What is the recommended diagnostic workup and treatment regimen for a patient suspected of having Helicobacter (H.) Pylori infection?

H. Pylori Diagnostic Workup and Treatment

Diagnostic Strategy Based on Clinical Presentation

For patients under 50-55 years without alarm symptoms (bleeding, weight loss, dysphagia, anemia, palpable mass), use non-invasive testing with laboratory-based monoclonal stool antigen test or urea breath test, both achieving 93% sensitivity and specificity. 1

• Patients over 50 years or any patient with alarm symptoms require immediate endoscopy with invasive H. pylori testing (histology, rapid urease test, or culture) 2, 1
• The "test and treat" strategy in young patients without alarm symptoms reduces unnecessary endoscopies by 62% while maintaining equivalent safety 1

Critical Pre-Testing Requirements

All medications that suppress bacterial load must be discontinued before testing to avoid false-negative results:

• Proton pump inhibitors: discontinue at least 2 weeks before testing 2
• Antibiotics and bismuth products: discontinue at least 2 weeks before testing 2
• Sucralfate: discontinue at least 4 weeks before testing 3
• H2-receptor antagonists do not affect bacterial load and can be substituted for PPIs during the waiting period 2

Important Testing Caveat

A positive test result can be trusted even if medications were not discontinued, as these agents cause false-negatives, not false-positives 2. However, if a false-negative is suspected, repeat testing after the appropriate medication-free interval 2.

Recommended Non-Invasive Tests

Laboratory-based monoclonal antibody stool antigen test (ELISA methodology) is the preferred non-invasive method for both initial diagnosis and post-treatment confirmation 1:

• Achieves 93% sensitivity and 93% specificity for initial diagnosis 1
• Post-treatment sensitivity 91.6% and specificity 98.4% 1
• Safe in children and pregnant women, unlike radioactive 13C-UBT 1

Urea breath test is equally accurate as stool antigen testing 1:

• Equivalent performance to monoclonal stool antigen test 1
• Must discontinue PPIs, antibiotics, bismuth, and sucralfate per timelines above 2, 3
• Can produce false-positives in achlorhydria (pernicious anemia, atrophic gastritis) due to non-H. pylori urease-producing organisms 2

Tests to Avoid

Never use serology for post-treatment confirmation, as antibodies remain elevated after successful eradication 1. Serology cannot distinguish active from past infection 2.

Invasive Testing (Endoscopy-Based)

When endoscopy is performed, obtain multiple biopsies for:

• Rapid urease test (CLO test): provides results within hours but requires cessation of PPIs, antibiotics, and bismuth 2
• Histology with immunohistochemical staining: most accurate when H. pylori is difficult to visualize, especially important when inflammation is present but organisms are scarce 2
• Culture with antimicrobial susceptibility testing: essential after treatment failures to guide salvage therapy 2, 4

First-Line Treatment Regimen

14-day bismuth quadruple therapy is the preferred first-line empiric treatment in North America where clarithromycin resistance exceeds 15% 3, 5, 4:

• Bismuth subsalicylate 2 tablets/capsules four times daily 30 minutes before meals 3
• Tetracycline HCl 500 mg four times daily 30 minutes after meals 3
• Metronidazole 500 mg four times daily 30 minutes after meals 3
• High-dose PPI (esomeprazole or rabeprazole 40 mg) twice daily 30 minutes before meals 3

Critical PPI Selection

Use esomeprazole 40 mg or rabeprazole 40 mg twice daily; avoid pantoprazole due to inferior potency 3:

• 20 mg esomeprazole = 32 mg omeprazole 3
• 20 mg rabeprazole = 36 mg omeprazole 3
• 40 mg pantoprazole = only 9 mg omeprazole (inadequate) 3

Alternative First-Line Option

Rifabutin triple therapy for 14 days (for patients without penicillin allergy who prefer fewer pills) 3:

• Rifabutin 150 mg twice daily 3
• Amoxicillin 1 gram three times daily 3
• Esomeprazole or rabeprazole 40 mg twice daily 3

Second-Line Treatment After First-Line Failure

If bismuth quadruple therapy was not used initially, optimized 14-day bismuth quadruple therapy is preferred 3, 5, 4.

Levofloxacin-containing triple therapy for 14 days is an alternative, but rising resistance rates must be considered 3, 5. Fluoroquinolones should be last-choice options due to serious side effects including tendon rupture and cartilage damage 3.

Third-Line and Salvage Treatment

After failure of second-line therapy, treatment must be guided by antimicrobial susceptibility testing whenever possible 2, 3, 4:

• Culture-based susceptibility testing available from Mayo Clinic, ARUP, Labcorp, Quest Diagnostics 2
• Molecular resistance testing using next-generation sequencing available from American Molecular Laboratories for clarithromycin, levofloxacin, metronidazole, amoxicillin, tetracycline, and rifabutin 2
• Reflex stool testing (automatic susceptibility testing if stool antigen positive) is cost-effective 2

Regimens to Avoid

Never use clarithromycin, metronidazole, or levofloxacin triple therapy empirically—only with confirmed susceptibility 3. These regimens expose patients to ineffective antibiotics that increase global antimicrobial resistance 3.

Mandatory Post-Treatment Confirmation

All patients require test-of-cure at least 4 weeks after completing eradication therapy 1, 3, 5:

• Use laboratory-based monoclonal stool antigen test or urea breath test 1, 5
• Discontinue PPIs for at least 2 weeks before testing 5
• Never use serology for confirmation 1
• Endoscopy-based testing necessary for complicated peptic ulcer, gastric ulcer, and MALT lymphoma 3

Special Populations Requiring Testing

Test first-degree relatives of patients with gastric cancer, as H. pylori eradication halts progression of atrophic gastritis and reduces gastric cancer risk 2, 1:

• First-generation immigrants from high-prevalence countries 1
• Patients with unexplained iron-deficiency anemia, idiopathic thrombocytopenic purpura, or vitamin B12 deficiency 1
• Family members of patients with peptic ulcer disease 1

Pediatric Considerations

H. pylori treatment in children must be conducted by pediatric specialists in specialized centers, not primary care 5:

• Weight-based dosing differs substantially from adult regimens 5
• Never use tetracycline in children under 8 years due to permanent tooth discoloration and impaired bone growth 5
• Avoid fluoroquinolones in children due to cartilage damage and tendon rupture risk 5

Common Pitfalls to Avoid

The most common cause of apparent treatment failure is false-positive testing due to inadequate medication discontinuation 2:

• When false-positive UBT is suspected (especially in achlorhydria), confirm with stool antigen test or endoscopy before retreatment 2
• Antibiotic resistance is the primary cause of true treatment failure—local surveillance of resistance patterns is mandatory 2, 3
• Patient compliance is crucial; ensure understanding of the full 14-day course 5
• Avoid using antibiotics to which the patient has been previously exposed 2