Culture-negative infective endocarditis (CNIE) accounts for 5-31% of all IE cases where standard blood cultures fail to identify the causative organism. The most common cause is prior antibiotic exposure (up to 45% of CNIE cases -- antibiotics suppress bacterial growth in culture media). Other causes include fastidious organisms requiring special growth conditions: HACEK group (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella -- require prolonged incubation), Coxiella burnetii (Q fever -- most common cause of CNIE worldwide, intracellular pathogen), Bartonella species (cat scratch, body lice), Brucella (unpasteurized dairy), Tropheryma whipplei (Whipple disease), and fungi (Candida, Aspergillus -- especially in prosthetic valves and IVDU). Non-infectious causes mimicking IE include Libman-Sacks endocarditis (SLE), marantic endocarditis (malignancy), and antiphospholipid syndrome.