Unveiling the Future of Infective Endocarditis Diagnosis: The Transformative Role of Metagenomic Next-Generation Sequencing in Culture-Negative Cases.

Culture-negative infective endocarditis (CNE) remains a significant diagnostic challenge in cardiology and infectious disease, often leading to delayed or empirical treatment. Metagenomic next-generation sequencing (mNGS) has emerged as a complementary diagnostic tool capable of identifying fastidious, unexpected, or novel pathogens without prior assumptions. This narrative review synthesizes evidence from 152 studies (2015-2024), evaluating mNGS within existing diagnostic frameworks for culture-negative IE. Compared to conventional diagnostics (blood cultures, PCR, 16 S rRNA sequencing), mNGS demonstrates enhanced detection capabilities for polymicrobial infections and rare pathogens, though methodological heterogeneity across studies precludes definitive performance comparisons. Performance varies substantially based on sample type, sequencing platform, and bioinformatic pipelines. Real-world applications reveal persistent challenges, including cost barriers, interpretive complexities in low-biomass samples, and contamination risks. Integration with host-response biomarkers and AI-driven interpretation platforms shows promise for advancing clinical utility. For mNGS to be effectively integrated into routine CNE care, standardization, regulatory clarity, and equitable implementation will be essential.