Third-Line and Later Susceptibility-Guided Helicobacter pylori Eradication Therapies: A Multicenter Study of Vonoprazan–Amoxicillin–Sitafloxacin/Rifabutin Regimens

<b>Background/Objectives</b>: Although vonoprazan-based triple therapy has improved the first- and second-line <i>Helicobacter pylori</i> eradication rates, a subset of patients still require third-line or later treatments. The present study aimed to evaluate the efficacy and safety of susceptibility-guided eradication strategies from third-line or later treatments in a multicenter setting. <b>Methods</b>: This retrospective multicenter study (2019-2024) enrolled 94 patients who had failed second-line eradication therapy and underwent <i>H. pylori</i> isolation and susceptibility testing. Based on sitafloxacin sensitivity, patients received vonoprazan, amoxicillin, and sitafloxacin (VAS) if sensitive, or vonoprazan, amoxicillin, and rifabutin (VAR) if resistant. Altogether, 75 patients received treatment according to this protocol. <b>Results</b>: Among the 75 patients, 61.3% were sitafloxacin-sensitive (VAS group), and 38.7% were resistant (VAR group). All strains were rifabutin-sensitive. The overall eradication rates were 92.0% and 95.8% in the intention-to-treat and per-protocol analyses, respectively. Adverse events occurred in 17.3% of cases. One patient in the VAR group discontinued therapy due to dizziness, whereas all other adverse events were mild and did not require treatment cessation. Subgroup analysis showed eradication rates of 93.5% (43/46) and 89.7% (26/29) for the VAS and VAR groups, respectively. The eradication rate for third-line therapy was 96.2% (50/52), whereas that for fourth-line therapy was 85.7% (18/21). Fifth-line therapy showed an eradication rate of 50.0% (1/2). <b>Conclusions</b>: Susceptibility-guided vonoprazan-based regimens from the third-line treatment onward achieved high eradication and tolerability in a multicenter cohort. This approach may offer a valuable treatment option for patients with refractory <i>H. pylori</i> infections.