bubble_chart Overview

Infective endocarditis refers to inflammation of the heart valves or ventricular endocardium caused by direct infection from bacteria, fungi, and other microorganisms (such as viruses, rickettsiae, chlamydia, spirochetes, etc.). It is distinct from non-infective endocarditis caused by wind-dampness heat, rheumatism, systemic lupus erythematosus, and other conditions. Previously, this condition was termed bacterial endocarditis, but this term is no longer used due to its lack of comprehensiveness. The typical clinical manifestations of infective endocarditis include fever, murmurs, anemia, embolism, skin lesions, splenomegaly, and positive blood cultures.

bubble_chart Etiology

It often occurs in hearts that already have pre-existing conditions, but in recent years, cases in individuals without prior cardiac pathology have been increasing, particularly among those receiving prolonged intravenous therapy, intravenous drug abusers, and patients with immunosuppression due to medications or diseases. Infectious endocarditis following artificial valve replacement has also become more common.

Left-sided endocarditis primarily affects the aortic and mitral valves, especially in cases of mild to grade II insufficiency. Right-sided endocarditis is less common and mainly involves the tricuspid valve. Among various congenital heart diseases, patent ductus arteriosus, ventricular septal defects, and tetralogy of Fallot are the most frequently associated conditions. Among single valve pathologies, bicuspid aortic valve stenosis is the most prone to develop this condition, while valve prolapse (aortic or mitral) also increases susceptibility. Pathological examinations of specimens from 82 cases of infectious endocarditis treated with artificial valve replacement at Shanghai Zhongshan Hospital between 1980 and 1995 revealed that among the 55 cases with pre-existing organic heart disease, congenital bicuspid aortic valve malformation accounted for 20 cases (36%), and aortic valve prolapse for 10 cases (18%). Hypertrophic obstructive cardiomyopathy, degenerative valve disease, and coronary artery disease have also been reported as predisposing factors.

Acute infective endocarditis is often caused by pyogenic bacteria invading the endocardium, usually due to highly virulent pathogens. Staphylococcus aureus accounts for over 50% of cases. Before the clinical use of antibiotics, 80% of subacute infective endocarditis cases were caused by non-hemolytic streptococci, primarily Streptococcus viridans. In recent years, due to the widespread use of broad-spectrum antibiotics, the spectrum of causative pathogens has significantly changed, with almost all known pathogenic microorganisms capable of causing the disease. The same pathogen can induce either an acute or subacute course, and cases involving rare drug-resistant microorganisms have increased. While the incidence of Streptococcus viridans has declined, it remains predominant. The proportions of Staphylococcus aureus, enterococci, Staphylococcus epidermidis, Gram-negative bacteria, and fungi have risen significantly. Anaerobes, actinomycetes, and Listeria are occasionally observed. Mixed infections with two bacterial species are sometimes found. Fungal infections are particularly common in patients undergoing cardiac surgery or intravenous drug abuse. Prolonged use of antibiotics, steroids, immunosuppressants, or intravenous catheter-administered hyperalimentation can increase the risk of fungal infections, with Candida, Aspergillus, and Histoplasma being the most frequently encountered.

In cases of valvular lesions, congenital cardiovascular malformations, or acquired arteriovenous fistulas, abnormal pressure gradients exist, leading to forceful blood jets and turbulence. The impact of these jets damages the endocardial endothelium, exposing collagen and forming platelet-fibrin thrombi. Turbulence can cause bacteria to deposit on the low-pressure chamber's proximal end or the damaged endocardium at abnormal blood flow sites. Although small numbers of bacteria occasionally enter the bloodstream from the oral cavity, nasopharynx, gums, or surgical wounds in healthy individuals, most bacteremias are transient and quickly cleared by the body, with little clinical significance. However, repeated transient bacteremias stimulate the production of circulating antibodies, particularly agglutinins, which promote the aggregation of small numbers of pathogens, facilitating their adhesion to platelet-fibrin thrombi and leading to infection.

In aortic insufficiency, common infection sites include the left ventricular surface of the aortic valve and the mitral valve chordae. In mitral insufficiency, lesions occur on the atrial surface of the mitral valve and the left atrial endocardium. With ventricular septal defects, infections arise on the endocardial surface of the defect and the ventricular surface of the pulmonary valve. However, when the defect is large enough to eliminate the pressure gradient between the left and right ventricles or when pulmonary hypertension reduces shunt flow, the condition is less likely to occur. Similarly, in congestive heart failure and atrial fibrillation, the weakened blood jets and turbulence reduce the likelihood of developing this disease.

Some people also believe it is due to receptor attachment, as certain Gram-positive pathogenic bacteria, such as enterococci, Staphylococcus aureus, and Staphylococcus epidermidis, possess surface components that react with receptors on the endocardial membrane cells, leading to inflammation of the endocardium.

Contaminated prosthetic valves, suturing materials, instruments, and hands are important causes of prosthetic valve endocarditis. Pathogens enter the body from infected chest wounds, urinary tracts, various arterial and venous catheters, tracheostomies, postoperative pneumonia, etc., leading to bacteremia. Additionally, the destruction of phagocytic function after blood passes through extracorporeal circulation reduces the body's ability to clear pathogens, which is also one of the contributing factors.

bubble_chart Pathological Changes

The basic pathological changes of this disease are vegetations attached to the surface of the heart valve membrane, composed of deposits of platelets, fibrin, red blood cells, white blood cells, and infectious pathogens. These vegetations can extend to the chordae tendineae, papillary muscles, and the endocardial membrane. The endocardium beneath the vegetations may exhibit inflammatory reactions and focal necrosis. Subsequently, the infectious pathogens are phagocytized by macrophages, and the vegetations become encapsulated by fibrous tissue, undergoing organization, hyaline degeneration, or calcification, eventually becoming endothelialized. However, the degree of healing of the vegetations varies in different parts of the heart; some areas may heal while inflammation remains active elsewhere, and some may recur after healing, forming new lesions. In severe cases, the heart valve membrane may develop deep ulcers or even perforation. Occasionally, rupture of the papillary muscles or chordae tendineae may occur.

The vegetations in this disease are larger and more fragile than those produced by rheumatic endocarditis, making them prone to breaking off and forming infected emboli. These emboli can disseminate through the systemic circulation to various parts of the body, causing embolisms, particularly in the brain, spleen, kidneys, and peripheral arteries, leading to infarctions or abscesses in the affected organs. Embolisms obstruct blood flow or damage the vascular wall, resulting in cystic dilation and the formation of bacterial aneurysms, which are often fatal complications. For example, if the nutrient vessels of a cerebral aneurysm are embolized, the aneurysm may rupture suddenly, causing intraventricular or subarachnoid hemorrhage and leading to death. Diffuse meningitis is more common than brain abscesses.

This disease often involves microemboli or small-vessel vasculitis caused by immune mechanisms, such as petechiae on the skin and mucous membranes, subungual hemorrhages, Osler nodes, and Janeway lesions. Infectious pathogens combine with corresponding antibodies produced in the body to form immune complexes, which deposit on the basement membrane of the renal glomeruli, causing focal glomerulonephritis or diffuse or membranous proliferative glomerulonephritis. The latter can lead to renal failure.

bubble_chart Clinical Manifestations

(1) Acute infective endocarditis often occurs in normal hearts, and endocarditis in the right heart among intravenous drug addicts also tends to be acute. The pathogens are usually highly virulent bacteria, such as Staphylococcus aureus or fungi. The onset is often sudden, accompanied by high fever, chills, and obvious systemic toxic symptoms, often as part of a severe systemic infection. The course is usually rapid and severe, easily masking the clinical symptoms of acute infective endocarditis. Due to the acute damage to the heart valves and chordae tendineae, high-pitched murmurs or rapid changes in the nature of existing murmurs may appear within a short period. It often progresses rapidly to acute congestive heart failure, leading to death.

On the affected endocardium, especially in fungal infections, large and fragile vegetations may adhere. Dislodged infected emboli can cause multiple embolisms and metastatic abscesses, including myocardial abscesses, brain abscesses, and suppurative meningitis. If the emboli originate from the infected right heart chambers, pneumonia, pulmonary embolism, and single or multiple lung abscesses may occur. The skin may exhibit polymorphic ecchymoses and purpura-like hemorrhagic lesions. A few patients may have splenomegaly.

(2) Subacute infective endocarditis Most patients have an insidious onset with only nonspecific symptoms, such as general malaise, fatigue, low-grade fever, and weight loss. A few cases begin with complications of the disease, such as embolism, unexplained stroke, progressive worsening of valvular disease, refractory heart failure, glomerulonephritis, or the appearance of valvular murmurs after surgery.

Fever is the most common symptom, with variable patterns, most often irregular, and may be intermittent or remittent, accompanied by chills and sweating. Some may only have low-grade fever. Temperatures mostly range between 37.5–39°C but can exceed 40°C. About 3–15% of patients have normal or subnormal temperatures, more common in elderly patients and those with embolism, fungal aneurysm rupture causing cerebral hemorrhage or subarachnoid hemorrhage, severe heart failure, or uremia. Additionally, those who have already received antibiotics, antipyretics, or hormones before diagnosis may temporarily have no fever.

70–90% of patients have progressive anemia, sometimes severe, even the most prominent symptom. Anemia causes general weakness, fatigue, and shortness of breath. Patients with a prolonged course often have generalized pain, possibly due to toxemia or embolisms in various parts of the body. Arthralgia, low back pain, and myalgia are common at onset, mainly affecting the calf and thigh muscles, ankles, wrists, and other joints, or may involve multiple joints. If severe bone pain occurs during the course, consider osteomyelitis, subperiosteal hemorrhage or embolism, embolic aneurysm compressing the bone, or bone vascular aneurysm.

Elderly patients have more variable clinical manifestations, and fever is often misdiagnosed as respiratory or other infections. Heart murmurs are also often mistaken for degenerative valvular disease in the elderly and overlooked. Some may have no fever or heart murmurs but present with neurological or psychiatric changes, heart failure, or hypotension. They are prone to neurological complications and renal insufficiency.

The main sign is the presence of murmurs from pre-existing heart disease or new murmurs in previously normal hearts. Changes in murmur characteristics during the course are often due to anemia, tachycardia, or other hemodynamic changes. About 15% of patients initially have no heart murmurs, but murmurs appear during treatment. A few patients may not develop murmurs until 2–3 months after treatment, and rarely, some may never develop murmurs even after cure. In subacute infective endocarditis, right-sided valvular damage is uncommon. Two-thirds of right-sided endocarditis, especially involving the tricuspid valve, may have vegetations on the ventricular endocardium or atherosclerotic plaques without murmurs, but the latter is rare.

The incidence of skin and mucosal petechiae, subungual splinter hemorrhages, Osler's nodes, Janeway lesions, and other skin manifestations has shown a significant decline over the past 30 years. Petechiae result from toxin-induced capillary fragility leading to rupture and hemorrhage or from emboli, often appearing in clusters or individually. They have the highest incidence rate, decreasing from 85% before antibiotic use to 19–40%. Commonly seen on the conjunctiva, oral mucosa, chest, and dorsum of hands and feet, they last for several days, fade, and reappear, sometimes with a pale center. However, subconjunctival hemorrhages can also occur due to lipid microemboli during cardiopulmonary bypass surgery, leading some to suggest that petechiae with grayish-white centers are more significant than those with yellow centers. Generalized purpura may occasionally occur. Subungual hemorrhages are characterized by linear streaks that do not reach the distal edge of the nail bed and may be painful upon pressure. The incidence of Osler's nodes has decreased from 50% to 10–20%. These nodes appear purple or red, slightly raised, and range from 1–2 mm to as large as 5–15 mm, typically occurring on the palms of fingers or toes, thenar or hypothenar eminences, or soles of the feet, often tender and lasting 4–5 days before fading. Osler's nodes are not pathognomonic and may also appear in systemic lupus erythematosus, cold-damage disease, or lymphoma. Small, painless hemorrhagic or erythematous lesions 1–4 mm in diameter on the palms or soles are called Janeway lesions. Clubbing of fingers or toes is now rare. Retinal lesions most commonly present as hemorrhages, either fan-shaped or round, sometimes with white centers. Occasionally, only round white spots, known as Roth spots, are observed on fundoscopy.

The spleen is often mildly to grade II enlarged, soft, and may be tender. The incidence of splenomegaly has significantly decreased compared to before.

[Special Types]

(1) Prosthetic Valve Infective Endocarditis Among cases of infective endocarditis complicating cardiac surgery, prosthetic valve endocarditis (PVE) accounts for approximately 2.1%, which is 2–3 times higher than other types of cardiac surgery. The incidence of PVE after double valve replacement is higher than after single valve replacement, with PVE of the aortic valve being more common than PVE of the mitral valve. This may be due to the longer duration of aortic valve replacement surgery, the higher pressure gradient across the aortic valve, and the formation of local turbulent flow. For patients with pre-existing native valve endocarditis, the risk of postoperative PVE increases fivefold. The incidence of PVE is similar for mechanical valves and bioprosthetic valves, at approximately 2.4%. Early PVE is more common with mechanical valves than with bioprosthetic valves. The mortality rate of PVE is relatively high, around 50%. Early PVE (within 2 months postoperatively) has a higher mortality rate than late-stage [third-stage] PVE (after 2 months postoperatively). The primary pathogens in early PVE are staphylococci (40–50%), including *Staphylococcus epidermidis* and *Staphylococcus aureus*. *Corynebacterium diphtheriae*, other Gram-negative bacilli, and fungi are also relatively common. Since the introduction of prophylactic antibiotic therapy before surgery, the incidence has decreased. Late-stage [third-stage] PVE resembles native valve endocarditis and is mainly caused by various streptococci (primarily *Streptococcus viridans*), enterococci, and *Staphylococcus aureus*. Notably, *Staphylococcus epidermidis* in late-stage PVE is more sensitive to antibiotics than in early PVE. Fungi (most commonly *Candida albicans*, followed by *Aspergillus*), Gram-negative bacilli, and *Corynebacterium diphtheriae* are also not uncommon.

The clinical manifestations of prosthetic valve endocarditis are similar to those of native valve endocarditis, but the sensitivity and specificity as diagnostic criteria are not high. This is because postoperative bacteremia, indwelling catheters, chest surgical wounds, postpericardiotomy syndrome, postperfusion syndrome, and anticoagulation therapy can all cause fever, petechiae, hematuria, and other manifestations. Over 95% of patients have fever, approximately 50% have elevated white blood cell counts, and anemia is common. However, skin lesions rarely occur in early PVE. Splenomegaly is more common in late-stage [third-stage] PVE. Sometimes, serum immune complex titers may be elevated, and rheumatoid factor may be positive, but negative serological tests do not rule out the presence of PVE.

Approximately 50% of patients exhibit regurgitant murmurs. Prosthetic bioprosthetic valve endocarditis primarily causes damage to the valve leaflets, resulting in murmurs of insufficiency, with abscesses of the valve ring rarely occurring. In contrast, infections of mechanical valves mainly occur at the valve ring attachment sites, leading to the loosening and splitting of sutures at the valve ring and valve membrane, forming perivalvular fistulas and resulting in new murmurs of insufficiency and hemolysis, which exacerbate anemia. Diffuse infection of the valve ring can even cause complete detachment of the prosthetic valve membrane. When a valve ring abscess forms, it can easily spread to adjacent cardiac tissues, leading to complications similar to those of native valve endocarditis. In the early stages of PVE, when the valve membrane has not yet sustained significant damage, murmurs may be absent; thus, the absence of new murmurs should not delay diagnosis. When vegetations obstruct the valve orifice, murmurs of valve stenosis may occur. Systemic embolisms can occur in any location, and in fungal PVE (particularly that caused by Aspergillus), embolism may be the sole clinical finding. Petechial hemorrhages on the skin lack diagnostic significance in early PVE, as they can also be observed after cardiopulmonary bypass during surgery. Other complications of PVE, similar to those of native valve endocarditis, may include cardiac insufficiency, embolism, myocardial abscesses, and mycotic aneurysms. A weakened closing sound of the prosthetic valve membrane, abnormal swinging and displacement of the prosthetic valve membrane observed under fluoroscopy (with an angle greater than 7°–10°), and the double-shadow sign (Stinson's sign) caused by valve ring dehiscence are all indicative findings. The presence of vegetations detected by two-dimensional echocardiography also aids in diagnosis. Blood cultures are often positive. If multiple blood cultures are negative, the possibility of fungal or rickettsial infections, as well as slow-growing diphtheroid bacilli infections, should be considered. The pathogens causing PVE often originate from hospitals and are thus likely to exhibit drug resistance.

(II) Staphylococcal endocarditis The onset is mostly abrupt, with a severe and dangerous condition, so it often presents as an acute type, with only a few cases being subacute. It is usually caused by penicillin G-resistant Staphylococcus aureus. It tends to invade normal hearts and often leads to severe and rapid valve damage, resulting in aortic and mitral regurgitation. The presence of metastatic infections and abscesses in multiple organs and tissues is of significant diagnostic importance.

(III) Enterococcal endocarditis This is more common in patients with prostate and genitourinary tract infections. It causes significant damage to heart valves and often presents with obvious murmurs, but it usually manifests in a subacute form.

(IV) Fungal endocarditis Due to the increased use of broad-spectrum antibiotics, hormones, and immunosuppressants, long-term intravenous therapy, the placement of vascular and intracardiac catheters, the widespread development of open-heart surgery, and the rise in intravenous drug addiction in some countries, the incidence of fungal endocarditis has gradually increased, with about 50% occurring after cardiac surgery. The causative agents are mostly Candida, Histoplasma, Aspergillus, or other fungi. Fungal endocarditis often has an abrupt onset, though a few cases are more insidious, and the incidence of embolism is very high. The vegetations are large and fragile, easily breaking off and causing embolisms in larger arteries such as the femoral and iliac arteries. Right-sided endocarditis can lead to fungal pulmonary embolism. Large vegetations blocking the valve orifice can cause valve stenosis, leading to severe hemodynamic disturbances. Fungal endocarditis may also present with skin lesions, such as subcutaneous ulcers in Histoplasma infections, or damage to the oral and nasal mucosa. Histological examination often provides important diagnostic value. Aspergillus infections can also induce disseminated intravascular coagulation.

(5) Right-sided infective endocarditis occurs in congenital heart disease with left-to-right shunts, after prosthetic tricuspid valve replacement, urinary tract infections, and septic late abortion. Cardiac pacing, right heart catheterization, and normal childbirth can also cause it. In recent years, some countries have seen a significant increase in the incidence of right-sided infective endocarditis (about 5–10%) due to the rise in intravenous drug addiction. Most addicts have no preexisting heart disease, which may be related to contaminated drugs, failure to follow aseptic techniques, or damage to the tricuspid valve by specific substances in intravenous injection materials. The most common pathogens are Staphylococcus aureus, followed by fungi, yeast, Pseudomonas aeruginosa, pneumococci, etc. Gram-negative bacilli can also cause it. Right-sided infective endocarditis mostly affects the tricuspid valve, with a minority involving the pulmonary valve. Vegetations are usually located on the tricuspid valve, right ventricular wall, or pulmonary valve. Embolization of vegetations can lead to pulmonary inflammation, septic pulmonary arteritis, and bacterial pulmonary infarction. If caused by Staphylococcus aureus, the infarcted area may develop into a lung abscess. Since clinical manifestations are primarily pulmonary, splenomegaly, hematuria, and skin lesions are rare. Patients may experience cough, sputum production, hemoptysis, pleuritic chest pain, and dyspnea. A murmur of tricuspid regurgitation may be present, but due to the small pressure gradient between the right atrium and ventricle (except in cases with organic heart disease and pulmonary hypertension), the systolic murmur is short, faint, and soft, easily confused with respiratory noise or mistaken for a flow murmur. However, an increase in murmur intensity during deep inspiration strongly suggests tricuspid regurgitation. If the pulmonary valve is involved, a diastolic murmur due to pulmonary regurgitation may be heard. Cardiac enlargement or right heart failure is uncommon. Chest X-rays typically show multiple nodular or patchy inflammatory infiltrates in both lungs, possibly accompanied by pleural effusion. Lung abscess or necrotizing pneumonia may lead to pyopneumothorax. The most common cause of death in right-sided infective endocarditis is pulmonary valve insufficiency and acute respiratory distress syndrome caused by recurrent septic pulmonary emboli. Uncontrolled sepsis, severe right heart failure, and simultaneous left-sided valve involvement are rare causes of death. With early diagnosis, prompt antibiotic therapy or surgical intervention, and timely management of complications, the prognosis of isolated right-sided infective endocarditis is generally favorable.

(6) Recurrence and relapse of infective endocarditis Relapse refers to the reappearance of infection signs or positive blood cultures within 6 months after the completion of antibiotic treatment, with a relapse rate of approximately 5-8%. Early relapses mostly occur within 3 months. This may be due to bacteria deeply embedded in vegetations that are difficult to eradicate, or a prolonged course of illness before treatment or insufficient prior antibiotic therapy, thereby increasing bacterial drug resistance and leading to severe complications such as cerebral or pulmonary embolism. It may also result from dual infections caused by the use of broad-spectrum antibiotics.

The reappearance of all cardiac manifestations and positive blood cultures of infective endocarditis more than 6 months after the initial episode is termed a recurrence. It is usually caused by different bacteria or fungi. The mortality rate of recurrence is higher than that of the initial episode.

bubble_chart Auxiliary Examination

(1) Blood Culture Approximately 75–85% of patients have positive blood cultures. A positive blood culture is the most direct evidence for diagnosing this disease and can also monitor whether bacteremia persists. Pathogens continuously disseminate from vegetations into the blood, and the quantity varies. For acute cases, 2–3 blood samples should be drawn within 1–2 hours before antibiotic administration; for subacute cases, 3–4 blood samples should be collected within 24 hours before antibiotic use. For patients who have previously received antibiotics, blood cultures should be drawn daily for at least 3 days to improve the positivity rate. The optimal time for blood collection is during shivering or a sudden rise in body temperature. The venipuncture site should be changed for each draw, and the skin must be strictly disinfected. Each draw should collect 10–15 ml of blood. For patients who have received antibiotic treatment, the volume of blood drawn should not be excessive, and the ratio of culture medium to blood should be at least 10:1. Excessive antibiotics in the blood cannot be diluted by the medium, which may inhibit bacterial growth. Routine aerobic and anaerobic cultures should be performed. For patients with prosthetic valve replacement, prolonged intravenous catheterization, urinary catheterization, or drug addiction, fungal cultures should also be conducted. The observation period should last at least 2 weeks, extending to 3 weeks if results remain negative. A confirmed diagnosis requires positive blood cultures on two or more occasions. Generally, venous blood cultures are performed; stirred pulse blood cultures do not have a higher positivity rate than venous blood cultures. In rare cases, bone marrow cultures may be positive in patients with negative blood cultures. For those with positive cultures, antibiotic susceptibility testing (either single or combined) should be performed to guide treatment.

(2) General Laboratory Tests Red blood cell count and hemoglobin levels are reduced, with the latter mostly ranging from 6% to 10 g%. Occasionally, hemolysis may occur. In uncomplicated cases, the white blood cell count may be normal or show grade I elevation, sometimes with a left shift. The erythrocyte sedimentation rate is often increased. More than half of the patients may exhibit proteinuria and microscopic hematuria. In cases complicated by acute glomerulonephritis, interstitial nephritis, or large renal infarction, gross hematuria, pyuria, and elevated blood urea nitrogen and creatinine levels may occur. Enterococcal endocarditis often leads to enterococcal bacteriuria, as does staphylococcal endocarditis, making urine cultures also helpful for diagnosis.

(3) Electrocardiogram (ECG) Findings Generally nonspecific. Characteristic changes may appear in cases complicated by embolic myocardial infarction or pericarditis. In the presence of a ventricular septal abscess or valve ring abscess, incomplete or complete atrioventricular block, bundle branch block, or ventricular premature beats may occur. Rupture of an intracranial bacterial stirred pulse aneurysm may lead to "neurogenic" T-wave changes.

(4) Radiographic Imaging Chest X-rays are only helpful for diagnosing complications such as heart failure or pulmonary infarction. In patients with prosthetic valve replacement, abnormal valve motion or displacement may suggest concurrent infective endocarditis.

Computed tomography (CT) or spiral CT may have some diagnostic value for suspected large aortic stirred pulse perivalvular abscesses. However, artifacts from prosthetic valves and cardiac motion affect the assessment of valve morphology, and reliance on contrast agents and limited cross-sectional imaging restricts its clinical application. Magnetic resonance imaging (MRI), unaffected by prosthetic valve artifacts, can serve as an adjunct when two-dimensional echocardiography cannot rule out an aortic root abscess, though it is more expensive.

(5) Echocardiography Vegetations on the valve membrane can be detected by echocardiography, playing a particularly important role in blood culture-positive infective endocarditis. It can identify the location, size, number, and morphology of the vegetations. Two-dimensional transthoracic echocardiography is highly valuable for the early diagnosis of prosthetic valve endocarditis (PVE) in biological valves but is less effective for mechanical valves. This is because it can clearly display the morphology of biological valve membranes, making it easier to detect vegetations (especially on porcine valves), whereas the multiple and variable reflections of ultrasound echoes from mechanical valves make it difficult to confirm vegetations. Additionally, it cannot detect vegetations smaller than 2–3 mm in diameter. Sometimes, it is challenging to distinguish between loose calcifications or pseudo-vegetations on the valve membrane.

The recently developed transesophageal two-dimensional echocardiography is significantly superior to transthoracic two-dimensional echocardiography. Vegetations can be detected in 90% of cases, and smaller vegetations with diameters of 1–1.5 mm can be identified. It is unaffected by echoes caused by mechanical valves and is more suitable for cases involving lung qi swelling, obesity, and thoracic deformities. This method greatly improves diagnostic accuracy. It can also assess the extent of valve membrane damage or perforation, chordae tendineae rupture, flail mitral or tricuspid valves, infectious main stirred pulse aneurysms, and mitral valve aneurysms caused by infectious main stirred pulse valve regurgitation leading to ventricular surface membrane damage of the mitral valve anterior leaflet, as well as various suppurative cardiac complications, such as main stirred pulse root or valve ring abscesses, ventricular septal abscesses, myocardial abscesses, and suppurative pericarditis. Additionally, it helps evaluate pre-existing cardiac conditions, the severity of valve membrane regurgitation, and left ventricular function, serving as a reference for prognosis assessment and determining the need for surgery.

(6) Cardiac catheterization and heart blood vessel angiography: In addition to diagnosing pre-existing cardiac conditions, especially those complicated by coronary artery disease, these procedures can assess valve membrane function. Some researchers have taken blood samples proximal and distal to the valve membrane via cardiac catheterization to measure differences in bacterial counts, suggesting that this can localize the site of infection. However, cardiac catheterization and heart blood vessel angiography may dislodge vegetations, causing embolization, or induce severe arrhythmias and exacerbate heart failure. Therefore, careful consideration and strict adherence to indications are required.

(7) Radionuclide ⁶⁷ Ga (gallium) cardiac scanning: This can aid in diagnosing inflammatory sites of endocarditis and myocardial abscesses, but positive results only appear after 72 hours. Its sensitivity and specificity are significantly inferior to two-dimensional echocardiography, and it has a high rate of false negatives, limiting its clinical utility.

(8) Serum immunological tests: In subacute infectious endocarditis lasting six weeks, 50% of cases show positive wind-dampness factors, which rapidly decline after antibiotic treatment. Hypergammaglobulinemia or hypocomplementemia may occur, particularly in patients with concurrent glomerulonephritis, with levels often correlating with renal dysfunction. Approximately 90% of patients have positive circulating immune complexes (CIC), often exceeding 100 µg/ml, which is higher than in septic patients without endocarditis, providing diagnostic value—especially in culture-negative cases. However, it should be noted that systemic lupus erythematosus, hepatitis B surface antigen-positive patients, and other immune disorders may also have serum CIC levels exceeding 100 µg/ml.

Other tests include precipitation antibody assays for fungal infections, agglutination reactions, complement fixation tests, and assays for antibodies against the cell wall acid of Staphylococcus aureus.

bubble_chart Diagnosis

Although the "classic" clinical manifestations of this disease are no longer very common, and some symptoms and signs appear only in the advanced stage of the disease, coupled with the fact that most patients have received antibiotic treatment and the limitations of bacteriological examination techniques, early diagnosis is difficult. However, in principle, it is still recommended that patients with valvular heart disease, congenital cardiovascular malformations, or prosthetic valve replacement who have unexplained fever for more than one week should be suspected of this disease, and blood cultures should be performed immediately. If accompanied by anemia, peripheral embolism, and murmurs, the diagnosis of this disease should be considered. Clinically, repeated short-term use of antibiotics and recurrent fever, especially in patients with valvular murmurs, should raise suspicion of this disease. Timely echocardiography is very helpful for diagnosis. Positive blood cultures have decisive diagnostic value and provide a basis for antibiotic selection.

Unexplained anemia, intractable heart failure, apoplexy, paralysis, peripheral arterial embolism, progressive obstruction of prosthetic valve orifices, and valve displacement or avulsion should all prompt consideration of this disease. In patients with recurrent pneumonia, followed by hepatomegaly, grade I jaundice, and ultimately progressive renal failure, even in the absence of cardiac murmurs, the possibility of right-sided infective endocarditis should be considered.

bubble_chart Treatment Measures

Early treatment can improve the cure rate, but sufficient blood cultures should be obtained before antibiotic therapy is initiated. Delaying antibiotic treatment for a few hours or even 1–2 days based on the severity of the condition does not affect the cure rate or prognosis of the disease. Identifying the pathogen and using the most effective antibiotics are the most fundamental factors in curing this disease.

(1) Drug Therapy Generally, bactericidal agents such as high-dose penicillin, streptomycin, or cephalosporins are preferred. These drugs can penetrate the platelet-fibrin vegetation matrix, kill bacteria, eradicate valvular infections, and reduce the risk of recurrence. The combination of bacteriostatic and bactericidal agents may sometimes yield good results. Efficacy depends on the sensitivity of the pathogen to antibiotics. If blood cultures are positive, drugs can be selected based on susceptibility testing. Since bacteria are deeply embedded in vegetations and covered by fibrin and thrombi, high-dose antibiotics are required to maintain effective bactericidal concentrations in the blood. When possible, the minimum bactericidal concentration (MBC) of the patient's serum can be measured in vitro, usually 1 hour after administration. Antibiotics should then be dosed to achieve an MBC at a serum dilution level of at least 1:8. The treatment course should also be sufficiently long, typically 4–6 weeks, to ensure a cure.

For patients suspected of having this disease, after obtaining serial blood cultures, intravenous penicillin G (6–12 million units daily) should be administered immediately, combined with intramuscular streptomycin (1–2 g daily). If fever persists after 3 days of treatment, the dose of penicillin G should be increased to 20 million units intravenously. If the response is favorable, this regimen can be maintained for 6 weeks. When using high-dose penicillin G, attention should be paid to its concentration in the cerebrospinal fluid. Excessive levels may lead to neurotoxic manifestations such as myoclonus, hyperreflexia, seizures, and unconsciousness. These symptoms must be differentiated from neurological manifestations of the disease to avoid misdiagnosis as disease progression and unnecessary dose escalation, which could be fatal. If the response is poor, alternative antibiotics such as semi-synthetic penicillins (e.g., oxacillin, amoxicillin, piperacillin, 6–12 g daily intravenously), cephalothin (6–12 g daily), or vancomycin (2–3 g daily) may be used. If subsequent blood cultures are positive, antibiotic selection and dosing can be adjusted based on bacterial susceptibility. To improve cure rates, intermittent intravenous or intramuscular injections are generally recommended. However, intramuscular injections may cause local pain, which patients often find intolerable. Alternatively, penicillin G potassium can be administered as a slow intravenous infusion during the day (note: 1.5 mEq/L of potassium is contained per million units of penicillin G potassium; high doses may risk hyperkalemia), supplemented with nighttime intramuscular injections.

For infections caused by viridans streptococci, penicillin G remains the first-line treatment, and most patients respond adequately to penicillin alone. For less penicillin-sensitive strains, aminoglycosides such as gentamicin (120,000–240,000 units daily), tobramycin (3–5 mg/kg daily), or amikacin (1 g daily) may be added. Penicillin, a cell wall inhibitor, enhances the intracellular penetration of aminoglycosides. For penicillin-allergic patients, erythromycin, vancomycin, or first-generation cephalosporins may be used. However, patients with severe penicillin allergies (e.g., anaphylaxis) should avoid cephalosporins due to potential cross-reactivity (approximately 1%).

Enterococcal endocarditis is less sensitive to penicillin G, requiring a dosage of 2 to 40 million units per day. Therefore, ampicillin (6–12 g/d) or a combination of vancomycin and aminoglycoside antibiotics should be the first choice, with a treatment course of 6 weeks. Cephalosporins are ineffective against enterococci and cannot replace penicillin. Recently, some strains producing β-lactamase and resistant to aminoglycosides have been reported, as well as strains resistant to vancomycin. Alternatives include fluoroquinolones such as ciprofloxacin, sulbactam-ampicillin (Unasyn), and imipenem.

For Staphylococcus aureus endocarditis, if it is not a penicillin-resistant strain, penicillin G is still the preferred treatment, with a dosage of 10 to 20 million units per day combined with gentamicin. For resistant strains, first-generation cephalosporins, vancomycin, rifampin (Riforpin), or various penicillinase-resistant penicillins such as oxacillin may be used. During treatment, careful examination should be conducted to identify and address any metastatic lesions or abscesses that require intervention, to prevent bacterial reseeding from these sites to the cardiac lesions. Staphylococcus epidermidis has low invasiveness but responds poorly to penicillin G; thus, a combination of vancomycin, gentamicin, and rifampin is recommended.

Endocarditis caused by Gram-negative bacilli has a high mortality rate, though it is relatively rare as a causative agent. Generally, a combination of β-lactam antibiotics and aminoglycosides is used. Based on drug sensitivity, third-generation cephalosporins such as cefoperazone (4–8 g/day), cefotaxime (6–12 g/day), or ceftriaxone (2–4 g/day) may be selected. Alternatively, ampicillin combined with aminoglycosides can be used.

For Pseudomonas aeruginosa-induced endocarditis, third-generation cephalosporins are preferred, with ceftazidime (6 g/day) being the most effective. Piperacillin combined with aminoglycosides or polymyxin B (100 mg/day) or polymyxin E (150 mg/day) may also be used.

For Serratia infections, piperacillin or ampicillin combined with aminoglycosides is recommended. For anaerobic infections, 0.5% metronidazole (1.5–2 g/day, divided into three intravenous infusions) or cefoxitin (4–8 g/day) may be used. Cefoperazone can also be considered (though it is ineffective against weak Bacteroides species among anaerobes).

Fungal endocarditis has a mortality rate of 80–100%, and drug cure is extremely rare. Early surgical removal of the affected valve tissue during antifungal therapy, especially for fungal prosthetic valve endocarditis (PVE), followed by continued postoperative antifungal treatment, offers the only chance for cure. Amphotericin B remains the drug of choice, starting at 0.1 mg/kg/day and gradually increasing to 1 mg/kg/day, with a total dose of 1.5–3 g. Amphotericin B is highly toxic and may cause fever, headache, severe gastrointestinal reactions, thrombophlebitis, renal impairment, and neurological or psychiatric changes. 5-Fluorocytosine (5-FC) is a less toxic antifungal agent but is only bacteriostatic when used alone and prone to resistance. Combined with amphotericin B, it enhances fungicidal effects, reduces amphotericin B dosage, and mitigates 5-FC resistance. The latter is administered at 150 mg/kg/day intravenously.

For rickettsial endocarditis, tetracycline (2 g/day intravenously for 6 weeks) is the treatment of choice.

For cases highly suspected clinically but with repeatedly negative blood cultures, empirical treatment for enterococcal or staphylococcal infection with high-dose penicillin and aminoglycosides for 2 weeks is recommended, alongside blood cultures and serological tests to exclude fungal, mycoplasma, or rickettsial infections. If ineffective, switch to other bactericidal agents such as vancomycin and cephalosporins.

In cases of recurrent infective endocarditis, retreatment is necessary, and the course of therapy should be appropriately prolonged.

(2) Surgical Treatment In recent years, the implementation of surgical treatment has reduced the mortality rate of infective endocarditis, especially in cases with significant heart failure, where the reduction in mortality is even more pronounced.

The surgical treatment of native valve endocarditis is primarily for refractory heart failure; other indications include uncontrolled infections, especially fungal and antibiotic-resistant Gram-negative bacterial endocarditis; multiple embolisms; and suppurative complications such as purulent pericarditis, sinus of Valsalva aneurysm (or rupture), ventricular septal perforation, and myocardial abscess. In cases of complete or high-grade atrioventricular block, temporary artificial cardiac pacing may be administered, with permanent cardiac pacing considered if necessary.

The mortality rate of prosthetic valve endocarditis (PVE) is higher than that of native valve endocarditis. Antibiotic treatment alone for PVE has a mortality rate of 60%, while combining antibiotics with prosthetic valve reoperation can reduce mortality to around 40%. Therefore, if PVE is suspected, at least three blood cultures should be drawn within hours, followed by treatment with at least two antibiotics. Early-stage PVE pathogens are often highly invasive, and early surgery is generally recommended. Late-stage PVE is mostly caused by streptococci and is primarily managed with medical therapy. Fungal PVE requires medical treatment only as an adjunct to urgent surgical valve replacement, which should be performed early. Drug-resistant Gram-negative bacterial PVE also warrants early surgical intervention. Other indications for surgery include moderate to severe (grade III) heart failure due to valve dysfunction, severe perivalvular leaks or bioprosthetic valve tears, valve stenosis, new-onset conduction block, persistent infections, and recurrent peripheral embolisms—all of which may necessitate replacement of the infected prosthetic valve.

Most cases of right-sided endocarditis respond well to medical treatment. Additionally, because the right ventricle tolerates tricuspid and pulmonary valve dysfunction relatively well, surgery is generally not considered. However, surgical intervention—either tricuspid valve excision or replacement—is often required for cases unresponsive to medical therapy, progressive heart failure, or infections involving Pseudomonas aeruginosa or fungi.

To reduce the risk of residual infection post-surgery during active infection, antibiotics should be continued for 4–6 weeks after the procedure.

bubble_chart Prevention

Patients with valvular heart disease, congenital or acquired cardiovascular malformations, or prosthetic valves should enhance their constitution, maintain hygiene, and promptly eliminate infectious foci. Prophylactic antibiotics should be administered for dental and upper respiratory tract procedures, lower gastrointestinal tract, gallbladder, genitourinary tract surgeries or manipulations, as well as other surgical procedures involving infections.

For dental and upper respiratory tract procedures, penicillin G 1 to 1.2 million units intravenously and procaine penicillin 800,000 units intramuscularly are generally administered 30 minutes to 1 hour before the procedure, with streptomycin 1g/day added if necessary, followed by 2 to 3 days of postoperative treatment. For gastrointestinal or genitourinary system surgeries or manipulations, ampicillin and gentamicin may be used in combination before and after the procedure.

bubble_chart Complications

(1) Congestive Heart Failure and Arrhythmias Heart failure is the most common complication of this disease. It does not occur in the early stages but develops later when the valve {|###|}membrane{|###|} is destroyed and perforated, or when its supporting structures, such as the papillary muscles and chordae tendineae, are damaged, leading to valvular insufficiency or worsening pre-existing insufficiency, which is the primary cause of heart failure. Severe mitral valve infection can cause septic abscesses in the papillary muscles or destruction of the mitral valve annulus, resulting in a flail mitral valve and severe mitral regurgitation. Alternatively, if the lesion occurs in the {|###|}aortic{|###|} valve, causing severe aortic valve insufficiency, heart failure is particularly likely to occur. Additionally, the infection can affect the myocardium, leading to inflammation, localized myocardial abscesses, or the lodging of numerous microemboli in myocardial blood vessels. Larger emboli entering the coronary {|###|}artery{|###|} can cause myocardial infarction, all of which may result in heart failure. Other rare causes of heart failure include large left-to-right shunts, such as rupture of an infected aneurysm of the sinus of Valsalva or perforation of the interventricular septum by an abscess.

Heart failure is the leading cause of death in this disease. Heart failure caused by aortic valve regurgitation can be exacerbated if the lesion involves the mitral valve, leading to severe mitral insufficiency and even progressing to refractory heart failure, with a mortality rate as high as 97%.

When the infection affects the myocardium or invades the conduction system, it can lead to arrhythmias. Most cases involve ventricular premature beats, with a few developing atrial fibrillation. If infective endocarditis occurs in the aortic valve or a bacterial {|###|}aneurysm{|###|} forms in the aortic sinus, the infection may invade the atrioventricular bundle or compress the interventricular septum, causing atrioventricular block or bundle branch block.

(2) Embolic Phenomena Embolism is the second most common complication after heart failure, with an incidence of 15–35%. The vegetations on the damaged valve {|###|}membrane{|###|} require six months to be fully covered by endothelial cells, so emboli can occur from a few days to several months after the onset of fever. Early embolic events are often acute and carry a high risk. Emboli can occur in arteries throughout the body, with the most common sites being the brain, kidneys, spleen, and coronary {|###|}artery{|###|}. Emboli to the myocardium, kidneys, or spleen are often asymptomatic and typically discovered during autopsy, whereas emboli to the brain, lungs, or peripheral vessels present with more noticeable symptoms.

Large splenic emboli can cause sudden left upper abdominal or left flank pain, splenomegaly, fever, and a splenic friction rub. Occasionally, splenic rupture may lead to intra-abdominal hemorrhage, peritonitis, or subphrenic abscess. Renal emboli may cause {|###|}low back pain{|###|} or {|###|}abdominal pain{|###|}, hematuria, or bacteriuria, but smaller emboli may not produce symptoms, and urinary findings may be minimal, making them easily misdiagnosed as {|###|}fistula disease{|###|}. Cerebral artery embolism occurs in about 30% of cases, most commonly affecting the middle cerebral artery and its branches, with hemiplegia being the most frequent symptom. Pulmonary embolism is more common in right-sided endocarditis. If vegetations on the left-sided heart valves are smaller than a patent foramen ovale, they can reach the lungs, causing pulmonary infarction. Pulmonary embolism may present with sudden {|###|}chest pain{|###|}, dyspnea, cyanosis, cough, hemoptysis, or shock, but smaller pulmonary infarctions may be asymptomatic. Chest X-rays may show irregular small shadows or large wedge-shaped shadows, which must be differentiated from other pulmonary lesions. Coronary artery embolism can cause sudden {|###|}chest pain{|###|}, shock, heart failure, severe arrhythmias, or even sudden death. Peripheral artery embolism can lead to limb pain, weakness, pallor, coldness, cyanosis, or even necrosis. Central retinal artery embolism can cause sudden blindness. Embolism may still occur 1–2 years after recovery from the disease, but this does not necessarily indicate recurrence and requires close monitoring.

(3) Other cardiac complications Myocardial abscesses are commonly seen in Staphylococcus aureus and Enterococcus infections, particularly with coagulase-positive staphylococci. They may be multiple or a single large abscess. Direct spread of myocardial abscesses or rupture of an aortic valve ring abscess into the pericardium can lead to purulent pericarditis, myocardial fistulas, or cardiac perforation. Mitral valve abscesses and ventricular septal abscesses secondary to aortic valve infections, often located in the upper part of the septum, can involve the atrioventricular node and the bundle of His, causing atrioventricular block or bundle branch block. Prompt surgical resection and repair are advisable. Other complications include myocardial ischemia secondary to coronary artery embolism, myocarditis caused by bacterial toxin damage or immune complex effects, etc. Non-purulent pericarditis can also result from immune reactions or congestive heart failure.

(4) Mycotic Aneurysm Fungal mycotic aneurysms are the most common. Mycotic aneurysms most frequently occur in the main sinus, followed by cerebral arteries, ligated arterial ducts, abdominal blood vessels, pulmonary arteries, coronary arteries, etc. Aneurysms that do not compress adjacent tissues are often asymptomatic and may present clinical symptoms only after rupture. Unrelieved localized headache suggests the presence of a cerebral aneurysm, while local tenderness or a pulsatile mass indicates an aneurysm at that site.

(5) Neuropsychiatric Complications The incidence is approximately 10–15%. Clinical manifestations include toxic symptoms such as headache, confusion, nausea, insomnia, and vertigo, as well as a series of symptoms caused by infectious emboli in cerebral blood vessels. Additionally, motor and sensory impairments such as hemiplegia, paraplegia, aphasia, disorientation, ataxia, and peripheral neuropathy may arise due to damage to cranial nerves, the spinal cord, or peripheral nerves.

Other complications include interstitial nephritis and acute or chronic proliferative glomerulonephritis caused by immune complexes.

bubble_chart Differentiation

Due to the diverse clinical manifestations of this disease, it is often easily confused with other conditions. Cases primarily presenting with fever and mild cardiac signs must be differentiated from cold-damage disease, subcutaneous nodules, upper respiratory infections, tumors, and collagen tissue diseases. When this disease occurs on the basis of rheumatic heart disease, and fever persists despite adequate antibiotic treatment with no improvement in heart failure, the possibility of concurrent wind-dampness activity should be suspected. In such cases, attention should be paid to examining changes in the pericardium and myocardium, such as progressive cardiac enlargement accompanied by gallop rhythm, pericardial friction rub, or pericardial effusion. However, these two conditions may also coexist. Fever, cardiac murmurs, and embolic manifestations sometimes also need to be differentiated from atrial myxoma.

For cases where neurological or psychiatric symptoms are the main manifestations, in elderly patients, differentiation should be made from cerebral thrombosis, cerebral hemorrhage, and psychiatric changes caused by cerebral stirred pulse sclerosis.