Infective Endocarditis - Factors and Causes


                    The characteristic pathology of infective endocarditis is the vegetation, a lesion that is the result of successive deposition of platelets and fibrin on the endothelial surface of the heart. Infection is the most common cause, and the usual pathogen is one of a variety of bacterial species, although fungi may be the cause in some patients. Microscopic colonies of the pathogen are buried beneath the surface of fibrin, usually in the absence of an inflammatory reaction. Most commonly the heart valve is the site of the vegetation, but in certain instances vegetations may occur on other parts of the endocardium. Involvement of extracardiac endothelial sites, which can produce an illness clinically similar to endocarditis, is properly termed endarteritis.


Non-Cardiac Risk Factors

              In population-based studies, the age and sex-adjusted incidence of infective endocarditis is about 5 per 100,000 person-years. However the incidence rate of infective endocarditis may be influenced by the prevalence of risk factors in the local population. For example, the incidence rate of infective endocarditis was found to be approximately 12 per 100,000 person-years the Philadelphia region, the excess incidence attributed almost entirely to the increased frequency of intravenous drug use in this region, where infective endocarditis in intravenous drug users represented 46% of all cases. Other significant non-cardiac risk factors risk factors (Table 1) for infective endocarditis are: 1) advancing age (in part due to the increased prevalence of predisposing cardiac lesions, e.g., prior infective endocarditis, degenerative cardiac lesions and prosthetic cardiac valves; and 2) male gender (in part due to the increased prevalence of certain cardiac lesions, such as bicuspid aortic valve, in males). In the pre-antibiotic era the median age of patients with infective endocarditis was between 30-40 years; now over 50% of patients are older than 50 years of age, although intravenous drug users with infective endocarditis tend to be younger. The incidence rate ratio for those 65 year of age or older is almost 9 times that of those under 65 years, and for males about 1.5 to 2.5 times that of females. Lower risk for infective endocarditis caused by oral flora has been found among edentulous cases than patients who had teeth but did not floss; also reduced risk was found among those who floss daily, which suggests that poor dental hygiene is a risk factor, especially among those with cardiac risk factors; but prior dental procedures have not been found to be risk factor for infective endocarditis caused by dental flora. Other non-cardiac risk factors for infective endocarditis that have been reported include uremia (probably related to dialysis catheter sepsis) and diabetes mellitus, and surgery and skin infections and “infectious episodes”.

Table 1: Risk Factors for Infective Endocarditis



IV drug abuse


Advancing age

Recent dental surgery or other invasive


Nosocomial bacteremia

Permanent venous access lines

Surgically constructed pulmonary shunts

Degenerative valvular lesions

Congenital heart disease

Prosthetic valves

Mitral valve prolapse with insufficiency

Rheumatic heart disease

Previous infective endocarditis

Hypertrophic cardiomyopathy


Cardiac Risk Factors

              Predisposing cardiac lesions are found in about 3/4 of patients with infective endocarditis. Patients without a predisposing cardiac risk factor more likely have nosocomial infective endocarditis, have infective endocarditis caused by more virulent organisms, such as S. aureus, or are intravenous drug users.

               Conditions that have been identified as cardiac risk factors (Table 1) in patients with infective endocarditis include various degenerative valvular lesions, congenital heart disease, bicuspid aortic valves, mitral valve prolapse with mitral insufficiency or thickened mitral leaflets, rheumatic valvular heart disease, prosthetic cardiac valves, and previous infective endocarditis. However, inferring risk from the relative frequency of various lesions in case series of infective endocarditis can be problematic, since those lesions found more frequently in the general population are also most likely to be common in case series of patients with infective endocarditis. For example, although rheumatic valvular heart disease is still common both in the general population and the most common cardiac risk for infective endocarditis in developing countries, the frequency of rheumatic valvular heart disease in developed countries both in the general population and in patients with infective endocarditis has markedly declined. Mitral valve prolapse is now the most frequent cardiac lesions found in patients with infective endocarditis in developed countries, which reflects the high prevalence of mitral valve prolapse in the general population, estimated to be between 2-21%.

               The true degree of risk for infective endocarditis of a specific cardiac lesion can be determined only by measuring the incidence rate of infective endocarditis among those who have a particular cardiac abnormality : The highest incidence rates (over 2000/100,000 patient years) occur in patients who undergo valve replacement of an infected prosthetic cardiac valve. Patients who either undergo prosthetic valve replacement for native-valve endocarditis, have had previous native-valve endocarditis, or have a prosthetic cardiac valve in place also have high incidence rates (300-740/100,000 patient-years). For prosthetic valve endocarditis, risk is greatest during the first few post-operative months as a result of intra-operative and peri-operative contamination, and probably does not vary by site of placement or type of prosthetic valve material. Similar incidence rates are found in patients with valvular rheumatic valvular heart disease.

               Surgically uncorrected congenital heart disease at risk for endocarditis include patent ductus arteriosus, ventricular septal defects, tetralogy of Fallot, and coarctation of the aorta. Surgical repair can eliminate the risk of infective endocarditis 6 months after surgery if no residual shunt or valvular lesion remains. However, corrective surgery is not always protective: prosthetic material and devices remain at risk for the first 6 months after placement because of incomplete endothelialization; also persistent risk remains for palliative shunts and conduits and sites of turbulent blood flow that remain despite placement of prosthetic material in an attempt to surgically correct congenital heart disease.

               Transvenous permanent pacemakers have been reported to have an incidence rate for infective endocarditis of about 50/100,000 patient-years.

               Similarly, the incidence rate for mitral valve prolapse with murmur is also about 50/100,000 patient-years (only about 10-fold higher than that of the general population), but mitral valve prolapse may be especially a problem in elderly males with mitral valve thickening. However, valvular rheumatic valvular heart disease, congenital heart disease and mitral valve prolapse represent groups of patients with diverse types and severity valvular abnormalities that have different levels of risk for acquisition of infective endocarditis, which complicates an accurate assessment of the true risk of acquisition of infective endocarditis in individual patients with a specific underlying cardiac condition.

               Patients with cardiac lesions at no greater risk than the general population include those with secundum atrial septal defects, atherosclerosis, previous coronary artery bypass graft surgery, mitral valve prolapse without murmur, and previous rheumatic valvular heart disease without valvular dysfunction.



              The following sequence of events is thought to result in infective endocarditis: The normal endothelium is non-thrombogenic; but when damaged the endothelium is a potent inducer of blood coagulation. Turbulent blood flow produced by certain types of congenital or acquired heart disease, e.g., flow from a high to low pressure chamber or across a narrowed orifice, traumatizes the downstream endothelium and predisposes for deposition of platelets and fibrin, the so-called “nonbacterial thrombotic endocarditis” lesion (NBTE), on the surface of the traumatized endothelium. Subsequent episodes of bacteremia with species capable of survival in the blood stream, adherence to the nonbacterial thrombotic endocarditis, and proliferation at this site can then result in infective endocarditis.

               The adherence of microorganisms in the blood stream to nonbacterial thrombotic endocarditis involves a complex interaction between multiple types of microbial adhesions, matrix molecules, and platelets on the surface of the damaged endothelium. Dextran and fimA serve as two of the adhesins for oral streptococci. The avidity of adherence in vitro to a fibrin-platelet matrix, as well as the ability to produce experimental infective endocarditis in rabbits with traumatized cardiac valves has been found to be related to the amount of dextran produced by these streptococci. Dextran-producing streptococci are also more likely to be recovered from blood of patients with viridans streptococcal infective endocarditis than are non-dextran producing strains. Viridans streptococci also contain fimA protein, a major adhesion to the fibrin/platelet matrix of the nonbacterial thrombotic endocarditis. In contrast, S. aureus can adhere directly to fibronectin that covers the surface of uninjured endothelial cells; uninjured endothelial cells in tissue culture can phagocytose adherent S. aureus, which multiply intracellularly, kill the endothelial cell, and thereby cause fibrin-platelet deposition; this may explain the propensity of S. aureus, unlike oral streptococci, to initiate infective endocarditis on normal heart valves.

               Further deposition of platelets and fibrin occurs on the surface of adherent bacteria. Bacteremia is sustained by subsequent fragmentation of the vegetation, which exposes the underlying microbial colonies. Scanning electron microscopy of vegetations, however, rarely shows bacteria on the luminal surface of the vegetation, as the exposed bacteria are rapidly covered by deposition of fibrin and platelets. The vegetation enlarges as circulating bacteria redeposit on the surface of the vegetation, which in turn stimulates further deposition of fibrin and platelets. The resultant vegetation then is composed of successive layers of fibrin and clusters of buried bacteria, with rare red blood cells and leukocytes. Sustained bacteremia with a constant number of bacteria per ml of blood is characteristic of infective endocarditis, and results from an equilibrium between the rate of release of bacteria from the vegetation and clearance of circulating bacteria by the reticuloendothelial system in liver, spleen, and bone marrow. On the left side of the heart, microorganisms become buried in the depths of the vegetation and secluded from host defenses, such as leukocytes and humoral factors; there the microorganisms, multiply initially as rapidly as do bacteria in broth cultures to reach maximal microbial densities of 108-11 colony forming units per gram of vegetation within a short time. Right-sided vegetations have lower bacterial densities, which may be the consequence of host defense mechanisms, such as polymorphonuclear leukocytic activity, that are active at this site. In the mature vegetations of streptococcal infective endocarditis, over 90% of the microorganisms are metabolically inactive and non-growing. Microorganisms in this phase are least responsive to the bactericidal effects of antibiotics that inhibit bacterial cell wall synthesis, such as the beta-lactams, as a consequence of lack of expression of penicillin binding proteins, the target of beta-lactam antibiotics.

               When healing occurs, either spontaneously, e.g., right-sided endocarditis, or under the influence of antibiotic therapy, the surface layer of fibrin is invaded by fibroblasts and the rough surface of the vegetation is progressively covered by smooth endothelium, which reduces the risk of reseeding of the vegetation.



                Compression of infected foci release large numbers of bacteria into the blood stream. Bacteremia can also occur spontaneously in uninfected individuals, perhaps related to unsuspected minor infected foci such as periodontitis, or following trauma to uninfected skin or mucosal surfaces that are populated by a dense endogenous micro flora. These mucosal sites include the gingival crevice, oropharynx, terminal ileum, colon, distal urethra, and vagina. The intensity of the resulting bacteremia is related directly to the magnitude of the trauma, the density of the microbial flora, and the presence of inflammation or infection at the site. For example, spontaneous and procedure-induced bacteremia occurs more frequently in the presence of periodontal infections, which is a likely consequence of hyperemia and a more abundant microflora in the infected periodontal tissues surrounding the teeth.

               Trauma to skin or mucosal site releases many different microbial species into the blood stream, the types of which depend on the unique endogenous microflora that colonizes the particular traumatized site. However, only a few of the many bacterial species that thus gain entry into the bloodstream, namely viridans streptococci, staphylococci, and enterococci, are commonly capable of causing infective endocarditis; these microorganisms account for over 80 % of cases of infective endocarditis. Bacteremia caused by viridans streptococci and other oral streptococci occurs in 18-85% of dental extractions and periodontal procedures. Bacteremia caused by oral streptococci also follows esophageal dilatation and sclerotherapy for esophageal varices. Enterococcal bacteremia occurs less frequently following genitourinary and gastrointestinal invasive procedures such as prostatic surgery, endoscopic retrograde cholaniopancreatography for biliary obstruction, biliary tract surgery, surgery on lower intestinal mucosa, and urethral dilatation.

               A history of such procedures within the preceding 2 months has been found in 25% of patients with viridans streptococcal infective endocarditis and 40% of patients with enterococcal infective endocarditis. However, it is now believed that the period between the inciting bacteremia and the clinical onset of infective endocarditis is more likely to be less than 2 weeks. Indeed, these medical procedures (particularly dental procedures) mentioned above are common in the general population, which makes assessment of the risk of the procedure for production of infective endocarditis difficult; the mere temporal association of a particularly common procedure, such as a dental procedure, with a rare disease like infective endocarditis does not necessarily infer causation. Minor mucosal trauma as routine as brushing teeth, flossing, chewing hard candy or other everyday experiences commonly causes asymptomatic bacteremia that is characterized by small numbers (usually <10 colony forming units/ml of blood), and short duration (15-30 minutes). Although transient bacteremia is a common, everyday event, and each event may be associated with only a very small risk for infective endocarditis, the cumulative risk of these transient episodes of low grade bacteremia may be sufficient to account in large part for the 75% of patients with viridans streptococcal infective endocarditis or 60% of patients with enterococcal infective endocarditis who fail to recall a medical or dental procedure that preceded the onset of their endocarditis. Even transient bacteremia from everyday events may be additionally responsible for some cases of infective endocarditis in patients who give a history of a recent preceding procedure. Two recent studies of patients with infective endocarditis that used age- and sex-matched controls failed to demonstrate a relationship between recent dental procedures and infective endocarditis due to oral microorganisms.



              Viridans streptococci (i.e., alpha-hemolytic streptococci), such as Streptococcus sanguis, S. mitis, S. mutans, S. salivarius, and S. bovis (a non-enterococcal Group D streptococcus), are responsible for 35-40% of cases. In addition, Abiotrophia and Granulicatella species, which are viridans streptococci (previously referred to as nutritionally variant streptococci or NVS) that require pyridoxal HCl or thiol-compounds for growth and satellite around staphylococcus when cultured on blood agar plates, cause about 5% of cases of infective endocarditis. Infective endocarditis caused by NVS and Gemella morbellorum is associated with greater mortality and morbidity (clinical and bacteriologic relapse, CHF, prosthetic valve placement, and embolization). S. bovis infective endocarditis occurs more frequently in the elderly and is associated with preexisting colonic lesions (e.g., colonic malignancies). Enterococcus species are responsible for up to 10% of cases. Occasional cases of infective endocarditis are due to beta-hemolytic streptococci or rarely Streptococcus pneumoniae. Infective endocarditis caused by the Streptococcus anginosus group (also known as S. milleri group that includes S. anginosus, intermedius and constellatus) is frequently complicated by destructive valvular lesions and purulent metastatic foci similar to that caused by S. aureus. S. pneumoniae, S. pyogenes, and Groups B, C, and G streptococci are relatively uncommon causes of infective endocarditis, but have also been associated with greater morbidity and mortality.

               In recent series, staphylococci have become the most common cause of infective endocarditis, perhaps due to the increasing frequency of nosocomial acquisition and prevalence of prosthetic valves and intravenous drug users; however infective endocarditis in the subgroup of patients who are adult non-intravenous drug users and acquire infective endocarditis in the community is reported to be still most commonly due to viridans streptococci. Coagulase-negative staphylococci, usually S. epidermidis, occasionally cause NVE in patients with underlying valvular abnormalities and commonly cause of early-onset PVE; in the case of PVE, they are almost always resistant to methicillin or oxacillin, which is consistent with their hospital-acquisition. S. aureus also causes PVE and nosocomial infective endocarditis, and infective endocarditis in intravenous drug users. Staphylococcus lugdunensis, a coagulase-negative staphylococcus, can cause a highly destructive NVE, similar to infective endocarditis caused by S. aureus.

               The so-called HACEK group of fastidious gram-negative bacilli (GNB) (Haemophilus aphrophilus, Actinobacillus actinomycetemocomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae) cause up to 5% of cases. GNB other than the HACEK group rarely cause infective endocarditis. However, GNB, including Enterobacteriaceae and Pseudomonas aeruginosa may cause infective endocarditis in intravenous drug users and in patients with a prosthetic cardiac valve. Strains of GNB that cause infective endocarditis exhibit resistance to complement-mediated lysis by normal human sera that perhaps allows their survival in the blood stream and on the endothelial surface of the cardiac valve.

              Most cases of fungal endocarditis also occur in intravenous drug users or in patients with a prosthetic cardiac valve; such patients often have central vascular catheters, and may be immunocompromised. The most common fungal species is Candida albicans, followed by Candida parapsilosis. Polymicrobial endocarditis is unusual, but is seen in intravenous drug users. Salmonella species are common causes of endarteritis on an atherosclerotic abdominal aortic plaque. Blood cultures may be negative in up to one third of patients with infective endocarditis; although in one half of these patients the negative blood cultures can be attributed to prior antibiotic therapy that has suppressed the infection. Other causes of culture-negative infective endocarditis (Table 2 and 3) include fastidious organisms such as Coxiella burnetii, Bartonella quintana, Tropheryma whipplei, and Brucella species. The frequency of culture-negative endocarditis and its etiologic agents is likely to be strongly correlated to epidemiology of the microbial agent in a particular geographic region, e.g., Brucella infective endocarditis is related to exposure to contaminated milk, cheese or meat and C. burnetii infective endocarditis to infectious aerosols or milk from infected farm animals in certain regions of the world. Bartonella quintana infective endocarditis is seen in the homeless, body lice-infested, and alcoholic population.

Table 2: Considerations for Testing in Culture Negative IE

Special Culture Requirements


Other Testing

Histoplasma capsulatum (fungal cultures)

H. capsulatum

Tropheryma whippelii (PCR of tissue)

Aspergillus (fungal cultures)

Coxiella burnetii


Blastomycosis dermatidis (fungal culture)

Chlamydia psittaci


Bartonella species (prolonged incubation)

Legionella species


Erysipelothrix sp. (fungal cultures)

Brucella species



Bartonella quintana or henselae



Table 3. Epidemiological Clues in Etiological Diagnosis of Culture-Negative Endocarditis  

Epidemiological Feature

Common Microorganism(s)


Injection drug use


S aureus, including community-acquired oxacillin-resistant strains Coagulase-negative staphylococci ß-Hemolytic streptococci Fungi Aerobic Gram-negative bacilli, including Pseudomonas aeruginosa Polymicrobial

Indwelling cardiovascular medical devices

S aureus Coagulase-negative staphylococci Fungi Aerobic Gram-negative bacilli Corynebacterium sp

Genitourinary disorders, infection, manipulation, including pregnancy, delivery, and abortion

Enterococcus sp Group B streptococci (S agalactiae) Listeria monocytogenes Aerobic Gram-negative bacilli Neisseria gonorrhoeae

Chronic skin disorders, including recurrent infections

S aureus ß-Hemolytic streptococci

Poor dental health, dental procedures

Viridans group streptococci "Nutritionally variant streptococci" Abiotrophia defectiva Granulicatella sp Gemella sp HACEK organisms

Alcoholism, cirrhosis

Bartonella sp Aeromonas sp Listeria sp S pneumoniae ß-Hemolytic streptococci

Burn patients

S aureus Aerobic Gram-negative bacilli, including P aeruginosa Fungi

Diabetes mellitus

S aureus ß-Hemolytic streptococci S pneumoniae

Early (1 y) prosthetic valve placement

Coagulase-negative staphylococci S aureus Aerobic Gram-negative bacilli Fungi Corynebacterium sp Legionella sp

Late (>1 y) prosthetic valve placement

Coagulase-negative staphylococci S aureus Viridans group streptococci Enterococcus species Fungi Corynebacterium sp

Dog–cat exposure

Bartonella sp Pasteurella sp Capnocytophaga sp

Contact with contaminated milk or infected farm animals

Brucella sp Coxiella burnetii Erysipelothrix sp


Homeless, body lice

Bartonella sp


Salmonella sp S pneumoniae S aureus

Pneumonia, meningitis

S pneumoniae

Solid organ transplant

S aureus Aspergillus fumigatus Enterococcus sp Candida sp

Gastrointestinal lesions

S bovis Enterococcus sp Clostridium septicum