Abstract
Blood culture-negative infective endocarditis (BCNE) is a challenging condition associated with significant morbidity and mortality. This review discusses the epidemiology, microbiology, diagnosis, and treatment of BCNE considering advancements in molecular diagnostics and increased access to cardiac surgery. BCNE can be categorized into bacterial endocarditis with sterilized blood cultures due to previous antibiotic treatment, endocarditis caused by fastidious microorganisms, and true BCNE caused by intracellular organisms that cannot be cultured using traditional techniques. Non-infectious causes such as nonbacterial thrombotic endocarditis should also be considered. Diagnostic approaches involve thorough patient history; blood and serum testing, including appropriate handling of blood cultures; serological testing; and molecular techniques such as targeted and shotgun metagenomic sequencing. Where available, evaluation of explanted cardiac tissue through histopathology and molecular techniques is crucial. The therapy for BCNE depends on the likely causative agent and the presence of prosthetic material, with surgical intervention often required.