Bismuth quadruple therapy shows higher H. pylori eradication in pediatric patients with clarithromycin resistance

Background & Aims: Clarithromycin (CLA) resistance severely compromises the efficacy of triple therapy (TT) against Helicobacter pylori (H. pylori). Bismuth-based regimens exhibit greater efficacy against CLA-resistant H. pylori than against strains resistant to other antibiotics, suggesting a resistance-specific vulnerability rather than broad antimicrobial activity. The mechanistic basis for this selectivity, however, remains unknown. We hypothesized that high-level CLA resistance confers a metabolically targetable vulnerability that can be exploited by bismuth, and that a quantitative MIC of CLA threshold could identify this responsive subset. Methods: We conducted a real-world retrospective analysis of 4,610 pediatric patients with H. pylori infection treated between 2019 and 2024, among whom 1,844 (40%) had complete follow-up data for eradication assessment. In parallel, we prospectively enrolled 51 patients with culture-positive isolates--the largest liquid checkerboard panel reported to date--to evaluate bismuth-CLA interactions and track treatment outcomes. Mechanistic validation included transcriptomic profiling and functional assays of iron and ATP metabolism, with iron chelation and supplementation experiments. Results: In the retrospective real-world cohort (n = 4,610; 1,844 with follow-up), bismuth quadruple therapy (BQT) achieved superior eradication specifically in CLA-resistant infections (93.1% vs 68.8% with TT; p = 0.017). In vitro, bismuth-CLA synergy was exclusive to resistant strains and intensified with increasing MIC of CLA. Mechanistically, bismuth triggered coordinated depletion of intracellular iron and ATP--a phenotype mimicked by iron chelation and reversed by iron supplementation. A baseline MIC of CLA [&ge;] 16 g/mL robustly predicted this synergy (AUC = 0.991) and was prospectively validated in an independent patient subset: bismuth cured 96% of high-level resistant patients (MIC [&ge;] 16 g/mL) versus 0% with triple therapy (p < 0.001). Conclusion: High-level CLA resistance defines an iron-dependent metabolic vulnerability in H. pylori that is selectively targeted by bismuth. The MIC threshold of [&ge;] 16 g/mL provides the first clinically actionable biomarker for resistance-guided therapy, transforming a marker of treatment failure into a positive predictor of bismuth response. These findings establish the mechanistic and clinical foundation for MIC-stratified eradication strategies and inform future randomized trials aimed at precision management of antibiotic-resistant H. pylori infection. Keywords Helicobacter pylori; Antibiotic Resistance; Clarithromycin Resistance; Bismuth-based Therapy; Iron Metabolism