Background: Helicobacter pylori infection remains a major global health concern and is strongly associated with peptic ulcer disease, gastric MALT lymphoma, and gastric cancer. Increasing resistance to clarithromycin and metronidazole has significantly reduced the effectiveness of standard concomitant quadruple therapy in many regions. In this context, optimizing acid suppression and utilizing amoxicillin in an appropriate time-dependent dosing schedule, in combination with bismuth, may offer an improved therapeutic strategy.

Methods: In this randomized clinical trial, treatment-naïve adult patients with confirmed H. pylori infection were assigned to one of two regimens. 1. High-Dose Triple Therapy for 14 days: Esomeprazole 40 mg, Amoxicillin 1 g, and Bismuth subcitrate 240 mg , three times daily. 2. Concomitant Quadruple Therapy for 12 days: Pantoprazole 40 mg, Amoxicillin 1 g, Clarithromycin 500 mg , and Metronidazole 500 mg twice daily. Eradication was assessed at least eight weeks after treatment using stool antigen testing. Adherence and adverse events were recorded. Analyses were conducted on both intention-to-treat (ITT) and per-protocol (PP) bases.

Results: High-dose triple therapy demonstrated significantly superior efficacy and tolerability compared with concomitant quadruple therapy. • Eradication Rate (PP): 95.8% in the triple therapy group vs. 74.3% in the concomitant therapy group (p < 0.001). • Excellent Treatment Adherence: 94.0% vs. 53.4% (p < 0.001). • Adverse Events: Significantly fewer and generally mild in the triple therapy group, compared with concomitant therapy group.

Conclusion: In this randomized clinical trial, the 14-day high-dose triple therapy regimen demonstrated a marked superiority over the commonly used 12-day concomitant quadruple therapy for first-line H. pylori eradication. The high-dose triple therapy achieved significantly higher eradication rates, both in intention-to-treat and per￾protocol analyses, while also showing substantially fewer adverse effects and markedly better patient adherence. These findings reflect the pharmacologic advantage of enhanced acid suppression combined with time-dependent delivery of high-dose amoxicillin, which maintains sustained antibiotic concentrations in the gastric environment, independent of clarithromycin or metronidazole resistance patterns. The improved tolerability and simplified regimen contributed to greater treatment continuity, which is a critical determinant of real-world eradication success. Importantly, by eliminating clarithromycin and metronidazole exposure, this regimen addresses the growing challenge of dual antibiotic resistance, which has significantly undermined the effectiveness of standard quadruple therapies in many regions. Taken together, our results strongly support 14-day high-dose triple therapy as a more effective, safer, and more practical first-line empirical treatment option for H. pylori eradication, particularly in settings where resistance to clarithromycin and metronidazole is prevalent. Adoption of this regimen in clinical practice may improve treatment outcomes, reduce the burden of repeated therapy, and contribute to broader strategies aimed at mitigating antibiotic resistance.