1. Introduction
   1. Hp
      1. WHO-designated carcinogen
      2. 89% of all gastric cancer are attributable to Hp
   2. Consequences of failed treatment
      1. Clinical complications related to Hp infection
      2. Repeated exposure to antibiotics and high dose acid supression
      3. Generation of antibiotic resistance
      4. Direct and indirect costs to the healthcare system
   3. Guidelines of treatment
      1. Limited high-quality evidence
2. Definition
   1. Refractory Hp infection
      1. Persistently positive non-serological Hp test
         1. At least 4 weeks following one or more completed course
3. Causes of Hp eradication treatment failure
   1. Antibiotic resistance
      1. More likely if there is in vitro resistance
         1. For example:
            1. Clarithromycin
            2. 7.0-fold higher likelihood of treament failure
            3. Levofloxacin
            4. 8.2-fold higher likelihood of treament failure
            5. Nitroimidazole
            6. 2.5-fold higher likelihood of treament failure
      2. Overall primary resistance rates
         1. 10-34% for clarithromycin
         2. 11-30% for levofloxacin
         3. 23-56% for metronidazole
      3. Secondary resistance rates
         1. 15-67% for clarithromycin
         2. 19-30% for levofloxacin
         3. 30-65% for metronidazole
      4. Selecting eradication therapies based on prior antibiotic exposure
         1. Not inferior to
            1. Selecting therapy based on in vitro antibiotic susceptibility
      5. Dominant molecular mechanisms
         1. Clarithromycin
            1. Mutations in the 23S ribosomal subunit
         2. Levofloxacin
            1. Mutations in DNA gyrase subunit A
         3. Amoxicillin
            1. Mutations in penicillin binding protein 1
         4. Tetracycline
            1. Mutations in genes encoding binding site for ribosomal 16S subunit
         5. Rifabutin
            1. Mutations in rpoB, the beta subunit of RNA polymerase gene
         6. Nitroimidazole
            1. Complex rdxA mutations
            2. This may contribute to
            3. Low predictive value of in vitro metronidazole resistance testing to treatment outcome
      6. Resistance rates were lower for amoxicillin, tetracycline and rifabutin (<5%)
   2. Patient nonadherence
      1. Adherence to >60% to >90% of the prescribed course
         1. Might be sufficient for successful eradication
            1. At least in primary H. pylori infection
      2. Common barriers
         1. Complexity of eradication regimens
         2. High pill burden
         3. Physical intolerance of medications
         4. Poor provider communication
         5. Lack of understanding of why therapy is indicated
      3. Physicians should provide anticipatory guidance
         1. Explaining the rationale for therapy
         2. Dosing instructions
         3. Expected adverse events
         4. Importance of completing the full therapeutic course
   3. Host genetics
      1. Polymorphisms that affect intragastric pH
         1. CYP2C19, IL-1B and MDR1
            1. Hp is most susceptible to antibiotics when intragastric pH is consistently between 6-8
            2. Since this is the optimal pH range for Hp replication
            3. Some antibiotics (clarithromycin and amoxicillin) also require intragastric acid suppression
            4. For maximum efficacy and sustained activity
            5. CYP2C19 polymorphisms
            6. Metabolism-enhancing phenotypes are associated with higher rates of eradication failure
            7. More in case of PPIs that are heavily metabolized by CYP2C19 (e.g. omeprazole, lansoprazole)
            8. More prevalent in non-asian groups
         2. Physicians should
            1. Give higher doses and/or increased frequency of first-generation PPIs
            2. Use of later generation, more potent PPIs
            3. Select potent non-PPI gastric acid suppressors, such as vonoprazan
   4. Other factors
      1. Age
      2. Smoking
         1. Smoking increases gastric acid secretion and impairs mucous secretion and gastric blood flow
            1. Decreasing local antibiotic delivery
4. Strategies to advance the field and potential adjunctive therapies
   1. Incorporate regional information of local success rates
   2. Non-invasive H. pylori antibiotic sensitivity testing on stool
   3. Addition of clavulanic acid to amoxicillin-based regimens
   4. Statins
   5. Probiotics
      1. Lactobacillus and Bifidobacterium
         1. Inhibitory effect as well as enhanced patient tolerance to the treatment
5. Antibiotic Susceptibility-based Approach
   1. Sensitivity testing should be considered after two failed attempts at treatment
   2. Lack of convincing data demonstrating superiority compared to empirically selecting treatment based on prior antibiotic exposure
   3. Culture-based methods
      1. Success rates of obtaining a useful result
         1. <80-95%
   4. Molecular resistance testing
      1. Can also be performed on formalin-fixed paraffin-embedded gastric biopsy tissue
6. Considerations in regimen selection for refractory Hp
   1. Macrolides and fluoroquinolones
      1. Should not be repeated in subsequent treatment attempts
   2. It is important to consider antibiotic history of usage of macrolides and fluroquinolones
   3. Amoxicillin, tetracycline, and rifabutin
      1. Have very low primary and secondary resistance
   4. Resistance to nitroimidazoles
      1. Should not be considered as an ‘absolute’ contraindication
      2. Might be potentially overcome with dose adjustments and addition of bismuth
         1. Metronidazole, at least in the 1.5-2 g/day range
   5. Achieve adequate threshold levels of amoxicillin and intragastric acid suppression
      1. 2-3g amoxicillin into at least three doses daily
      2. Higher doses, greater frequency (e.g. TID or QID PPI dosing), and the use of more potent PPIs (e.g. esomeprazole or rabeprazole)
      3. Vonoprazan
         1. First-in-class potassium-competitive acid blocker
   6. Longer treatment durations
7. Proposed treatment algorithm
   1. Only FDA-approved for refractory Hp infection
      1. PPI, bismuth, metronidazole, tetracycline (PBMT)
   2. If PBMT fails as a first-line treatment
      1. Levofloxacin- or rifabutin-based triple therapy regimens with high-dose dual proton pump inhibitor (PPI) and amoxicillin
      2. An alternative bismuth-containing quadruple therapy
   3. If levofloxacin resistance rates >15%
      1. Should not be considered