the patient has prior macrolide exposure for any indication, as cross-resistance is universal within the macrolide family. 2
• Do not use standard-dose PPI once daily—always use twice-daily dosing to maximize gastric pH elevation. 2
• Avoid concomitant use of other antacids (e.g., H2-receptor antagonists) with PPIs during treatment. 1
• In vulnerable populations such as the elderly, carefully weigh the benefits of H. pylori eradication against the inconvenience and risks of repeated antibiotic exposure. 1