Administration of antimicrobial agents to IE patients before blood cultures are obtained reduces the recovery rate of bac- teria by 35% to 40%.228 232 The antimicrobial susceptibility of the organism, the dose, and the duration and nature of pre- vious antimicrobial therapy together determine the length of time that blood cultures will remain negative.232 IE patients with blood cultures that are initially negative after only a few days of antibiotic therapy may have positive blood cultures after several days without antibiotics. The blood cultures of patients who receive longer courses of high-dose bactericidal antimicrobials may remain negative for weeks. Selection of medical therapy for patients with culture- negative IE is difficult. On the one hand, there is a need to provide empirical antimicrobials for all likely pathogens. On the other hand, certain therapeutic agents, including amino- glycosides, have potentially toxic effects that dictate limita- tion or avoidance of use if at all possible. Moreover, some of the laboratory-based diagnostic techniques to define fas- tidious or unusual pathogens are not available in most clinical laboratories and require considerable time for completion of testing if specimens are sent to a referral laboratory.233 During this period, patients are often treated empirically for the more common bacterial causes of IE, which can result in exposure to potentially toxic therapy that could be avoided with earlier pathogen identification. An evaluation of epidemiological factors (Table 6), history of prior infections including cardiovascular infections, expo- sure to antimicrobials, clinical course, severity, and extracar- diac sites of infection of the current infection should be done in all IE cases. 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. 