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

H. Pylori Treatment Regimen

Bismuth quadruple therapy for 14 days is the preferred first-line treatment for H. pylori infection in North America, consisting of a PPI twice daily, bismuth subsalicylate 262 mg or bismuth subcitrate 120 mg four times daily, metronidazole 500 mg three to four times daily, and tetracycline 500 mg four times daily. 1, 2, 3, 4

First-Line Treatment Selection

Bismuth quadruple therapy (BQT) is strongly recommended as first-line treatment because:

• Clarithromycin resistance now exceeds 15-20% in most regions of North America, making traditional triple therapy unacceptably ineffective with eradication rates dropping to approximately 20% versus 90% with susceptible strains 1, 3
• BQT achieves eradication rates of 80-90% even against metronidazole-resistant strains due to bismuth's synergistic effect with other antibiotics 1, 2
• Bacterial resistance to bismuth is extremely rare, and bismuth can overcome in vitro metronidazole resistance 2, 3
• The regimen 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 2

Alternative first-line options when bismuth is unavailable:

• Concomitant non-bismuth quadruple therapy: PPI twice daily + amoxicillin 1000 mg twice daily + clarithromycin 500 mg twice daily + metronidazole 500 mg twice daily for 14 days 2, 3, 5
• This regimen administers all antibiotics simultaneously, preventing the development of resistance during treatment 2

Triple therapy is only acceptable in areas with documented clarithromycin resistance <15%:

• PPI twice daily + clarithromycin 500 mg twice daily + amoxicillin 1000 mg twice daily for 14 days 1, 3
• This option should be abandoned when regional clarithromycin resistance exceeds 15-20% 1, 2

Critical Treatment Optimization Factors

High-dose PPI (twice daily) is mandatory:

• Standard once-daily PPI dosing is inadequate and significantly reduces treatment efficacy 1, 2, 3
• High-dose PPI increases eradication efficacy by 6-10% compared to standard doses by reducing gastric acidity and enhancing antibiotic activity 1, 3
• Esomeprazole or rabeprazole 40 mg twice daily may increase cure rates by 8-12% 2
• PPIs should be taken 30 minutes prior to eating or drinking on an empty stomach, without concomitant use of other antacids 6

Treatment duration of 14 days is superior:

• Extending treatment from 7 to 14 days improves eradication success by approximately 5% 1, 2, 3, 5
• All H. pylori eradication regimens should now be given for 14 days due to increasing treatment failure rates 5, 4

FDA-Approved Regimens for H. Pylori

Triple therapy with clarithromycin and lansoprazole:

• Amoxicillin 1 gram + clarithromycin 500 mg + lansoprazole 30 mg, all given twice daily (every 12 hours) for 14 days 7
• This regimen is indicated for H. pylori infection and duodenal ulcer disease to eradicate H. pylori and reduce the risk of duodenal ulcer recurrence 7

Dual therapy with lansoprazole (for clarithromycin-allergic or resistant patients):

• Amoxicillin 1 gram + lansoprazole 30 mg, given three times daily (every 8 hours) for 14 days 7
• This is indicated for patients who are allergic or intolerant to clarithromycin or in whom clarithromycin resistance is known or suspected 7

Second-Line Treatment After First-Line Failure

After failure of clarithromycin-containing therapy:

• Bismuth quadruple therapy for 14 days (if not previously used) 1, 3, 4
• Levofloxacin-based triple therapy: PPI twice daily + amoxicillin 1000 mg twice daily + levofloxacin 500 mg once daily or 250 mg twice daily for 14 days 6, 1, 3

Critical caveat: Do not use levofloxacin empirically as first-line therapy due to rapidly rising fluoroquinolone resistance rates (11-30% primary, 19-30% secondary) 2, 3

Never re-use antibiotics that failed previously:

• Avoid repeating clarithromycin or levofloxacin where resistance develops rapidly after exposure 2, 3, 4
• Bismuth, amoxicillin, and tetracycline can be re-used because resistance to these agents remains rare (1-5%) 2, 3

Third-Line and Rescue Therapies

After two failed eradication attempts:

• Antimicrobial susceptibility testing should guide further treatment whenever possible 6, 1, 3, 8, 4
• Molecular testing for clarithromycin and levofloxacin resistance is available and can guide therapy selection earlier in the treatment algorithm 6

Rifabutin-based triple therapy as rescue option:

• Rifabutin 150 mg twice daily + amoxicillin 1000 mg twice daily + PPI twice daily for 14 days 6, 2, 3
• Rifabutin resistance is extremely rare (<15%), making it highly effective as rescue therapy after multiple treatment failures 6, 2
• Rifabutin should be reserved for patients who have failed at least 2-3 prior eradication attempts 6, 2, 5

High-dose dual amoxicillin-PPI therapy:

• Amoxicillin 2-3 grams daily in 3-4 split doses + high-dose PPI twice daily for 14 days 6, 2
• This is an alternative rescue therapy when other options have been exhausted 6

Special Populations

Patients with penicillin allergy:

• Bismuth quadruple therapy is the first choice, as it contains tetracycline, not amoxicillin 2, 3
• Verify penicillin allergy with testing before excluding amoxicillin-based regimens, as amoxicillin resistance remains rare 2

Pediatric patients:

• First-line options include PPI + amoxicillin + clarithromycin, PPI + amoxicillin + metronidazole, or bismuth + amoxicillin + metronidazole 2
• Fluoroquinolones and tetracyclines should not be used in children 3
• Treatment should only be conducted by pediatricians in specialist centers 6

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 1, 2, 3
• Serology should not be used to confirm eradication as antibodies may persist long after successful treatment 1, 3

Common Pitfalls to Avoid

Inadequate acid suppression:

• Always use high-dose PPI (twice daily), never standard once-daily dosing 1, 2, 3
• Standard-dose PPI once daily is inadequate and significantly reduces treatment efficacy 2

Assuming low clarithromycin resistance without data:

• Never assume low clarithromycin resistance without local surveillance data—most regions now have high resistance rates 2
• Clarithromycin resistance has increased globally from 9% in 1998 to 17.6% in 2008-2009 1, 3

Repeating failed antibiotics:

• Avoid repeating clarithromycin if the patient has prior macrolide exposure for any indication, as cross-resistance is universal within the macrolide family 2
• Never re-use clarithromycin or levofloxacin after treatment failure 2, 3

Patient factors affecting success:

• Smoking increases risk of eradication failure with an odds ratio of 1.95 2
• High BMI, especially in obese patients, increases risk of failure due to lower drug concentrations at the gastric mucosal level 2
• Address compliance issues, as more than 10% of patients are poor compliers, leading to much lower eradication rates 6

Adjunctive Therapies

Probiotics:

• Consider adjunctive probiotics to reduce the risk of diarrhea (which occurs in 21-41% of patients during the first week) and improve patient compliance 2, 3
• Evidence for increased eradication rates with probiotics is limited, but they can help reduce antibiotic-associated side effects 1, 3, 8
• Proposed adjunctive therapies, including probiotics, are of unproven benefit for refractory H. pylori infection and should be considered experimental 6