Susceptibility‐Guided Versus Empirical Therapy for <i>Helicobacter pylori</i> Infection in a High Resistance Setting: A Randomised Controlled Trial

Clarithromycin resistance is a major determinant of treatment failure, and the benefits of susceptibility-guided therapy in high-resistance settings remains incompletely understood. To evaluate the clinical effectiveness of the susceptibility-guided compared with the empirical therapy in treatment-naïve H. pylori infection in a high resistance setting. In this single-centre, randomised, superiority trial, 500 treatment-naïve adults were allocated (1:1) to susceptibility-guided sequential therapy (SGT) or empirical clarithromycin -containing quadruple therapy (ET). Clarithromycin and levofloxacin antimicrobial resistance were determined using PCR. The primary endpoint was first-line eradication in the intention-to-treat (ITT) population. Sensitivity analyses were performed using complete-case and multiple imputation approaches. Among the 494 analysed participants (244 SGT, 250 ET), resistance to clarithromycin and levofloxacin was 69.3% and 51.6%, respectively. In the ITT analysis, first-line eradication was achieved in 59.8% of participants in the SGT group and 62.8% in the ET group [absolute risk difference -3.0%; odds ratio (OR) = 0.882, 95% confidence interval (CI, 0.614-1.268), p = 0.499]. Per-protocol eradication rates were 84.4% and 89.7%, respectively [absolute risk difference -5.3%; OR = 0.620, 95% CI (0.328-1.173), p = 0.139]. Notably, despite a clarithromycin resistance rate approaching 70%, empirical clarithromycin-containing quadruple therapy achieved a high per-protocol eradication rate. Sensitivity analyses yielded consistent results. In a high resistance region, PCR-based susceptibility-guided sequential therapy did not demonstrate superiority over empirical treatment. However, empirical clarithromycin -containing quadruple therapy maintained satisfactory efficacy. Overall, these findings have implications for treatment strategy selection in high-resistance microbiological settings. Trial Registration: ClinicalTrials. gov Identifier: NCT05549115.