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Background Clarithromycin (CLA) resistance is a major driver of Helicobacter pylori (H. pylori) eradication failure in the Asia-Pacific region, with traditional triple therapy (TT) showing poor efficacy. Bismuth quadruple therapy (BQT) is empirically effective for CLA-resistant infections, but the mechanistic basis and clinical predictive biomarkers remain unclear. We hypothesized that high-level CLA resistance induces an iron-dependent metabolic vulnerability exploitable by bismuth, and aimed to validate this mechanism and establish a clinically actionable MIC threshold for pediatric patients in China.Methods We performed a real-world retrospective analysis of 4,610 Chinese pediatric patients with H. pylori (2019–2024, 1,844 with complete follow-up) and prospective validation in 51 culture-positive isolates (the largest pediatric checkerboard panel to date). Mechanistic studies included transcriptomics, iron/ATP metabolism assays, and iron chelation/supplementation experiments.Results BQT achieved superior eradication for CLA-resistant infections (93.1% vs 68.8% with TT, p=0.017). Bismuth-CLA synergy was exclusive to resistant strains and correlated with MIC of CLA. High-level CLA resistance induced iron/ATP metabolic dyshomeostasis, which was targeted by bismuth—an effect reversed by iron supplementation (IDDF2026-ABS-0349 Figure 1. Clarithromycin resistance confers susceptibility to bismuth via altered iron homeostasis in H pylori). MIC of CLA≥16 μg/mL robustly predicted bismuth response (AUC=0.991), with 96% eradication in prospective high-level resistant patients (vs 0% with TT, p<0.001).Conclusions This first study of collateral sensitivity in H. pylori identifies iron-dependent metabolic vulnerability in high-level CLA-resistant strains, with MIC of CLA ≥16 μg/mL as the first actionable biomarker for Chinese pediatric patients (IDDF2026-ABS-0349 Figure 2. Quantitative clarithromycin (CLA) susceptibility testing is performed following confirmation of H. pylori infection). This MIC-stratified strategy provides a precision eradication approach for refractory H. pylori in the Asia-Pacific, transforming antibiotic resistance from a treatment failure marker to a therapeutic opportunity.Abstract IDDF2026-ABS-0349 Figure 1Abstract IDDF2026-ABS-0349 Figure 2