Contemporary first-line pharmacological management of Helicobacter pylori infection.

INTRODUCTION: Eradication of Helicobacter pylori has become challenging as antimicrobial resistance has risen worldwide. The efficacy of clarithromycin-based triple therapy has declined to unacceptable levels in most regions, urging a fundamental evaluation of first-line treatment and emergence of several competing regimens whose relative benefits depend on local resistance and drug availability. AREAS COVERED: This review assesses the pharmacological basis and clinical evidence for contemporary first-line H. pylori eradication regimens in treatment-naive adults - bismuth quadruple, non-bismuth quadruple concomitant, potassium-competitive acid blocker-based, and rifabutin-based therapy. The impact of antimicrobial resistance, relative effectiveness of these regimens, current guideline recommendations, susceptibility-guided treatment, and safety and tolerability are examined. PubMed, the Cochrane Library, and Google Scholar were searched from January 2012 through August 2026, emphasizing the past five years. EXPERT OPINION: Bismuth quadruple therapy is the preferred first-line option where available, given its resilience across resistance profiles; where bismuth is unavailable, concomitant quadruple therapy is appropriate provided dual clarithromycin-metronidazole resistance is low. Potassium-competitive acid blocker-based dual therapy is well-tolerated, but the evidence remains predominantly Asian. Susceptibility-guided therapy is ideal but constrained by limited testing and infrastructure. Improving outcomes depends less on new regimens than on resistance surveillance and susceptibility testing directing existing regimens where effective.