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. True culture-negative IE can be caused by uncommon or rare pathogens that do not grow in routinely used blood The organisms that have garnered the most attention are Bartonella species, Chlamydia species, C burnetii, Brucella species, Legionella species, Tropheryma whipplei, Candida, and non-Candida fungi (particularly Aspergillus species). The last 2 groups of organisms are espe- cially relevant to PV recipients. With the use of special diag- nostic techniques, Bartonella species, C burnetii, and Brucella species have been identified in the majority of cases of cul- ture-negative IE caused by fastidious organisms. Additional laboratory screening is required to identify the causes of In some cases, serological and special blood culture techniques can be helpful. In other cases, tissue (usually valve) screening is required. Diagnostic methods for resected valve tissue include microbiological, histopathologi- cal, and molecular techniques, the last of which includes gene amplification with PCR methods. Unfortunately, most clinical laboratories do not perform molecular screening, and speci- mens must be sent to reference laboratories. The most prevalent pathogen among these uncommon causes of culture-negative IE in this group has varied glob- ally according to published data.236 Incidence data from population-based surveys for IE caused by these organisms are lacking in the United States. 