During the period between the collection of blood cultures and the determination of a pathogen or if blood cultures are ultimately deemed culture negative, empirical therapy is generally required. Consultation with an infectious diseases specialist to define the most appropriate choice of therapy is recommended. Collection of additional clinical and laboratory data often dictates subsequent revisions in initial empirical therapy that will be administered over the treatment course. For patients with acute (days) clinical presentations of native valve infection, coverage for S aureus, -hemolytic streptococci, and aerobic Gram-negative bacilli is reasonable. Empirical coverage could include vancomycin and cefepime as an initial regimen. For patients with a subacute (weeks) presentation of NVE, empirical coverage of S aureus, VGS, HACEK, and enterococci is reasonable. One treatment option could include vancomycin and ampicillin-sulbactam to pro- vide some coverage for these organisms. Subsequent regimen revision can be done when a pathogen is recovered from blood cultures. For patients with culture-negative PVE, coverage for staphylococci, enterococci, and aerobic Gram-negative bacilli is reasonable if the onset of symptoms is within 1 year of prosthetic valve placement. A regimen could include vanco- mycin, rifampin, gentamicin, and cefepime. If symptom onset is >1 year after valve placement, then IE is more likely to be caused by staphylococci, VGS, and enterococci, and antibiotic therapy for these potential pathogens is reasonable. One initial treatment option could include vancomycin and ceftriaxone. If subsequent blood culture results or other laboratory methodologies define a pathogen, then empirical therapy should be revised to focused therapy that is recommended for the specific pathogen identified. 