Pathogenesis Early histopathologic studies in humans and decades-long investigations that have included an animal model of experi- mental endocarditis have confirmed 2 critical histopathologic findings: (1) Damaged or denuded endothelium is necessary for initial pathogen colonization of a cardiac nidus; and (2) Gram-positive cocci, the predominant pathogens in both native and prosthetic value infections, express multiple adhesins that serve as virulence factors through their ability to enhance host cell/substrate attachments that are important in both the initia- tion and propagation of endocardial infection. (Adhesins are discussed further in a separate section.) Denuded cardiac endothelium can occur when there is tur- bulence caused by abnormal cardiac structures, in particular stenotic or regurgitant valves, that results in high-velocity jets of blood. Once the endothelium is damaged, the host response includes platelet and fibrin deposition, leading to so-called nonbacterial thrombotic endocarditis (NBTE), at the wound site. NBTE serves as an excellent nidus for subsequent bac- terial or fungal colonization in a patient with bacteremia or fungemia. The prevailing notion is that activities of daily living, such as chewing food, toothbrushing, and flossing, account for most bloodstream seeding of an NBTE site. There are additional mechanisms involved in endocardi- tis pathogenesis. Right-sided endocarditis can occur when there are intravenous catheters, illicit intravenous drug use, or cardiovascular implantable electronic device leads that dwell in the right side of the heart. Damage to the endothe- lium occurs by 2 mechanisms. One involves direct damage produced by the foreign body rubbing directly against the endothelial surface. The other is via an indirect effect, such as when a foreign device interferes with normal tri- cuspid valve function and causes regurgitant jets of blood. Bacteremia may be caused by entry of organisms at the skin site of percutaneous catheters or leads, via the catheter lumen, or in contaminated infusate. 