Objectives: Eradication of H. pylori infection could reduce the occurence or recurrence of gastric cancer and peptic ulcer diseases. However, it was estimated that 15-20% of patients would fail from first line standard eradication therapy and need second line rescue therapy. About 15-30% of patient would fail from second line therapy. Bismuth quadruple therapy and triple therapy containing levofloxacin are currently the recommended rescue therapies in the second line and third line treatment. Recently, our pilot study showed that modified sequential therapy containing levofloxacin achieved high eradication rate (95%) in the second line therapy. The regimen includes a PPI plus amoxicillin for 5-7 days, followed by a PPI plus levofloxacin and metronidazole for another 5-7 days. However, whether this modified sequential therapy containing levofloxacin is more effective than bismuth quadruple therapy in the second line and third line treatment remains unknown. Besides, the impact of these regimens on the antibiotic resistance , microbiota of gut flora, and metabolic factors remains unknown.

Aims: Therefore, the investigators aimed to

1. compare the eradication rates and long term re-infection rates of sequential therapy containing levofloxacin for 14 days versus bismuth quadruple therapy for 10 days in the second line and third line treatment
2. assess the impact of antibiotic resistance and CYP2C19 polymorphism on the eradication rate of these regimens
3. assess the impact of these eradication regimens on the antibiotic resistance and microbiota of the gut flora
4. assess the impact of eradication therapy on the metabolic factors

Methods:

This will be a multi-center, open labeled, randomized comparative trial with cross-over design Patients: Participants with refractory H. pylori infection after one eradication therapy

Testing for H. pylori infection Before Second Line Treatment : Any two positive of CLO test, histology, and culture or a positive UBT will be considered as H. pylori infected

After Second Line Treatment: C13-UBT will be used to assess the existence of H. pylori 6-8 weeks after first line therapy.

Long term reinfection: C13-UBT will be used to assess the recurrence of H. pylori 1 year after eradication therapy

Interventions:

Second line therapy: eligible patients will be randomized into one of the two groups Group (A): sequential therapy containing levofloxacin for 14 days (EAML) D1-D7: (esomeprazole 40mg bid + amoxicillin 1gm bid) for 7 days D8-D14: (esomeprazole 40mg bid + levofloxacin 250mg bid + metronidazole 500mg bid) for another 7 days

Group (B): bismuth quadruple therapy for 10 days (BQ) D1-D10: (esomeprazole 40mg bid + Dibismuth trioxide 120mg qid + metronidazole 500mg tid + tetracycline 500mg qid) for 10 days

Third line therapy: patients who fail from second line treatment will be rescue with the following treatment Group (A) Patient who fail from levofloxacin sequential therapy will be retreated with bismuth quadruple therapy for 10 days D1-D10: (esomeprazole 40mg bid + Dibismuth trioxide 120mg qid + metronidazole 500mg tid + tetracycline 500mg qid) for 10 days

Group (B) Patient who fail from bismuth quadruple therapy will be retreated with levofloxacin sequential therapy for 14days D1-D7: (esomeprazole 40mg bid + amoxicillin 1gm bid) for 7 days D8-D14: (esomeprazole 40mg bid + levofloxacin 250mg bid + metronidazole 500mg bid) for another 7 days

Outcome Measurement:

Primary End Point: Eradication rate in the second line according to intention to treat (ITT) and per-protocol (PP) analysis in the two treatment groups

Inclusion Criteria:

1. H. pylori infected patients who failed from first line standard triple therapy with clarithromycin, amoxicillin, and a proton pump inhibitor were eligible in this study

Exclusion Criteria:

1. children and teenagers aged less than 20 years,
2. history of gastrectomy,
3. gastric malignancy, including adenocarcinoma and lymphoma,
4. previous allergic reaction to antibiotics (bismuth, metronidazole, levofloxacin, tetracycline) and PPI (esomeprazole),
5. contraindication to treatment drugs,
6. pregnant or lactating women,
7. severe concurrent disease, or
8. Unwilling to accept random assignment of subjects

The investigators will not share the data.