Beyond Blood Cultures and Echocardiography: Emerging Diagnostics for Infective Endocarditis

Management of infective endocarditis (IE) is often confounded by the presence of prosthetic valves, transcatheter prostheses, and cardiovascular implantable electronic devices, as well as by changing epidemiologic risks and antimicrobial resistance patterns. For the diagnosis of IE, blood cultures and echocardiography remain foundational, but important gaps persist, particularly in culture-negative and prosthetic/device-associated infections. Contemporary diagnostic criteria and guidelines now support a multimodality approach incorporating molecular microbiology and advanced imaging. This review summarizes emerging technologies including broad-range 16S/18S/28S rRNA polymerase chain reaction and sequencing, fluorescence in situ hybridization coupled with sequencing, targeted and shotgun metagenomic next-generation sequencing (mNGS), plasma microbial cell-free DNA, cardiac computed tomography, and 18F-fluorodeoxyglucose positron-emission tomography/computed tomography. We also examine the potential role of artificial intelligence in echocardiographic interpretation and of large language models in multimodal data integration. Current evidence suggests that tissue-based molecular testing generally provides greater microbiologic yield than valve culture in culture-negative IE, while blood-based mNGS and microbial cell-free DNA may extend pathogen detection after antibiotic exposure and reduce reliance on tissue-based diagnosis. However, heterogeneity in specimen handling, sequencing pipelines, contamination control, reporting thresholds, and clinical interpretation remains a major barrier to implementation. Future progress should move beyond pathogen detection toward rapid, reproducible, clinically actionable diagnosis that integrates organism identification, anatomic localization, disseminated disease, and personalized treatment. Prospective outcome trials, standardized workflows, cost-effectiveness studies, and multidisciplinary Endocarditis Team integration can help determine whether these technologies translate into better antimicrobial stewardship, procedural decision-making, and patient outcomes.