Antibiotic Combinations in Bismuth‐Containing Quadruple Therapy for Helicobacter pylori Eradication: A Systematic Review and Network Meta‐Analysis

ABSTRACT Background and Aims The rising antibiotic resistance of Helicobacter pylori has led to variability in efficacy of bismuth‐containing quadruple therapy (BcQT). This network meta‐analysis (NMA) aimed to compare the efficacy of antibiotic combinations in first‐line BcQT. Methods Following PRISMA guidelines with PROSPERO registration (CRD420251005598), we systematically searched PubMed, Embase, Web of Science, and Cochrane Library for randomized controlled trials (RCTs) published between January 1, 2005 and March 21, 2025. Eligible studies were selected by predefined criteria. Dichotomous outcomes included H. pylori eradication rates, adverse events, and compliance, analyzed as odds ratios (ORs) with 95% credible intervals (95% CrI) or 95% confidence intervals (95% CI). Treatments were ranked via surface under the cumulative ranking curve (SUCRA). Results This NMA included 25 RCTs ( n = 7624) evaluating 19 regimens. Amoxicillin‐metronidazole ranked highest globally (SUCRA = 0.866) in intention‐to‐treat analyses and in Asia (SUCRA = 0.851), particularly during 2016–2025 (SUCRA = 0.859; OR = 3.43, 95% CrI 1.17–10.05). Metronidazole‐tetracycline was optimal in Europe (SUCRA = 0.969; OR = 2.13, 95% CrI 1.15–3.95), amoxicillin‐minocycline in China (SUCRA = 0.733). Notably, regimens including levofloxacin or clarithromycin significantly decreased eradication rates in China (OR = 1.32; 95% CI 1.04–1.66; p = 0.02). Amoxicillin‐furazolidone had the poorest adverse events (SUCRA = 0.792). Compliance was highest with amoxicillin‐moxifloxacin (SUCRA = 0.878). Conclusion Superior eradication was achieved with BcQT by utilizing dual low‐resistance antibiotics per local surveillance data. Amoxicillin‐metronidazole may represent optimal regimens for primary H. pylori eradication efficacy in BcQT. Substantial efficacy variation in antibiotic combinations necessitates tailored treatment guided by antibiotic resistance surveillance.