Definition
Infective endocarditis (IE) is a microbial infection of the endothelial surface of the heart or heart valves that most often occurs in proximity to congenital or acquired cardiac defects. A clinically and pathologically similar infection that may occur in the endothelial lining of an artery, usually adjacent to a vascular defect (e.g., coarctation of the aorta) or a prosthetic device (e.g., arteriovenous [AV] shunt), is called infective endarteritis. Although bacteria most often cause these diseases, fungi and other microorganisms also may cause such infection; thus, the designation infective is used in keeping with this multimicrobial origin. The term bacterial endocarditis (BE) is in common use, reflecting the fact that most cases of IE are caused by bacteria; however, IE has become the preferred nomenclature and is therefore used in this chapter.
Previously, IE was classified as acute or subacute to reflect the rapidity of onset and duration of symptoms before diagnosis; however, this classification was found to be somewhat arbitrary. It has now largely been replaced by a classification that is based on the causative microorganism (e.g., streptococcal endocarditis, staphylococcal endocarditis, candidal endocarditis) and the type of valve that is infected (e.g., native valve endocarditis [NVE], prosthetic valve endocarditis [PVE]). IE also is classified according to the source of infection—that is, whether it is community acquired or hospital acquired—or whether the patient is an intravenous drug user (IVDU).
Infective endocarditis is a disease of significant morbidity and mortality that is difficult to treat; therefore, emphasis has long been directed toward prevention. Historically, various dental procedures have been reported to be a significant cause of IE because bacterial species found in the mouth frequently have been found to be the causative agent. Furthermore, whenever a patient is given a diagnosis of IE caused by oral flora, dental procedures performed at any point within the previous several months typically have been blamed for the infection. As a result, antibiotics have been administered before certain invasive dental procedures in an attempt to prevent infection. Of note, however, the effectiveness of such prophylaxis in humans has never been substantiated, and evidence remains lacking on the validity of this practice.
Complications
Complications may include heart failure, embolization, stroke, myocardial infarction (MI), peripheral abscesses, failure of organs: septic shock, invasive infection, prosthetic valve dehiscence, heart block, and mycotic aneurysm, and death.
Epidemiology
Infective endocarditis is a serious, life-threatening disease that affects more than 15,000 patients each year in the United States; the overall mortality rate approaches 40%, which is worse than that for many cancers. IE is a relatively rare disease that occurs most frequently in middle-aged and elderly persons and is more common in men than in women. The incidence rate varies with the population studied. In the general population, the incidence has remained relatively stable over the past 3 decades, ranging between 0.16 and 5.4 cases per 100,000 person-years. A somewhat higher incidence has been reported in several studies. A community study in Minnesota reported an incidence of 5 to 7 cases per 100,000 person-years, and a study in the metropolitan Philadelphia area reported an overall incidence of 11.6 per 100,000 person-years. In the Philadelphia study, the rate of community-acquired IE was found to be 4.45 per 100,000 person-years, which is comparable to that reported in previous studies; however, the higher overall incidence was attributed to a high prevalence of IVDUs in the population studied.
When populations at enhanced risk are considered, the incidence rate is increased. One study reported the lifetime risk of acquiring IE with various conditions. In that study, the risk ranged from 5 per 100,000 person-years in the general population to 2160 per 100,000 person-years in patients who underwent surgical replacement of an infected prosthetic valve ( Table 2.1 ) . Previously, the most common underlying condition predisposing to endocarditis was rheumatic heart disease (RHD) ( Fig. 2.1 ); however, in developed countries, the frequency of RHD has markedly declined over the past several decades, and this disorder has become a much less significant factor. Mitral valve prolapse (MVP) ( Fig. 2.2 ), which accounts for 25% to 30% of adult cases of NVE, is now the most common underlying condition among patients who acquire IE. Aortic valve disease (either stenosis or regurgitation or both) ( Fig. 2.3 ) appears to account for about 30% of cases. Congenital heart disease (e.g., patent ductus arteriosus, ventricular septal defect, bicuspid aortic valve) ( Fig. 2.4 ) is the substrate for IE in 10% to 20% of younger adults and in 8% of older adults. Tetralogy of Fallot, the most common type of congenital cyanotic heart disease, generally requiring extensive reconstructive surgery for survival ( Fig. 2.5 ), accounts for fewer than 2% of cases. The incidence of PVE ( Fig. 2.6 ) is increasing, and this entity accounts for about one third of all cases of IE. Of note, in many patients with IE, a predisposing cardiac condition cannot be identified ( Table 2.2 ).
| Predisposing Condition or Factor | No. of Patients/100,000 Patient-Years |
|---|---|
| General population | 5 |
| MVP without audible cardiac murmur | 4.6 |
| MVP with audible murmur of mitral regurgitation | 52 |
| Rheumatic heart disease | 380–440 |
| Mechanical or bioprosthetic valve | 308–383 |
| Cardiac valve replacement surgery for native valve | 630 |
| Previous endocarditis | 740 |
| Prosthetic valve replacement in patients with PVE | 2160 |
| Underlying Condition | Frequency of IE (%) |
|---|---|
| Mitral valve prolapse | 25–30 |
| Aortic valve disease | 12–30 |
| Congenital heart disease | 10–20 |
| Prosthetic valve | 10–30 |
| Intravenous drug abuse | 5–20 |
| No identifiable condition | 25–47 |
The incidence of IE among IVDUs ranges from 150 to 2000 per 100,000 person-years. Conversely, among patients with IE, the concomitant rate of intravenous (IV) drug abuse ranges from 5% to 20%. Several unique features characterize the IE in IVDUs. In most cases, the cardiac valves are normal before infection. Such infection usually affects the valves of the right side of the heart (tricuspid), and Staphylococcus aureus is the most common pathogen. Thus, because of these unique characteristics, IE in IVDUs historically has not been linked to dental treatment.
Complications
Complications may include heart failure, embolization, stroke, myocardial infarction (MI), peripheral abscesses, failure of organs: septic shock, invasive infection, prosthetic valve dehiscence, heart block, and mycotic aneurysm, and death.
Epidemiology
Infective endocarditis is a serious, life-threatening disease that affects more than 15,000 patients each year in the United States; the overall mortality rate approaches 40%, which is worse than that for many cancers. IE is a relatively rare disease that occurs most frequently in middle-aged and elderly persons and is more common in men than in women. The incidence rate varies with the population studied. In the general population, the incidence has remained relatively stable over the past 3 decades, ranging between 0.16 and 5.4 cases per 100,000 person-years. A somewhat higher incidence has been reported in several studies. A community study in Minnesota reported an incidence of 5 to 7 cases per 100,000 person-years, and a study in the metropolitan Philadelphia area reported an overall incidence of 11.6 per 100,000 person-years. In the Philadelphia study, the rate of community-acquired IE was found to be 4.45 per 100,000 person-years, which is comparable to that reported in previous studies; however, the higher overall incidence was attributed to a high prevalence of IVDUs in the population studied.
When populations at enhanced risk are considered, the incidence rate is increased. One study reported the lifetime risk of acquiring IE with various conditions. In that study, the risk ranged from 5 per 100,000 person-years in the general population to 2160 per 100,000 person-years in patients who underwent surgical replacement of an infected prosthetic valve ( Table 2.1 ) . Previously, the most common underlying condition predisposing to endocarditis was rheumatic heart disease (RHD) ( Fig. 2.1 ); however, in developed countries, the frequency of RHD has markedly declined over the past several decades, and this disorder has become a much less significant factor. Mitral valve prolapse (MVP) ( Fig. 2.2 ), which accounts for 25% to 30% of adult cases of NVE, is now the most common underlying condition among patients who acquire IE. Aortic valve disease (either stenosis or regurgitation or both) ( Fig. 2.3 ) appears to account for about 30% of cases. Congenital heart disease (e.g., patent ductus arteriosus, ventricular septal defect, bicuspid aortic valve) ( Fig. 2.4 ) is the substrate for IE in 10% to 20% of younger adults and in 8% of older adults. Tetralogy of Fallot, the most common type of congenital cyanotic heart disease, generally requiring extensive reconstructive surgery for survival ( Fig. 2.5 ), accounts for fewer than 2% of cases. The incidence of PVE ( Fig. 2.6 ) is increasing, and this entity accounts for about one third of all cases of IE. Of note, in many patients with IE, a predisposing cardiac condition cannot be identified ( Table 2.2 ).
| Predisposing Condition or Factor | No. of Patients/100,000 Patient-Years |
|---|---|
| General population | 5 |
| MVP without audible cardiac murmur | 4.6 |
| MVP with audible murmur of mitral regurgitation | 52 |
| Rheumatic heart disease | 380–440 |
| Mechanical or bioprosthetic valve | 308–383 |
| Cardiac valve replacement surgery for native valve | 630 |
| Previous endocarditis | 740 |
| Prosthetic valve replacement in patients with PVE | 2160 |
| Underlying Condition | Frequency of IE (%) |
|---|---|
| Mitral valve prolapse | 25–30 |
| Aortic valve disease | 12–30 |
| Congenital heart disease | 10–20 |
| Prosthetic valve | 10–30 |
| Intravenous drug abuse | 5–20 |
| No identifiable condition | 25–47 |
The incidence of IE among IVDUs ranges from 150 to 2000 per 100,000 person-years. Conversely, among patients with IE, the concomitant rate of intravenous (IV) drug abuse ranges from 5% to 20%. Several unique features characterize the IE in IVDUs. In most cases, the cardiac valves are normal before infection. Such infection usually affects the valves of the right side of the heart (tricuspid), and Staphylococcus aureus is the most common pathogen. Thus, because of these unique characteristics, IE in IVDUs historically has not been linked to dental treatment.
Etiology
About 90% of community-acquired cases of native valve IE are caused by streptococci, staphylococci, or enterococci, with streptococci being the most common causative organisms. In IE associated with IV drug abuse or secondary to health care contact, staphylococci are the most common pathogen identified. Overall, streptococci continue to be the most common cause of IE, but staphylococci have been gaining increasing importance. Viridans streptococci (α-hemolytic streptococci), constituents of the normal oral flora and gastrointestinal (GI) tract, remain the most common cause of community-acquired NVE, without regard for IV drug abuse, and they cause 30% to 65% of cases of IE. The species that most commonly cause endocarditis are Streptococcus sanguis, Streptococcus oralis (mitis), Streptococcus salivarius, Streptococcus mutans, and Gemella morbillorum (formerly called Streptococcus morbillorum ). Group D streptococci, which include Streptococcus bovis and the enterococci ( Enterococcus faecalis ), are normal inhabitants of the GI tract and account for 5% to 18% of cases of IE. Streptococcus pneumoniae has decreased in prevalence and now accounts for only 1% to 3% of cases of IE. Group A β-hemolytic streptococci rarely cause IE.
Staphylococci are the cause of at least 30% to 40% of cases of IE; of these, 80% to 90% are caused by coagulase-positive S. aureus . S. aureus , the cause of most cases of acute IE, is the most common pathogen in IE associated with IV drug abuse. It also is the most common pathogen in nonvalvular cardiovascular device infections. Of note, S. aureus is not a normal constituent of the oral flora. In PVE, staphylococci are the most common pathogens in early and intermediate infections; however, streptococci predominate in late PVE. The proportion of cases of S. aureus –related IE appears to be increasing at community-based and university hospitals. This increase appears to be due in large part to increasing health care contact, such as through surgical procedures or the use of indwelling catheters.
Other microbial agents that less commonly cause IE include the HACEK group ( Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella ), Pseudomonas aeruginosa, Corynebacterium pseudodiphtheriticum, Listeria monocytogenes, Bacteroides fragilis , and fungi.
Pathophysiology and Complications
Although the precise mechanism whereby IE occurs has not been fully elucidated, it is thought to be the result of a series of complex interactions of several factors involving endothelium, bacteria, and the host immune response. The sequence of events leading to infection usually begins with injury or damage to an endothelial surface, most often of a cardiac valve leaflet. Although IE can occur on normal endothelium, most cases begin with a damaged surface, usually in proximity to an anatomic defect or prosthesis. Endothelial damage can result from any of a variety of events, including the following :
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Directed flow from a high-velocity jet onto the endothelium
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Flow from a high- to a low-pressure chamber
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Flow across a narrowed orifice at high velocity
Fibrin and platelets then adhere to the roughened endothelial surface, where they form small clusters or masses, resulting in a condition called nonbacterial thrombotic endocarditis (NBTE) ( Fig. 2.7 ). A similar and frequently indistinguishable condition is found in some patients with systemic lupus erythematosus and is called Libman-Sacks verrucous endocarditis. Initially, these masses are sterile and do not contain microorganisms. With the occurrence of a transient bacteremia, however, bacteria can be seeded into and adhere to the mass. Additional platelets and fibrin are then deposited onto the surface of the mass, which serves to sequester and protect the bacteria, which undergo rapid multiplication within the protection of the vegetative mass ( Fig. 2.8 ). After the vegetative process is established, the metabolic activity and cellular division of the bacteria are diminished, which decreases the effectiveness of antibiotics. Bacteria are slowly and continually released from the vegetations and shed into the bloodstream, resulting in a continuous bacteremia; fragments of the friable vegetations break off and embolize. A variety of host immune responses to bacteria may occur. This sequence of events results in the clinical manifestations of IE.
The clinical outcome of IE depends on several factors, including
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Local destructive effects of intracardiac (valvular) lesions
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Embolization of vegetative fragments to distant sites, resulting in infarction or infection
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Hematogenous seeding of remote sites during continuous bacteremia
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Antibody response to the infecting organism, with subsequent tissue injury caused by deposition of preformed immune complexes or antibody–complement interaction with antigens deposited in tissues
Although combination antibiotic and surgical treatment is effective for many patients, complications are common and serious. The most common complication of IE, and the leading cause of death, is heart failure, which results from severe valvular dysfunction. This pathologic process most commonly begins as a problem with aortic valve involvement followed by mitral and then tricuspid valve infection. Embolization of vegetation fragments often leads to further complications such as stroke. MI can occur as the result of embolism of the coronary arteries, and distal emboli can produce peripheral metastatic abscesses. Pulmonary emboli, usually septic in nature, occur in 66% to 75% of IVDUs who have tricuspid valve endocarditis. Emboli also may involve other systemic organs, including the liver, spleen, and kidney, as well as abdominal mesenteric vessels. The incidence of embolic events is markedly reduced by the prompt initiation of antibiotic therapy. Renal dysfunction also is common and may be due to immune complex glomerulonephritis or infarction.
Clinical Presentation
Signs and Symptoms
The classic findings in IE include fever, heart murmur, and positive blood culture, although the clinical presentation may vary. Of particular significance is that the interval between the presumed initiating bacteremia and the onset of symptoms of IE is estimated to be less than 2 weeks in more than 80% of patients with IE. In many cases of IE that have been purported to be caused by dentally induced bacteremia, the interval between the dental appointment and the diagnosis of IE has been much longer than 2 weeks (sometimes months), so it is very unlikely that the initiating bacteremia was associated with dental treatment.
Fever, the most common sign of IE, occurs in up to 80% to 95% of patients. It may be absent, however, in older adults and in patients with heart failure or renal failure. New or changing heart murmurs, systolic or diastolic, are found in 80% to 85% of patients. Heart murmurs often are not heard initially in patients who are IVDUs but appear later in the course of the disease. This sequence is characteristic of tricuspid valve IE caused by S. aureus . Peripheral manifestations of IE caused by emboli or immunologic responses are less frequently seen since the advent of antibiotics. These include petechiae of the palpebral conjunctiva, the buccal and palatal mucosa, and the extremities ( Fig. 2.9 ), Osler nodes (small, tender, subcutaneous nodules that develop in the pulp of the digits) ( Fig. 2.10 ), Janeway lesions (small, erythematous or hemorrhagic, macular nontender lesions on the palms and soles), splinter hemorrhages in the nail beds ( Fig. 2.11 ), and Roth spots (oval retinal hemorrhages with pale centers) ( Fig. 2.12 ). Other signs include splenomegaly and clubbing of the digits ( Fig. 2.13 ). Sustained bacteremia is typical of IE, and blood culture results are positive in most cases. Although up to 30% of cases of IE initially are found to be “culture negative,” when strict diagnostic criteria are used, only 5% of cases are culture negative. Many patients with negative blood cultures have taken antibiotics before the diagnosis of IE. Three separate sets of blood cultures obtained over a 24-hour period are recommended in the evaluation of a patient for suspected IE.
The diagnosis of IE should be considered for a patient with fever along with one or more of the following cardinal elements of IE: a predisposing cardiac lesion or behavior pattern, bacteremia, embolic phenomena, and evidence of an active endocardial process. The clinical presentation in IE is variable, and other conditions can cause similar signs and symptoms. The Duke criteria were developed and later modified to facilitate the definitive diagnosis of IE. Application of this set of diagnostic criteria involves ascertaining the presence or absence of major and minor criteria.
Major criteria are two of the aforementioned cardinal elements:
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Positive blood cultures
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Evidence of endocardial involvement (e.g., positive findings on echocardiography, presence of new valvular regurgitation)
Minor criteria include the following factors:
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Predisposing heart condition or IV drug use
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Fever
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Vascular phenomena, including embolic events
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Immunologic phenomena
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Microbiologic evidence other than positive blood culture
Definitive diagnosis of IE requires the presence of two major criteria, one major and three minor criteria, or five minor criteria.
Laboratory and Diagnostic Findings
In addition to blood culturing, the diagnosis of IE is aided by a complete blood count with differential, electrolyte panel, renal function tests, urinalysis, plain chest radiography, and electrocardiography (ECG). Patients with IE frequently are found to have a normocytic, normochromic anemia that tends to worsen as the disease progresses. The white blood cell (WBC) count may or may not be elevated. Urinalysis often reveals microscopic hematuria and proteinuria. Appearance on chest radiographs may be abnormal with evidence of heart failure. ECG may show evidence of conduction block with myocardial involvement or infarction. Other abnormal findings may include an elevated erythrocyte sedimentation rate, increased immune globulins, circulating immune complexes, and positive rheumatoid factor.
Echocardiography, transthoracic or transesophageal, is used to confirm the presence of vegetation in patients suspected of having IE; it has become a cornerstone in the diagnostic process. Echocardiographic evidence of vegetation is one of the major findings included in the Duke criteria.
Medical Management
Before the advent of antibiotics, IE almost always was fatal. This poor outcome has changed dramatically with early diagnosis and the institution of antibiotic therapy or surgical treatment (or both). Although the survival rate has greatly improved, the overall mortality rate hovers around 40%. However, Wallace et al reported a higher survival rate with mortality at discharge of 18% and at 6 months of 27%. The duration of illness before admission, age, sex, valve infected, infecting organism, and left ventricular function were not predictors of adverse mortality rates. However, abnormal WBC count, serum albumin concentration, serum creatinine concentration, or cardiac rhythm, the presence of two major Duke criteria, or visible vegetation conferred a poor prognosis. The mortality rate varies significantly among groups of patients with IE of differing causes. For example, for viridans group streptococcal PVE, the reported mortality rate is approximately 20%, but for viridans group streptococcal NVE, it is 5% or less. For S. aureus endocarditis in non-IVDU patients, the mortality rate ranges between 25% and 40%, and for fungal endocarditis, the mortality rate exceeds 80%. For IE of the tricuspid valve in IVDUs, the mortality rate is between 2% and 4%. The current medical and surgical treatment of IE is presented in Table 2.3 . The management of patients with IE requires effective antibiotic therapy and, in cases involving significant structural damage, surgical intervention.
| Organism and Regimen * | Comments |
|---|---|
| PCN-SUSCEPTIBLE VIRIDANS STREPTOCOCCI (MIC ≤0.1 µg/mL) AND STREPTOCOCCUS GALLOLYTICUS (FORMERLY S. BOVIS ) | |
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| RELATIVELY PCN-RESISTANT VIRIDANS STREPTOCOCCI (MIC 0.12–<0.5 µg/mL) | |
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— |
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| ENTEROCOCCI † AND PCN-RESISTANT VIRIDANS STREPTOCOCCI (PCN MIC >0.5 µg/mL) | |
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| STAPHYLOCOCCUS AUREUS | |
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| COAGULASE-NEGATIVE STAPHYLOCOCCI, PROSTHETIC VALVE INFECTION | |
| HACEK Strains | |
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— |
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| Non-HACEK Gram-Negative Bacilli | |
| Enterobacteriaceae | |
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Treat for a minimum of 6–8 wk; some species exhibit inducible resistance to third-generation cephalosporins; valve surgery is required for most patients with left-sided endocarditis caused by gram-negative bacilli; consultation with a specialist in infectious diseases is recommended |
| Pseudomonas Aeruginosa | |
| High-dose tobramycin (8 mg/kg/day IV or IM in once-daily doses) with maintenance of peak and trough concentrations of 15–20 µg/mL and ≤2 µg/mL, respectively, in combination with an extended-spectrum PCN (e.g., ticarcillin, piperacillin, azlocillin); ceftazidime, cefepime, or imipenem in full doses; or imipenem | Treat for a minimum of 6–8 wk; early valve surgery usually required for left-sided Pseudomonas endocarditis; consultation with a specialist in infectious diseases is recommended |
| Fungi | |
| Treatment with a parenteral antifungal agent (usually a lipid-containing amphotericin B product, 3–5 mg/kg/day IV for at least 6 weeks) and valve replacement Fluconazole, 400 mg daily PO is an alternative for susceptible yeasts; other azoles, such as voriconazole, may be required for resistant yeasts or molds |
Long-term or lifelong suppressive therapy with PO antifungal agents often required; consultation with a specialist in infectious diseases is recommended |
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