Susceptibility-guided Bismuth Quadruple Therapy for Multiple-resistant Helicobacter Pylori Strains

The goal of this clinical trial is to learn if the 14-day susceptibility-guided bismuth quadruple therapy works to treat multiple drug resistant Helicobacter pylori (H. pylori) in adults. It will also learn about the adverse effects of bismuth quadruple therapy. The main questions it aims to answer are:

* Does 14-day susceptibility-guided bismuth quadruple therapy higher the eradication rate?
* What medical problems do participants have when taking 14-day susceptibility-guided bismuth quadruple?
* Does bismuth suppress the expression of virulence factors of H. pylori?

Researchers will record 14-day susceptibility-guided bismuth quadruple to see if 14-day susceptibility-guided bismuth quadruple works to treat multiple drug resistant H. pylori.

Participants will:

* Take susceptibility-guided bismuth quadruple every day for 14 days
* Visit the clinic once 4-6 weeks for checkups and tests
* Keep a diary of their symptoms during taking susceptibility-guided bismuth quadruple

Helicobacter pylori (H. pylori) infection is the major culprit of dyspeptic symptoms, peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. The Tokyo consensus stated that infection with H. pylori should be regarded as a pathogenic infectious disease rather than commensals only and should be eradicated.

H. pylori eradication regimen evolved with the increase of resistance rate in different regions. In Taiwan, clarithromycin resistance rate is arising from 9.5% in 2009 to around 14-17% in 2016 when conducting the first-line therapy. As a result, Taiwan gastroenterological association consensus suggested using 14-day clarithromycin-based (hybrid, sequential, concomitant, or triple) therapy as the first-line therapy and levofloxacin-based therapy as the second line therapy according to endemic resistance rate.

After twice eradication failure, H. pylori culture for susceptibility test is strongly recommended, which guide clinician to choose appropriate susceptibility-based therapy. Progressive increased dual (clarithromycin and levofloxacin) resistance and triple (dual and metronidazole) resistance, however, made it difficult for eradication. The regimens at physicians' discretion varied a lot and the overall successful eradication rate around 60% was still unsatisfactory.

Susceptibility-guided therapy is currently the consensus recommendation for 3rd-line H. pylori eradication. Bismuth quadruple therapy could overcome either clarithromycin or metronidazole resistant strains. Several evidences of clinical randomized-controlled trials demonstrated that adding bismuth as the first line therapeutic regimen can capture additional 30-40% successful eradication rate for the resistant strain, further contributing to the overall eradication rate. Accordingly, the aim of our study was to validate the susceptibility-guided bismuth quadruple therapy in patients with multiple drug resistant H. pylori infection in terms of efficacy and side effects.

Almost more than 99.5% ingested bismuth salt can be excreted from intestinal lumen without absorption. Bismuth may be able to form complexes in bacterial wall and periplasmic space, as well as inhibits enzymes, ATP synthesis and bacterial adherence to gastric mucosa. The MIC90 of bismuth to Helicobacter pylori ranged from 4-32 ng/L and there was no resistance been reported. Lots of H. pylori virulence factors are important players to establish colonization in gastric environment in each steps. Urease activity adjusts the pericellular environment to less acidity. Flagella direct bacterial motility and chemotaxis to mucosal surface. Colonization to epithelium is facilitated by lots of adhesion-receptor interaction, including BabA to Lewis B, SabA to sialyl-Lewis X, and CagL to α5β1 integrin. Bismuth drugs may affect the urease activity in jack bean plant and Klebsiella aerogenes. Bismuth inactivates H. pylori nickel-responsive transcription factor (NikR) protein, an important regulator for nickel homeostasis and iron metabolism in H. pylori. Since nickel iron is crucial in the catalytic function of urease, it is reasonable to assuming that it may impose effect on the urease activity in H. pylori. Furthermore, a pilot study showed that nickel-free diet can enhance the H. pylori eradication rate, which was speculated due to decreased urease activity.

Eligibility Criteria:
Inclusion Criteria:

* H. pylori-infected with treatment experience with at least one course of eradication failure
* H. pylori-infected with treatment naïve but having multiple-drug resistant H. pylori (\>= three antibiotics)
* H. pylori infection confirmed by H. pylori culture

Exclusion Criteria:

* Previous allergic reactions to regimens, including amoxicillin, bismuth subcitrate, esomeprazole, metronidazole, rifabutin, and tetracycline,
* Severe comorbidities,
* Chronic kidney disease with estimated glomerular filtration rate \< 60 ml/min/1.73 m2,
* Pregnant or breastfeeding women.
* Dual-resistant H. pylori infection
* Mono-resistant H. pylori infection
* All susceptible H. pylori infection
* Positive RUT but negative H. pylori culture
* Negative RUT and negative H. pylori culture
* Decline to participate