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Background International guidelines recommend bismuth quadruple therapy (BQT) for Helicobacter pylori (H. pylori) in high clarithromycin (CLA) resistance regions, but remain silent on dose optimisation for metronidazole (MET) resistance—now exceeding 50% in the Asia-Pacific. This study aimed to address this unmet clinical need in Chinese paediatric patients.Methods A single-centre retrospective cohort study (2019–2024) at China’s National Children’s Medical Centre enrolled 4,610 treatment-naïve children (6–18 years) with first-episode H. pylori. Diagnosis/follow-up adhered to ESPGHAN/NASPGHAN guidelines; antimicrobial susceptibility testing followed EUCAST criteria. Checkerboard assays defined the bismuth-MET ‘additive window’.Results Among 1,844 children with complete follow-up, MET resistance (54.0%) was double CLA resistance (25.3%). In MET-resistant infections, BQT offered no benefit over triple therapy (TT) (80.0% vs 73.8%, p=0.367) (IDDF2026-ABS-0350 Figure 1. Closing the Additive Window: The Most Resisted Drug Is the Most Underdosed-A Call for Urgent Dose Optimisation). Checkerboard assays confirmed bismuth-MET additivity requires a concentration threshold—the ‘additive window’—unachieved by current dosing (IDDF2026-ABS-0350 Figure 2. Checkerboard assay demonstrating the ‘additive window’ for bismuth–metronidazole interaction against H. pylori, and corresponding PK/PD coverage).Conclusions Current guideline-recommended MET doses (below half the licensed safety limit) fail to overcome high-level resistance in Chinese children. Dose optimisation to 20–30 mg/kg/day—an evidence-based, safe adjustment—reopens the additive window, restoring bismuth and MET efficacy ( IDDF2026-ABS-0350 Figure 1. Closing the Additive Window: The Most Resisted Drug Is the Most Underdosed-A Call for Urgent Dose Optimisation). Randomised trials are urgently needed to inform Asia-Pacific and global paediatric H. pylori guideline revision.Abstract IDDF2026-ABS-0350 Figure 1Abstract IDDF2026-ABS-0350 Figure 2