1. This study aims to compare the efficacy of empirical vonoprazan-based therapy versus susceptibility-guided vonoprazan-based therapy for third-line eradication of H. pylori.
2. We also plan to explore the impact of eradication therapy on gut microbiota, fecal antibiotic resistance, and metabolic parameters before and after treatment.

Methods:

• Study design: Open-labeled, randomized controlled trial
• Participants: A total of 220 patients who have failed at least two previous H. pylori eradication treatments will be enrolled.

Determination of antibiotic resistance of H. pylori: Agar dilution test will be used to determine the minimum inhibitory concentrations of levofloxacin, tetracycline, rifabutin, and clarithromycin to guide the selection of antibiotics.

Treatment regimens and assignment: Eligible patients will be randomized to receive either one of the treatments (A) Empirical vonoprazan-based therapy or (B) Susceptibility-guided vonoprazan-based therapy

Outcome Measurement:

Primary End Point: Eradication rate by intention-to-treat analysis. Secondary End Point: 1. Eradication rate by per-protocol analysis; 2. Frequency of adverse effects.

Inclusion Criteria:

1. Helicobacter pylori infected individuals who have failed at least two previous eradication therapies.
2. Willing to undergo third-line eradication therapy.
3. Subjects must be 20 years of age or older.

Exclusion Criteria:

1. History of gastrectomy.
2. Individuals unsuitable for the study medication, such as those with a history of allergy or severe adverse reactions to the study drugs, quinolone or fluoroquinolone antibiotics, or women who are pregnant or breastfeeding.
3. Presence of severe acute or chronic diseases such as renal failure, liver cirrhosis, incurable malignant tumors, or a history of aortic aneurysm or dissection.
4. Patients with chronic hepatitis (AST or ALT > 100 U/L).
5. Unwillingness to comply with the treatment plan or sign the informed consent form.