Minimizing the Impact of Antibiotic Resistance on Helicobacter pylori Eradication: From Mechanisms to Clinical Application

Rising resistance in Helicobacter pylori to metronidazole, clarithromycin, and fluoroquinolones has significantly reduced eradication efficacy. This narrative review explores evidence-based strategies that minimize the impact of antibiotic resistance. Current practical approaches include empirical therapy (EMT), in which regimens are selected without individual susceptibility testing based on local or regional resistance patterns, previous antibiotic exposure, guideline recommendations, and expected effectiveness, and susceptibility-guided therapy (SGT), which avoids antibiotics to which the infecting strain is resistant. EMT does not simply exclude every antibiotic with a high resistance prevalence because regimen-level efficacy may remain high despite resistance to one component. When susceptibility testing is unavailable, optimized 14-day bismuth quadruple therapy is a guideline-preferred empirical regimen and can remain effective despite metronidazole resistance with adequate dosing and treatment duration. Rifabutin-based triple therapy provides an additional empirical or rescue option for selected patients without penicillin allergy. SGT is not universally superior to well-selected EMT, but may improve eradication rates in selected populations, particularly in settings with high clarithromycin resistance or where rapid molecular testing is available. However, susceptibility testing may be time-consuming, costly, and limited to only a few antibiotics. Emerging approaches include potassium-competitive acid blockers (PCABs), antimicrobial stewardship, probiotics, N-acetylcysteine, nanomaterial-based drug delivery, and vaccination. Among these, vonoprazan-based regimens are the most clinically mature. Vonoprazan-amoxicillin dual therapy can reduce exposure to resistance-prone antibiotics, although its use should reflect regional effectiveness, availability, and cost. Other non-antibiotic approaches remain investigational. In conclusion, management should move from undifferentiated empirical regimen selection toward risk-stratified precision treatment. Locally validated EMT remains appropriate when susceptibility testing is unavailable, whereas SGT should be prioritized after treatment failure or in patients at high risk of resistance. Rifabutin-based and vonoprazan-amoxicillin therapies provide additional options according to treatment history, penicillin allergy, regional evidence, and accessibility.