Blood Culture-Negative Infective Endocarditis: A Review

Blood culture-negative infective endocarditis (BCNIE) represents a diagnostically challenging subset of infective endocarditis in which routine blood cultures remain negative despite fulfillment of Duke-ISCVID diagnostic criteria. BCNIE arises primarily from prior antibiotic exposure, infection with fastidious or nonculturable organisms, or noninfectious conditions that mimic endocarditis. Common fastidious pathogens include Coxiella burnetii, Bartonella species, Brucella species, Tropheryma whipplei, fungi, and nutritionally variant streptococci. Because delayed pathogen identification may postpone targeted therapy, BCNIE is associated with increased diagnostic complexity and substantial morbidity and mortality. Modern evaluation relies on a multimodal strategy integrating serologic testing, prolonged culture incubation, histopathology, advanced molecular diagnostics, and multimodality imaging. Emerging molecular techniques, including 16S/18S polymerase chain reaction and metagenomic next-generation sequencing, have significantly improved microbiologic yield, particularly from excised valve tissue, and are now incorporated into updated Duke-ISCVID criteria. Echocardiography remains central to diagnosis, while cardiac computer tomography and 18 fluoro-2-deoxy-D-glucose positron emission tomography/computer tomography provide complementary value in prosthetic valve disease and detection of periannular complications. Management requires empiric antimicrobial therapy followed by organism-directed treatment once a pathogen is identified, with surgery frequently necessary for heart failure, uncontrolled infection, fungal disease, or structural complications. Multidisciplinary endocarditis teams are increasingly recognized as essential to optimizing outcomes in this complex disease process.