eMedicine Specialties > Infectious Diseases > Cardiovascular and Intravascular Infections

Infective Endocarditis

Author: John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance
Contributor Information and Disclosures

Updated: Dec 7, 2007

Introduction

Background

Infective endocarditis (IE) is an infection of the endocardial surface of the heart. The intracardiac effects of this infection include severe valvular insufficiency, which may lead to intractable congestive heart failure and myocardial abscesses. IE also produces a wide variety of systemic signs and symptoms through several mechanisms, including both sterile and infected emboli and various immunological phenomena.

Endocarditis has evolved into several variations, keeping it near the top of the list of diseases that must not be misdiagnosed or overlooked. The history of IE can be divided into several eras. Lazaire Riviere first described gross autopsy findings of the disease in 1723. In 1885, William Osler presented the first comprehensive description of endocarditis in English. Lerner and Weinstein presented a thorough discussion of this disease in modern times in their landmark series of articles, "Infective Endocarditis in the Antibiotic Era," published in 1966 in the New England Journal of Medicine.

Since the 1980s, IE could be described as infective endocarditis in the era of intravascular devices because infection of intravascular lines has been determined to be the primary risk factor for Staphylococcus aureus bloodstream infections (BSIs). S aureus is currently the primary pathogen of endocarditis.

Since the 1960s, the clinical characteristics of IE have changed significantly. The dramatic "graying" of the disease and the increase in recreational drug use and proliferation of invasive vascular procedures underlie this phenomenon. Varieties of IE that were uncommon in the early antibiotic era have become prominent. Cases of nosocomial infective endocarditis (NIE), intravenous drug abuse (IVDA) IE, and prosthetic valve endocarditis (PVE) have markedly increased. Valvular infections have entered the era of IE caused by intravascular devices and procedures.

The underlying valvular pathology has also changed. Rheumatic heart disease currently accounts for less than 20% of cases, but 6% of patients with rheumatic heart disease eventually develop IE. Approximately 50% of elderly patients have calcific aortic stenosis as the underlying pathology. Congenital heart disease accounts for 15% of cases, with the bicuspid aortic valve being the most common example.

Other contributing congenital abnormalities include ventricular septal defects, patent ductus arteriosus, and tetralogy of Fallot. Atrial septal defect (secundum variety) is rarely associated with IE. Mitral valve prolapse is the most common predisposing condition found in young adults and is the predisposing condition in 30% of cases of native valve endocarditis (NVE) in this age group.

Calcific aortic stenosis is the underlying defect in 50% of cases of IE among elderly individuals. IE complicates 5% of cases of asymmetrical septal hypertrophy, usually involving the mitral valve.

The most significant risk factor for IE is residual valvular damage caused by a previous attack of endocarditis.

In 75% of cases of IVDA IE, no underlying valvular abnormalities are noted, and 50% of these infections involve the tricuspid valve.

PVE accounts for 10-20% of cases of IE. Eventually, 5% of mechanical and bioprosthetic valves become infected. Mechanical valves are more likely to be infected within the first 3 months of implantation, and, after 1 year, bioprosthetic valves are more likely to be infected. The valves in the mitral valve position are more susceptible than those in the aortic area.

Analogous to PVE are infections of implantable pacemakers and cardioverter-defibrillators. Usually, these devices are infected within a few months of implantation.

Infection of pacemakers includes that of the generator pocket (the most common), infection of the proximal leads, and infection of the portions of the leads in direct contact with the endocardium. This last category represents true pacemaker IE, is the least common infectious complication of pacemakers (0.5% of implanted pacemakers), and is the most challenging to treat. Of pacemaker infections, 75% are produced by staphylococci, both coagulase-negative and coagulase-positive.

NIE is defined as an infection that manifests 48 hours after the patient is hospitalized or that is associated with a hospital, based on a procedure performed within 4 weeks of clinical disease onset. The term health care–associated infective endocarditis (HCIE) is preferable to NIE, since it is inclusive of all sites that deliver patient care, such as hemodialysis centers. The term NIE should be applied to cases of IE acquired in the hospital. 

Two types of NIE have been described. The right-sided variety affects a valve that has been injured by placement of an intravascular line (eg, Swan-Ganz catheter). Subsequently, the valve is infected by a nosocomial bacteremia. The second type develops in a previously damaged valve and is more likely to occur on the left side. S aureus has been the predominant pathogen of NIE/HCIE since the recent prevalence of intravascular devices. Enterococci are more frequently isolated in these cases.

The classic clinical presentation and clinical course of IE has been characterized as either acute or subacute. Acute IE frequently involves normal valves. It is a rapidly progressive illness in persons who are healthy or debilitated. Subacute IE typically affects only abnormal valves. Its course, even in untreated patients, may extend over many months. Indiscriminate antibiotic usage and an increase in immunosuppressed patients have blurred the distinction between these 2 major types of IE (see below). However, the classification still has clinical merit.

Organism clinical features

• S aureus
• Overall, S aureus infection is the most common cause of IE, including PVE, acute IE, and IVDA IE.
• Approximately 35-60.5% of staphylococcal bacteremias are complicated by IE.
• More than half the cases are not associated with underlying valvular disease.
• The mortality rate of S aureus IE is 40-50%.
• S aureus infection is the second most common cause of nosocomial BSIs, second only to coagulase-negative staphylococci (CONS) infection.
• The incidence of methicillin-resistant S aureus (MRSA) infections, both the hospital- and community-acquired varieties, has dramatically increased (50% of isolates). Sixty percent of individuals are intermittent carriers of MRSA or methicillin-sensitive S aureus.
• The primary risk factor for S aureus BSI is the presence of intravascular lines. Other risk factors include cancer, diabetes, corticosteroid use, IVDA, alcoholism, and renal failure.
• The realization that approximately 50% of hospital- and community-acquired staphylococcal bacteremias arise from infected vascular catheters has led to the reclassification of staphylococcal BSIs. BSIs are acquired not only in the hospital but also in any type of health care facility (eg, nursing home, dialysis center).
• Of S aureus bacteremia cases in the United States, 7.8% (200,000) per year are associated with intravascular catheters.
• Streptococcus viridans
• This organism accounts for approximately 50-60% of cases of subacute disease.
• Most clinical signs and symptoms are mediated immunologically.
• Streptococcus intermedius group
• These infections may be acute or subacute.
• S intermedius infection accounts for 15% of streptococcal IE cases.
• S intermedius is unique among the streptococci; it can actively invade tissue and can cause abscesses.
• Nutritionally variant streptococci
• Approximately 5% of subacute cases of IE are due to infection with nutritionally variant streptococci.
• They require active nutritionally variant streptococci forms of vitamin B-6 for growth.
• The condition is associated with large vegetations that lead to embolization and a high rate of posttreatment relapse.
• Group D streptococci
• Most cases are subacute.
• The source is the gastrointestinal or genitourinary tract.
• It is the third most common cause of IE.
• They pose major resistance problems for antibiotics.
• Nonenterococcal group D organisms
• The condition is subacute.
• Infection often reflects underlying abnormalities of the large bowel (eg, ulcerative colitis, polyps, cancer).
• The organisms are sensitive to penicillin.
• Group B streptococci
• Acute disease develops in pregnant patients and older patients with underlying diseases (eg, cancer, diabetes, alcoholism).
• The mortality rate is 40%.
• Complications include metastatic infection, arterial thrombi, and congestive heart failure.
• It often requires valve replacement for cure.
• Group A, C, and G streptococci
• Acute disease resembles that of S aureus IE (30-70% mortality rate), with suppurative complications.
• Group A organisms respond to penicillin alone.
• Group C and G organisms require a combination of synergistic antibiotics (as with enterococci).
• Coagulase-negative S aureus
• This causes subacute disease.
• It behaves similarly to S viridans infection.
• It accounts for approximately 30% of PVE cases and less than 5% of NVE cases.
• Pseudomonas aeruginosa
• This is usually acute, except when it involves the right side of the heart in IVDA IE.
• Surgery is commonly required for cure.
• HACEK organisms (ie, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae)
• These organisms usually cause subacute disease.
• They account for approximately 5% of IE cases.
• They are the most common gram-negative organisms isolated from patients with IE.
• Complications may include massive arterial emboli and congestive heart failure.
• Cure requires ampicillin, gentamicin, and surgery.
• Fungi
• These usually cause subacute disease.
• The most common organism of both fungal NVE and fungal PVE is Candida albicans.
• Fungal IVDA IE is usually caused by Candida parapsilosis or Candida tropicalis.
• Aspergillus species are observed in fungal PVE and NIE.
• Bartonella species
• The most commonly involved species is Bartonella quintana.
• IE typically develops in homeless males who have extremely substandard hygiene. Bartonella must be considered in cases of culture-negative endocarditis among homeless individuals.
• Polymicrobial infective endocarditis
• Pseudomonas and enterococci are the most common combination of organisms.
• It is observed in cases of IVDA IE.
• The cardiac surgery mortality rate is twice that associated with single-agent IE.

IE remains a diagnostic and therapeutic challenge. Its manifestations may be muted by the indiscriminate use of antimicrobial agents or by underlying conditions in frail and elderly individuals or immunosuppressed persons. Effective therapy has become progressively more difficult to achieve because of the proliferation of implanted biomechanical devices and the rise in the number of resistant organisms. Antibiotic prophylaxis has probably had little effect in decreasing the incidence of IE.

Pathophysiology

1. Bacteremia (nosocomial or spontaneous) that delivers the organisms to the surface of the valve
2. Adherence of the organisms
3. Eventual invasion of the valvular leaflets

The common denominator for adherence and invasion is nonbacterial thrombotic endocarditis, a sterile fibrin-platelet vegetation. The development of subacute IE depends on a bacteria inoculum sufficient to allow invasion of the preexistent thrombus. This critical mass is the result of bacterial clumping produced by agglutinating antibodies.

In acute IE, the thrombus may be produced by the invading organism (ie, S aureus) or by valvular trauma from intravenous catheters or pacing wires (ie, NIE). S aureus can invade the endothelial cells (endotheliosis) and increase the expression of adhesion molecules and of procoagulant activity on the cellular surface. Nonbacterial thrombotic endocarditis may result from stress, renal failure, malnutrition, systemic lupus erythematosus, or neoplasia.

The Venturi effect also contributes to the development and location of nonbacterial thrombotic endocarditis. This principle explains why bacteria and the fibrin-platelet thrombus are deposited on the sides of the low-pressure sink that lies just beyond a narrowing or stenosis. In patients with mitral insufficiency, bacteria and the fibrin-platelet thrombus are located on the atrial surface of the valve. In patients with aortic insufficiency, they are located on the ventricular side. In these examples, the atria and ventricles are the low-pressure sinks. In the case of a ventricular septal defect, the low-pressure sink is the right ventricle and the thrombus is found on the right side of the defect. Nonbacterial thrombotic endocarditis may also form on the endocardium of the right ventricle, opposite the orifice that has been damaged by the jet of blood flowing through the defect (ie, the MacCallum patch).

IE develops most commonly on the mitral valve, closely followed in descending order of frequency by the aortic valve, the combined mitral and aortic valve, the tricuspid valve, and, rarely, the pulmonic valve. Mechanical prosthetic and bioprosthetic valves exhibit equal rates of infection.

The microorganisms that most commonly produce endocarditis (ie, S aureus; S viridans; group A, C, and G streptococci; enterococci) resist the bactericidal action of complement and possess fibronectin receptors for the surface of the fibrin-platelet thrombus. Among the many other characteristics of IE-producing bacteria demonstrated in vitro and in vivo, some features include the following:

• Increased adherence to aortic valve leaflet disks by enterococci, S viridans, and S aureus
• Mucoid-producing strains of S aureus
• Dextran-producing strains of S viridans
• S viridans and enterococci that possess FimA surface adhesin
• Platelet aggregation by S aureus and S viridans and resistance of S aureus to platelet microbicidal proteins

The pathogenesis of pacemaker IE is similar. Shortly after implantation, the development of a fibrin-platelet thrombus (similar to the nonbacterial thrombotic endocarditis described above) involves the generator box and conducting leads. After 1 week, the connective tissue proliferates, partially embedding the leads in the wall of the vein and endocardium. This layer may offer partial protection against infection during a bacteremia.

Many possible risk factors for the development of pacemaker infection have been described, including diabetes mellitus, age, and use of anticoagulants and corticosteroids. The evidence for these is conflicting. The major risk factor is probably surgical intervention to any part of the pacemaker system, especially elective battery replacements. The rate of infection associated with battery replacements is approximately 5 times that of the initial implantation (6.5% vs 1.4%). Other significant risk factors include the development of a postoperative hematoma, the inexperience of the surgeon, and a preceding temporary transvenous pacing.

Bacteremia (either spontaneous or due to an invasive procedure) infects the sterile fibrin-platelet vegetation. BSIs develop from various extracardiac types of infection, such as pneumonias or pyelonephritis, but most commonly from gingival disease. Of those with high-grade gingivitis, 10% have recurrent transient bacteremias (usually streptococcal species). Most cases of subacute disease are secondary to the bacteremias that develop from the activities of daily living (eg, brushing teeth, bowel movements).

Bacteremia can result from various invasive procedures, ranging from oral surgery to sclerotherapy of esophageal varices to genitourinary surgeries to various abdominal operations. The potential for invasive procedures to produce a bacteremia varies greatly. Procedures, rates, and organisms are as follows:

• Endoscopy
  • Rate of 0-20%
  • CONS, streptococci, diphtheroids
• Colonoscopy
  • Rate of 0-20%
  • Escherichia coli, Bacteroides species
• Barium enema
  • Rate of 0-20%
  • Enterococci, aerobic and anaerobic gram-negative rods
• Dental extractions
  • Rate of 40-100%
  • S viridans
• Transurethral resection of the prostate
  • Rate of 20-40%
  • Coliforms, enterococci, S aureus
• Transesophageal echocardiography
  • Rate of 0-20%
  • S viridans, anaerobic organisms, streptococci

The incidence of nosocomial bacteremias, mostly associated with intravascular lines, has more than doubled in the last few years. Up to 90% of BSIs caused by these devices are secondary to the placement of various types of central venous catheters. Hickman and Broviac catheters are associated with the lowest rates, presumably because of their Dacron cuffs. Peripherally placed central venous catheters are associated with similar rates.

Intravascular catheters are infected from 1 of 4 sources, including (1) infection of the insertion site, (2) infection of the catheter, (3) bacteremia arising from another site, and (4) contamination of the infused solution. Bacterial adherence to intravascular catheters depends on the response of the host to the presence of this foreign body, the properties of the organism itself, and the position of the catheter. Within a few days of insertion, a sleeve of fibrin and fibronectin is deposited on the catheter. S aureus adheres to the fibrin component. S aureus also produces an endotheliosis that is important in producing the continuous bacteremia of S aureus BSIs.

Four days after placement, the risk of infection markedly increases. Lines positioned in the internal jugular are more prone to infection than those placed in the subclavian vein. Colonization of the intracutaneous tract is the most likely source of short-term catheter-related BSIs. Among lines in place for more than 2 weeks, infection of the hub is the major source of bacteremia. In some cases, the infusion itself may be a reservoir of infection.

Colonization of heart valves by microorganisms is a complex process. Most transient bacteremias are short-lived, are without consequence, and are often not preventable. Bacteria rarely adhere to an endocardial nidus before the microorganisms are removed from the circulation by various host defenses.

Once microorganisms establish themselves on the surface of the vegetation, platelet aggregation and fibrin deposition accelerate at the site. As the bacteria multiply, they are covered by ever-thickening layers of platelets and thrombin, which protect them from neutrophils and other host defenses. Organisms deep in the vegetation hibernate because of the paucity of available nutrients and are therefore less susceptible to bactericidal antimicrobials that interfere with bacterial cell wall synthesis (see Treatment).

Complications of subacute endocarditis result from embolization, slowly progressive valvular destruction, and various immunological mechanisms. The pathological picture of subacute IE is marked by valvular vegetations in which bacteria colonies are present both on and below the surface.

The cellular reaction occurs primarily with mononuclear cells and lymphocytes, with few polymorphonuclear cells. The surface of the valve beneath the vegetation shows few organisms. Proliferation of capillaries and fibroblasts is marked. Areas of healing are scattered among areas of destruction. Over time, the healing process falls behind, and valvular insufficiency develops secondary to perforation of the cusps and damage to the chordae tendineae. Compared with acute disease, little extension of the infectious process usually occurs beyond the valvular leaflets.

Levels of agglutinating and complement-fixing bactericidal antibodies and cryoglobulins are markedly increased in patients with subacute endocarditis. Many of the extracardiac manifestations of this form of the disease are due to circulating immune complexes. Among these include glomerulonephritis, peripheral manifestations (eg, Osler nodes, Roth spots, subungual hemorrhages), and, possibly, various musculoskeletal abnormalities. Janeway lesions usually arise from infected microemboli.

The complication of arterial embolization is second in frequency to congestive heart failure for both subacute and acute IE. The frequency of this complication has decreased, from 80% in the preantibiotic era to 15-35% today. The emboli are usually sterile because of the minimally invasive nature of the causative organisms (eg, S viridans). The persons most at risk are younger (20-40 y), have mitral or aortic valve (native or prosthetic) involvement, and are infected with certain organisms such as Candida or Aspergillus species, S aureus, Haemophilus parainfluenzae, group B streptococci, and nutritionally variant streptococci.

The prevalence of embolization appears to be the same for both types of disease. The most common areas of deposition include the coronary arteries, kidneys, brain, and spleen. Infarction at the site of embolization is common; abscess formation is not. Cerebral emboli occur in 33% of patients. The middle cerebral artery is involved most often.

Other neurological embolic damage includes cranial nerve palsies, cerebritis, and mycotic aneurysms caused by weakening of the vessel walls and produced by embolization to the vasa vasorum. Mycotic aneurysms may occur in the abdominal aorta and the splenic, coronary, and pulmonary arteries.

Congestive heart failure due to aortic valve insufficiency is the most common intracardiac complication of subacute endocarditis. It develops after months of untreated disease but may occur a full year following microbiological cure.

The microscopic appearance of acute bacterial endocarditis differs markedly from that of subacute disease. Vegetations that contain no fibroblasts develop rapidly, with no evidence of repair. Large amounts of both polymorphonuclear leukocytes and organisms are present in an ever-expanding area of necrosis. This process rapidly produces spontaneous rupture of the leaflets, of the papillary muscles, and of the chordae tendineae. The complications of acute bacterial endocarditis result from intracardiac disease and metastatic infection produced by suppurative emboli. Because of their shortened course, immunological phenomena are not a part of acute IE.

The frequency of aneurysms and other suppurative intracardiac complications is high. In addition to valvular insufficiency, other intracardiac complications of acute IE include (1) aortocardiac and other fistulas, (2) aneurysms of the sinus of Valsalva, (3) intraventricular abscesses, (4) ring abscesses, (5) myocardial abscesses, (6) mycotic aneurysms, (7) septic coronary arterial emboli, and (8) pericarditis.

In patients with acute disease, especially disease caused by S aureus infection, emboli almost inevitably lead to abscesses in the areas where they are deposited. Multiple abscesses can occur in almost every organ, including the kidneys, heart, and brain. Mycotic aneurysms may occur in almost any artery. Paradoxically, they are less common in patients with acute IE.

Frequency

United States

The incidence of IE is approximately 2-4 cases per 100,000 persons per year. This rate has not changed in the past 50 years.

International

The incidence of IE in other countries is similar to that in the United States.

Mortality/Morbidity

• If left untreated, IE is generally fatal. Anecdotal reports describe the resolution of right-sided valvular infection caused by S aureus infection in individuals who abuse intravenous drugs after just a few days of oral antibiotics.
• Early detection and appropriate treatment of this uncommon disease can be lifesaving.

Sex

• IE is 3 times as common in males as in females.

Age

• IE may occur in a person of any age. Frequency is increasing in elderly individuals, with 25-50% of cases occurring in those older than 60 years.

Clinical

History

The diagnosis of subacute infective endocarditis (IE) is suggested by a history of an indolent process characterized by fever, fatigue, anorexia, back pain, and weight loss. Less common developments include a cerebrovascular accident or congestive heart failure.

The patient should be questioned about invasive procedures and recreational drug use that may be causing the bacteremia. Most subacute disease caused by S viridans infection is related to dental disease. However, most cases are not caused by dental procedures but by transient bacteremias caused by gingivitis. In 85% of patients, symptoms of endocarditis appear within 2 weeks of dental or other procedures. The interval between the onset of disease and diagnosis averages approximately 6 weeks. The fact that less than 50% of patients have previously diagnosed underlying valvular disease significantly limits the effectiveness of antibiotic prophylaxis.

Acute IE is a much more aggressive disease. The patient notices an acute onset of high-grade fevers and chills and a rapid onset of congestive heart failure. Again, a history of antecedent procedures or illicit drug use must be investigated.

The distinction between these 2 polar types of IE has become less clear. Intermittent use of antibiotics aimed at treating misdiagnosed endocarditis can suppress bacterial growth within the valvular thrombus, giving rise to the state of muted IE. This is often the case in nosocomial infective endocarditis (NIE), which commonly manifests with elements of a sepsis syndrome (ie, hypotension, metabolic acidosis fever, leukocytosis, and multiple organ failure). The source of the bacteremia may be an infection in another organ (eg, pneumonia, pyelonephritis) or in a central venous catheter. Most often, these patients are in the intensive care unit. Approximately 45% of cases of NIE occur in patients with prosthetic valves. Muted IE due to S aureus infection may resemble IE that results from S viridans infection.

• The symptoms of early subacute native valve endocarditis (NVE) are usually subtle and nonspecific. They include low-grade fever (absent in 3-15% of patients), anorexia, weight loss, influenzalike syndromes, polymyalgialike syndromes, pleuritic pain, syndromes similar to rheumatic fever (eg, fever, dulled sensorium as in typhoid, headaches), and abdominal symptoms (eg, right upper quadrant pain, vomiting, postprandial distress, appendicitislike symptoms). 
  • When appropriate therapy is delayed for weeks or months, additional clinical features, embolic or immunological in origin, develop.
  • Signs and symptoms secondary to emboli include acute meningitis with sterile spinal fluid, hemiplegia in the distribution of the middle cerebral artery, regional infarcts that cause painless hematuria, infarction of the kidney or spleen, unilateral blindness caused by occlusion of a retinal artery, and myocardial infarction due to embolization of a coronary artery.
  • The emboli of right-sided IE commonly produce pulmonary infarcts. The rate of embolization is related to the organism, the size of the vegetation and its rate of growth or resolution, and its location.
  • The vegetations of S aureus, Haemophilus influenzae, H parainfluenzae, and the fungi are much more likely to embolize than those of S viridans. Those larger than 10 mm in diameter and mobile or prolapsing have a high rate of embolization. A vegetation that grows during therapy is associated with a significant increase in the risk of embolization but with the persistence of bacteremia.
  • Clinically separating the importance of the absolute size and the rate of change in the size of the vegetation from the causative organism is difficult. The vegetations of the mitral valve are much more likely to embolize than those in any other location (see Echocardiographic predictors of embolization). The risk of embolization markedly decreases after 1 week of appropriate antibiotic therapy.
  • The deposition of circulating immune complexes in the kidney may produce interstitial nephritis or proliferative glomerulonephritis, with renal failure progressing to the point of uremia at the time of the patient's presentation. Similarly, various musculoskeletal symptoms (44% of patients) arise from immunologically mediated synovitis.
  • Osler nodes and Roth spots arise from immune-mediated vasculitis. Patients may experience palpitations, ie, the symptoms of an immune-mediated myocarditis.
  • The origin of lumbosacral back pain in patients with subacute IE (15%) is unclear but probably results from the deposition of immune complexes in the disk space. However, antibiotic therapy rapidly abolishes these symptoms. In 50% of patients with cerebral emboli, this event is the first manifestation of IE and is associated with a 2- to 4-times higher mortality rate. Stroke in younger people should always raise the possibility of underlying IE.
• Rarely observed today, the bacteria-free state of IE is one in which patients have multiple negative blood culture results in the presence of severe congestive heart failure, renal failure, multiple sterile emboli, massive splenomegaly, severe anemia, brown facial pigmentation, bilateral thigh pain, and massive leg edema. These patients are usually afebrile. This process appears to indicate prolonged and unchecked stimulation of the immune system.
• The clinical symptoms of acute IE result from either embolic or intracardiac suppurative complications. The onset of illness is abrupt, with rapidly progressive destruction of the infected valve. The valvular leaflets are quickly destroyed by bacteria that multiply rapidly within the ever-growing friable vegetations. Complications develop within a week. These include the dyspnea and fatigue of severe congestive heart failure and a wide spectrum of neuropsychiatric complications resulting from CNS involvement.
• Patients with right-sided IVDA IE (53% of cases) frequently present with pleuropulmonary (pneumonia and/or empyema) manifestations. 
  • Symptoms due to metastatic infection develop early disease course caused by S aureus.
  • Infection with P aeruginosa has a high rate of neurological involvement, with 2 distinctive features: (1) mycotic aneurysms with a higher-than-average rate of rupture and (2) panophthalmitis (10% of patients). The course of infection with P aeruginosa is much slower than that of S aureus.
  • Right-sided disease is associated with a low rate of congestive heart failure and valvular perforation.
  • The course of left-sided IVDA IE is similar to that of non-IVDA disease.
  • Approximately 5-8% of febrile individuals who abuse intravenous drugs have underlying IE. Many users of illicit drugs may lose their fever within a few hours of hospitalization. This phenomenon, termed cotton wool fever, is probably caused by the presence of adulterants contained within the injected drugs.
• Early prosthetic valve endocarditis (PVE) is defined as infection occurring within 60 days of valve implantation. Late PVE occurs after this period. For valvular infection with CONS, this division should be extended to 12 months. 
  • Clinical features of PVE closely resemble those of NVE.
  • Congestive heart failure occurs earlier and is more severe in persons with PVE. The patient may present with symptoms of myocarditis or pericarditis. The rate of embolic stroke is high in the first 3 days of PVE.
• The clinical presentation in a person with a pacemaker infection and pacemaker IE depends on several factors, including the site of infection (eg, generator pocket vs intravascular leads or epicardial leads), the type of organism, and the origin of the infection (eg, pocket erosion, localized infection of the generator pocket, bacteremia from a remote site). 
  • Early infections, within a few months of implantation, manifest as acute or subacute infections of the pulse-generator pocket. Bacteremia may be present even in the absence of clinical signs and symptoms. Fever is the most common finding and may be the only finding in approximately 33% of patients.
  • Late infections of the pocket may be due to erosion of the overlying skin without systemic involvement. Such erosions always indicate infection of the underlying device.
  • The most significant late infections involve the transvenous or epicardial leads. With epicardial infection, signs and symptoms of pericarditis or mediastinitis may be present along with bacteremia. Infection of the transvenous electrode produces signs and symptoms of right-sided endocarditis. Those that occur early after implantation (33% of cases) show prominent systemic signs of infection, often with obvious localization to the pacemaker pocket.
  • Late infections have much more subtle manifestations. They may occur up to several years after implantation or reimplantation.
  • Fever is almost universal in persons with pacemaker IE. Signs of right-sided endocarditis (ie, pneumonia, septic emboli) are observed in up to 50% of patients.
• NIE commonly manifests with elements of a sepsis syndrome (ie, hypotension, metabolic acidosis fever, leukocytosis, and multiple organ failure).  
  • The source of bacteremia may develop from an infection in another organ (eg, pneumonia, pyelonephritis) or from a central venous catheter.
  • Most often, these patients are in the intensive care unit.
  • Approximately 45% of cases of NIE/health care–associated infective endocarditis (HCIE) occur in patients with prosthetic valves.

Physical

Approximately 3-15% of patients with subacute IE (primarily elderly and chronically ill individuals) have normal or subnormal temperatures. The vast majority of patients have detectable heart murmurs. The presence of a murmur is so common (99% of cases) that its absence should cause clinicians to reconsider the diagnosis of IE. The major exception is right-sided IE, in which only one third of patients have a detectable murmur. Because many of these murmurs are hemodynamically insignificant and have been present for years, their role in the patient's illness may be underestimated. The saying "a changing murmur is extremely helpful in diagnosing subacute IE" is a myth. Only 15% do so.

• The peripheral lesions of subacute IE are observed in only approximately 20% of patients, compared with 85% in the preantibiotic era. Currently, the most common of these is petechiae. They may occur on the palpebral conjunctivae, the dorsa of the hands and feet, the anterior chest and abdominal walls, the oral mucosa, and the soft palate.
• Subungual hemorrhages (ie, splinter hemorrhages) are linear and red. They are usually caused by workplace trauma to the hands and feet rather than by valvular infection. Hemorrhages that do not extend for the entire length of the nail are more likely the result of infection rather than trauma.
• Osler nodes are smallish tender nodules that range from red to purple and are located primarily in the pulp spaces of the terminal phalanges of the fingers and toes, soles of the feet, and the thenar and hypothenar eminences of the hands. Their appearance is often preceded by neuropathic pain. They last from hours to several days. They remain tender for a maximum of 2 days. The underlying mechanism is probably the circulating immunocomplexes of subacute IE. They have been described in various noninfectious vasculitides.
• Clubbing of fingers and toes was found almost universally, but it is now observed in less than 10% of patients. It primarily occurs in those patients who have an extended course of untreated IE.
• The arthritis associated with subacute IE is asymmetrical and is limited to 1-3 joints. Clinically, it resembles the joint changes found in patients with rheumatoid arthritis, Reiter syndrome, or Lyme disease. The fluid is usually sterile.
• Splenomegaly is observed more commonly in patients with long-standing subacute disease. It may persist long after successful therapy.
• Roth spots are retinal hemorrhages with pale centers. The Litten sign represents cotton-wool exudates.
• Murmurs are absent in approximately one third of patients with acute IE. The most common type is an aortic regurgitation murmur. Because of the suddenness of onset, the left ventricle does not have a chance to dilate. In this situation, the classic finding of increased pulse pressure in significant valvular insufficiency is absent.
• Fever is always present and is usually high.
• Janeway lesions are irregular erythematosus and painless macules (1-4 mm in diameter). They most often are located on the thenar and hypothenar eminences of the hands and feet. They usually represent an infectious vasculitis of acute IE resulting from S aureus infection.
• Acute septic monoarticular arthritis in patients with acute IE most often is caused by S aureus infection.
• Purulent meningitis may be observed in patients with acute IE, compared with the aseptic type observed in patients with subacute disease. Other neurological findings are similar to those observed in patients with subacute disease.

Causes

The following is a summary of particular pathogens associated with subtypes of IE.

• S aureus is the most common bacteria found in patients with IVDA IE. Groups A, C, and G streptococci and enterococci are also recovered from patients with IVDA IE. Currently, gram-negative organisms are involved infrequently. P aeruginosa and the HACEK family are the most common examples.
• CONS are the most frequent cause of PVE (30%). S aureus causes 17% of early PVE and 12% of late PVE. Corynebacterium, nonenterococcal streptococci, fungi (eg, C albicans, Candida stellatoidea, Aspergillus species), Legionella, and the HACEK organisms cause the remaining cases.
• The organisms that cause NIE obviously are related to the type of underlying bacteremia. The gram-positive cocci (ie, S aureus, CONS, enterococci, nonenterococcal streptococci) are the most common pathogens.

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