Pathogenesis of Infective Endocarditis
Infective endocarditis develops through a sequential process requiring damaged endothelium, transient bacteremia, bacterial adherence via specific adhesins, and proliferation within vegetations composed of platelets and fibrin. 1
The Sequential Pathogenic Process
Step 1: Endothelial Damage and NBTE Formation
Turbulent blood flow from abnormal cardiac structures—particularly stenotic or regurgitant valves—traumatizes the endothelium, creating high-velocity jets that denude the endothelial surface. 1 This initial injury is the critical prerequisite for infection, as intact endothelium resists bacterial colonization. 1
Once damaged, the host response triggers platelet and fibrin deposition at the wound site, forming nonbacterial thrombotic endocarditis (NBTE). 1 This sterile vegetation serves as an excellent nidus for subsequent bacterial colonization during bacteremia. 1
Step 2: Transient Bacteremia
Activities of daily living—including chewing food, toothbrushing, and flossing—account for most bloodstream seeding of NBTE sites, occurring far more frequently than medical procedures. 1, 2 Tooth brushing alone causes bacteremia in 20-68% of instances. 2
The frequency and intensity of bacteremia relate to the magnitude of tissue trauma, density of microbial flora, and degree of inflammation at the traumatized site. 1 Poor oral hygiene with gingivitis and periodontitis significantly increases bacteremia risk during daily oral activities. 2
Step 3: Bacterial Adherence via Adhesins
Gram-positive cocci—the predominant IE pathogens—express multiple adhesins that serve as critical virulence factors by enhancing attachment to host cell substrates and extracellular matrix proteins. 1
Staphylococcal Adhesins (MSCRAMMs)
Staphylococcus aureus expresses microbial surface components recognizing adhesive matrix molecules (MSCRAMMs), which mediate attachment to collagen, thrombospondin, laminin, fibrinogen, and fibronectin. 1 These interactions are important not only for initial adherence but also for bacterial persistence and engulfment by host cells including endothelial cells and platelets. 1
Streptococcal Adhesins
Viridans group streptococci contain FimA protein (lipoprotein receptor antigen I) that serves as a major adhesin to the fibrin-platelet matrix of NBTE. 1 Pilus structures, such as Pil1 in Streptococcus gallolyticus, mediate attachment to collagen and biofilm formation—experimental models showed 82% infection rate with Pil1+ strains versus 36% with Pil1− strains (P=0.03). 1
Enterococcal Adhesins
Enterococcus species express multiple bacterial surface structures critical for adherence and persistence in endocarditis pathogenesis. 1
Step 4: Proliferation Within Vegetations
Microorganisms adherent to the vegetation stimulate further deposition of fibrin and platelets on their surface, creating a secluded focus where bacteria multiply to reach maximal densities of 10^8 to 10^11 colony-forming units per gram of vegetation. 1
In left-sided vegetations, bacteria proliferate rapidly and apparently uninhibited by host defenses. 1 More than 90% of microorganisms in mature vegetations are metabolically inactive rather than in active growth phase, contributing to antibiotic resistance. 1
Right-sided vegetations have lower bacterial densities, possibly due to active host defense mechanisms including polymorphonuclear activity and platelet-derived antibacterial proteins. 1
Alternative Pathogenic Mechanisms
Right-Sided Endocarditis from Indwelling Devices
Intravenous catheters, illicit intravenous drug use, or cardiovascular implantable electronic device leads cause right-sided endocarditis through two mechanisms: direct endothelial damage from the foreign body rubbing against the surface, and indirect damage when devices interfere with tricuspid valve function causing regurgitant jets. 1
Bacteremia occurs via entry at the skin site of percutaneous catheters or leads, through the catheter lumen, or in contaminated infusate. 1
Direct Device Infection
IE can occur as direct infection of an indwelling device at the time of placement into a cardiac locus (valves, leads, other devices), representing a surgical site infection. 1 These infections can occur despite antibiotic prophylaxis administration at device placement. 1
Prosthetic Valve Endocarditis and Biofilm
Biofilm formation is operative in prosthetic valve infection, creating a unique environment where antimicrobial agents and immune cells have difficulty penetrating, and metabolic changes of organisms greatly reduce antibiotic killing ability. 1 This mechanism increases infection relapse risk at prosthetic valve sites. 1
Key Bacterial Characteristics for IE Pathogenesis
Classical IE pathogens (S. aureus, Streptococcus species, and Enterococcus species) share the ability to adhere to damaged valves, trigger local procoagulant activity, and nurture infected vegetations where they can survive. 1
These organisms are equipped with surface determinants that mediate adherence to host matrix molecules (fibrinogen, fibronectin, platelet proteins) and trigger platelet activation. 1 Following colonization, adherent bacteria must escape host defenses—IE-causing bacteria are consistently resistant to platelet microbicidal protein (PMP)-induced killing, whereas similar bacteria from other infection types are susceptible. 1
Clinical Pitfalls and Caveats
The "big 3" pathogens—viridans group streptococci, S. aureus, and Enterococcus species—account for the large majority of IE cases and have been the primary focus of pathogenesis studies. 1 However, intracellular bacteria such as Coxiella burnetii, Bartonella, Chlamydia, and Tropheryma whipplei can cause IE with constantly negative blood cultures, accounting for up to 5% of all cases. 1
The magnitude of bacteremia and the pathogen's ability to attach to damaged valves are both important—even low-grade, short-duration spontaneous bacteremia from daily activities can cause IE due to high cumulative incidence, explaining why most IE cases are unrelated to invasive procedures. 1