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Moreover, after specific exposure to thrombin (which is plentiful at the surface of damaged endothelium), release of α-granule–derived platelet microbicidal proteins (PMPs) or thrombocidins with bactericidal activity against most gram-positive cocci that cause IE has been shown.155

Although the ability of S. aureus to adhere to and aggregate platelets is a related property, the resistance to PMPs is an independent phenotypic characteristic and a potential virulence factor.158

PMPs are low-molecular-weight (8–10 kDa) cationic proteins that act primarily on the bacterial cell membrane or cell wall, synergistically with antibiotics, to kill bacteria.

Microbial resistance to the microbicidal activity of PMPs may contribute to the pathogenesis of IE. This hypothesis was supported by a reduction in vegetation weight and bacterial concentration in rabbits with experimental aortic valve S. aureus endocarditis after treatment with aspirin.160

Several clinical studies also emphasized the important association between PMP resistance and the pathogenesis of intravascular infections. Bloodstream isolates of viridans streptococci and S. aureus from patients with IE tended to be substantially more resistant to PMPs in vitro.162

S. aureus bloodstream isolates arising from an intravascular source (catheter or IE) were significantly more resistant than bloodstream isolates arising from a deep tissue source.165

Furthermore, PMP-resistant S. aureus bloodstream isolates from patients with IE were significantly more likely to have arisen from an intravascular catheter source.166

In IE, the bacterial colonies are found beneath the surface of the vegeta- tion (at variable depth, depending on the intracardiac location170) and infiltration by phagocytic cells is minimal; the vegetation creates an environment of impaired host resistance. These conditions allow for relatively unbridled bacterial growth, resulting in extremely high colony counts of 109 to 1011 bacteria per 1 g of tissue

However, the best evidence suggests that coagulation activation initiated by tissue factor,178 with subsequent local thrombus formation, is responsible for the initiation of vegetation growth and persistence on the cardiac valve. It seems that some organisms (e.g., S. aureus) induce tissue factor production by endothelium without the necessity for host cytokines.179

Many important studies have elucidated the interactions among the invading microbe, the endothelium, and the monocyte in the pathogenesis of IE.

After internalization by endothelial cells in vitro, microbes such as S. aureus evoke a potent proinflammatory chemokine response, including, for example, increased expression of interleukin (IL)-6 or IL-8 or of monocyte chemotactic peptide.180,181 This event also is associated with increased expression on the endothelial cell surface of several key adhesion molecules, especially intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1).124,180,181

Several studies have emphasized that organisms with low protease production (e.g., enterococci) are associated with larger, more friable vegetations with an increased tendency for embolization.

IE results in stimulation of humoral and cellular immunity, as mani- fested by hypergammaglobulinemia, splenomegaly, and the presence of macrophages in the peripheral blood.

This effect may depend on the infecting organism, however, because antibody to S. epidermidis or S. aureus did not prevent the development of IE in immunized animals and did not result in reduced bacterial concentrations in infected vegetations or kidneys,189 perhaps because of the inability of immune sera to enhance opsonophagocytosis of staphylococci.

The role of preformed antibody in the pathogenesis of IE is unclear.

Intravascular agglutination of bacteria may decrease the frequency of IE by reduc- ing the actual number of circulating organisms, but cross-protection was not achieved with passive transfer of high-titer immune globulin from Streptococcus defectivus–immunized rabbits to control animals.187

The role of the glycocalyx of S. aureus, and of antibodies directed against this exopolysaccharide, in the pathogenesis of IE is controversial. Most experimental studies suggest that microencapsulation of strains by the common capsular types (5 and 8) may mitigate virulence of the organism in IE by obscuring key surface-expressed adhesins involved in colonization or persistence at endovascular damage sites.191

However, large clinical trials have not been able to document salutary outcomes using active or passive immunization strategies directed against the staphylococcal capsule or candidate surface adhesins (e.g., clumping factor).194–197

Rheumatoid factor (anti-IgG IgM antibody) develops in about 50% of patients with IE of longer than 6 weeks’ duration.200

Rheumatoid factors were found at the time of admission in 24% of patients with acute staphylococcal IE (<1

Rheumatoid factor may play a role in the disease process by blocking IgG opsonic activity (i.e., by reacting with the Fc fragment), stimulating phagocytosis, or accelerating microvascular damage. Rheumatoid factor (IgM) has not been eluted from the immune complex glomerulonephritis associated with IE.202 Antinuclear antibodies also occur in IE and may contribute to the musculoskeletal manifestations, low-grade fever, or pleuritic pain.203

Opsonic (IgG), agglutinating (IgG, IgM), and complement-fixing (IgG, IgM) antibodies and cryoglobulins (IgG, IgM, IgA, C3, fibrinogen); various antibodies to bacterial heat-shock proteins; and macroglobulins all have been described in IE.204–206

Antineutrophil cytoplasmic antibodies (ANCAs) were present in 12 of 50 patients (24%) in a recent series and were associated with longer duration of symptoms before IE diagnosis.207

Circulating immune complexes are found with increased frequency in connection with a long duration of illness, extravalvular manifestations, hypocomplementemia, and right-sided IE. Levels decrease and become undetectable with successful therapy. Patients with IE and circulating immune complexes may develop a diffuse glomerulonephritis that is analogous to the nephritis seen with infected ventriculoatrial shunts.209

Immune complexes plus complement are deposited subepithelially along the glomerular basement membrane to form a “lumpy-bumpy” pattern. Immune globulin eluted from these lesions has been shown to cross react with bacterial antigens.211 In addition, bacterial antigens have been shown within circulating immune complexes.212

Some of the peripheral manifestations of IE, such as Osler nodes, also may result from a deposition of circulating immune complexes. Pathologically, these lesions resemble an acute Arthus reaction. The finding of positive culture aspirates in Osler nodes213 suggests, however, that they may be caused by septic emboli rather than immune complex deposition.

In some diffuse purpuric lesions in IE, immune complex deposits (IgG, IgM, and complement) have been shown in the dermal blood vessels by immunofluorescence.214

Effective treatment leads to a prompt decrease, with eventual disappearance of circulating immune complexes.215

The classic vegetation of IE usually is located along the line of closure of a valve leaflet on the atrial surface of atrioventricular valves or on the ventricular surface of semilunar valves.

Microscopically, the lesion consists primarily of fibrin, platelet aggregates, and bacterial masses; neutrophils and red blood cells are rare.

vegetation in acute cases is larger, softer, and more friable and may be associated with suppuration, more necrosis, and less healing than in subacute cases.46,218

Staphylococcal IE frequently results in valve ring abscesses219 with fistula formation into areas of the myocardium or pericardial sac. Aneurysm of the valve leaflet or sinus of Valsalva also is common. Valvular stenosis may result from large vegetations.

Myocardial abscesses are found in 20% of the autopsy cases and are associated primarily with acute staphylococcal IE with hectic fever, a rapid onset of CHF, and conduction disturbances. Myocardial infarcts are found in 40% to 60% of the autopsied cases, often without diagnostic changes on the elec- trocardiogram. Pericarditis is much more common in patients with acute IE

Embolic phenomena are common in IE. In the preantibiotic era, 70% to 95% of patients had clinically demonstrable embolic events, but this has decreased to 15% to 35% today. Pathologic evidence of emboliza- tion still is detected in 45% to 65% of autopsies, most frequently involving the renal, splenic, coronary, or cerebral circulation. Emboli and immune complex deposition contribute to the extracardiac manifestations of IE and may involve almost any organ system.

If large emboli occlude major vessels, fungal endocarditis, marantic endocarditis, or an intracardiac myxoma should be suspected

Three pathologic processes may be found in the kidney in patients with IE: abscess, infarction, and glomerulonephritis. Abscesses are uncommon, but infarctions have been seen in 56% of the autopsy cases.2

When renal biopsy specimens are obtained during active IE, the renal architecture is abnormal in all cases,222 even in the absence of clinical or biochemical evidence of renal disease.

“Focal” glomerulonephritis is found in 48% to 88% of the cases but is rare in acute IE. It is a focal, local, and segmental process characterized by endothelial and mesangial proliferation, hemorrhage, neutrophilic infiltration, fibrinoid necrosis, crescent formation, and healing by fibrosis

Diffuse glomerulonephritis is found in 17% to 80% of the cases and consists of generalized cellular hyperplasia in all glomerular tufts. A less common condition, termed membranoproliferative glomerulonephritis, is associated with IE due to S. epidermidis and is characterized by marked mesangial proliferation and by splitting of the glomerular basement membrane. Renal interstitial cellular infiltration is common.222

Between 10% and 15% of patients with IE exhibit an immune complex glomerulonephritis similar to that seen in SLE.209,211,215,216

Mycotic aneurysms usually develop during active IE but occasionally are detected months or years after successful treatment. They are more common with viridans streptococcal infections and are found in 10% to 15% of autopsied cases. They may arise by any of several mechanisms: (1) direct bacterial invasion of the arterial wall with subsequent abscess formation or rupture, (2) septic or bland embolic occlusion of the vasa vasorum, or (3) immune complex deposition with resultant injury to the arterial wall.

Cerebral emboli are the most common neurologic manifestation of IE.225 Although 20% to 30% of patients with IE have clinically apparent cerebral emboli, the actual rate of cerebrovascular complications is significantly higher.

In a study from Sweden, patients with left-sided IE were prospectively evaluated with cerebral MRI regardless of neu- rologic symptoms. The total cerebrovascular complication rate was 65%, including 35% that were symptomatic and 30% that were clinically silent.226 This finding was externally validated in a French study that prospectively evaluated 130 IE patients with cerebral MRI with angi- ography within 7 days of admission and prior to any potential surgical intervention. MRI identified cerebral lesions in 82% of patients and led to changes in the diagnostic or therapeutic plan in 28% of the study patients.224

The middle cerebral artery and its branches are involved most commonly.46 Three percent of the cerebral emboli from all causes are secondary to IE.

Cerebral infarction, arteritis, abscesses, mycotic aneurysms, intracerebral or subarachnoid hemorrhage, encephalomalacia, cerebritis, and meningitis have been reported.228

Hemorrhagic transformation of an ischemic infarct due to septic emboli is the most common mechanism leading to fatal intracerebral hemorrhage during IE.229

True acute purulent meningitis is rare except in pneumococ- cal endocarditis, but multiple microabscesses (cerebritis) due to S. aureus are relatively common in acute staphylococcal IE.

Splenic infarctions have been reported in 44% of autopsy cases but often are clinically silent.46

Splenic abscesses are an uncommon complica- tion of IE and typically manifest as fever, left upper quadrant abdominal pain, and leukocytosis. Diagnosis is established with computed tomog- raphy (CT) or ultrasonography.230,231 Although splenectomy is a standard therapy for splenic abscess, percutaneous drainage may be an alternative in selected patients.232

Lung When right-sided IE is present, pulmonary embolism with or without infarction, acute pneumonia, pleural effusion, or empyema is common. These septic pulmonary emboli commonly manifest on chest radiographs as rounded, “cannonball” lesions. Emboli may be septic or bland.220

Osler nodes consist microscopically of arteriolar intimal prolifera- tion with extension to venules and capillaries and may be accompanied by thrombosis and necrosis. A diffuse perivascular infiltrate consisting of neutrophils and monocytes surrounds the dermal vessels. Immune complexes have been shown in the dermal vessels.

Skin Petechiae are found in 20% to 40% of cases (Fig. 80.2) (see later discus- sion).

Janeway lesions consist of bacteria, neutrophilic infiltration, necrosis, and subcutaneous hemorrhage (Fig. 80.3). Janeway lesions (see later description) are caused by septic emboli and reveal subcutaneous abscesses at histologic examination.233

Eye Roth spots consist microscopically of lymphocytes surrounded by edema and hemorrhage in the nerve fiber layer of the retina (Fig. 80.4).234

The incidence of so-called blood culture– negative endocarditis has ranged from 2.5% to 31% in published series.282,283 If the patient has not received previous antibiotic therapy and the blood cultures are obtained as outlined, these cases should represent less than 5% of the total.3

Because of improvements in blood culture media and automated blood culture incubation systems, extended incubation times of blood cultures are no longer necessary to recover HACEK organisms (see later discus- sion).280,286

Serologic studies are necessary for the diagnosis of Q fever or murine typhus.287 Psittacosis endocarditis usually is diagnosed with serologic methods, but one case288 yielded positive blood and pharyngeal cultures. Special culture techniques (e.g., for Legionella spp.289) are indicated in patients with suspected prosthetic valve IE if initial cultures are “negative.”

Cultures of bone marrow or urine rarely may be positive when blood cultures are negative

Bartonella, recognized as an important cause of apparent blood culture–negative IE (especially in homeless alcoholic patients), also can be isolated by prolonged incubation and subculture of the aerobic broth media (see Chapter 234).290–294

Although still rare, fungal IE is increasing in frequency and usually affects narcotic addicts, patients with prosthetic valves, or hospitalized patients receiving antibiotics or hyperalimentation or both.302

Historically, over half of cases of fungal IE exhibited negative blood cultures.305 The Castaneda principle (a culture of blood in a bottle containing agar and liquid broth) has been shown to increase the yield of fungal cultures.279

The characteristic finding is a shaggy, dense band of irregular echoes in a nonuniform distribution on one or more leaflets, with full unre- stricted motion of the valve. The smallest vegetation detected was approximately 2 mm, but the acoustic impedance of the mass relative to the surrounding structures is a more important factor than size in identifying the vegetation. If the vegetation is calcified (which may occur early and independent of the healing process), the sensitivity of echocardiography may be increased.

It seems from most analyses that TTE should be performed in all patients in whom IE seems to be a reasonable diagnosis.

TTE may be technically inadequate in 20% of adult patients owing to obesity, chronic obstructive pulmonary disease, or chest wall deformities.

These studies also suggest the following: (1) TTE has variable sensitivity for the detection of vegetations (<0% to >90% positive), indicating that a negative study does not exclude IE; (2) the sensitivity of TTE for detecting vegetations is highest in right-sided IE, because the tricuspid and pulmonic valves lie relatively close to the chest wall; (3) false-positive results are extremely rare; (4) only technically adequate studies are of value, a characteristic that depends on examiner experience; (5) echocardiography is extremely valuable in assessing local complications of IE, especially surrounding the aortic valve, although the sensitivity for detecting these complications is relatively low for TTE (see later discussion); and (6) patients with a “vegetation” identified with echocardiography are at an increased risk for subsequent systemic emboli, CHF, need for emergency surgery, and death, especially with aortic valve involvement. This apparent influence on prognosis has hastened earlier surgery in some cases,314 but this point is controversial.315

In one analysis from the Mayo Clinic,316 emboli were not statistically more common in patients with left-sided native valve IE and echocardiographically documented vegetations within 72 hours after beginning antimicrobial therapy than in patients without vegetations visualized by transthoracic techniques. The occurrence of emboli was correlated positively with the infecting microorganism, being more common in IE due to viridans streptococci than in IE due to S. aureus.

Most studies have suggested that mitral valve vegetations (particularly vegetations attached to the anterior leaflet), regardless of size, are associated with higher rates of embolization (25%) than are aortic valve vegetations (10%). This association implicates the mechanical effects of abrupt mitral valve leaflet excursions, occurring twice per heartbeat, in enhancing the embolic potential of vegetations.317

Serial echocardiograms often reveal the persistence of vegeta- tions after successful therapy, but sequential studies may be useful in the timing of surgical intervention. Although the finding is still con- troversial, larger vegetation size has been associated with an increased risk for cerebral emboli.

Short-term changes in vegetation size during therapy do not correlate well with clinical outcome.320

One study suggested that an increase in vegetation size, as seen with echocardiography during treatment of IE, can identify a subset of patients with a higher rate of complications, independent of the presence of persistent bacteremia or overt clinical stigmata of IE.321,322

Some studies have suggested that highly mobile vegetations constitute an independent increase in risk for complications in IE.323 In other studies, vegetation mobility at echocardiography has not been an important independent risk factor for embolic events in IE, because it is correlated strongly with vegetation size.288,314

One problem in considering the significance of these echocardio- graphic characteristics is the high degree of interobserver variability in interpreting the echocardiographic images.324 Inexperienced physicians do not understand this issue.

In one investigation involving four readers independently interpreting TTE studies from 41 cases of IE, Heinle and colleagues reported that investigators agreed on vegetation mobility in 57% of the cases, vegetation shape in 36%, and vegetation attachment in 40%.325 In a more recent study of intraobserver and interobserver agreement for a random sample of 110 echocardiograms from the ICE registry, interobserver agreement was highest for aortic abscess (kappa = 1.0) and vegetation location (kappa = 0.95) and lowest for mobility (kappa = 0.69).326 This overall improved agreement relative to the Heinle study was attributed to digital image acquisition and inclusion of transesophageal echocardiograms.

However, in one prospective cohort of 144 consecutive patients, 3D TEE was less sensitive than 2D TEE, with only one additional case of a vegetation detected with 3D TEE but not 2D TEE.333

TEE is also more sensitive than conventional TTE in the detection of intracardiac vegetations (approximately 95% vs. 60%–65%, respec- tively), particularly in the setting of prosthetic valves (see Chapter 81)

In one report of 96 patients with IE,330 the sensitivity of TEE was 100%, compared with 63% for TTE, and the specificity values were identical (98%). The advantage of TEE was particularly evident for vegetations smaller than 10 mm in diameter. In another study,331 vegetations were detected with TEE in 82% of the cases, compared with 69% for TTE.

Potential sources of false-negative TEE studies include small vegetations and previous embolization of vegetations. If the clinical suspicion of IE is high and the results of an initial TEE examination are negative, another TEE study is warranted within 7 to 10 days.334

Other investigations have shown TEE to be superior in the diagnosis of valvular perforation,337 pacemaker IE,338 eustachian valve IE,339 IE in the elderly,340 and other presentations.

TEE should be performed (unless contraindicated, as by significant esophageal disease) in all IE patients with a complicated course if perivalvular extension is suspected.

Two cost-effectiveness analyses favored the increased use of TEE.342,343 Using outcomes among a cohort of consecutive patients with intravascular catheter–associated S. aureus bacteremia (SAB), Rosen and colleagues343 found that TEE was a cost- effective method of defining the duration of antibiotic therapy (2 weeks vs. 4 weeks), compared with empirical courses of either 2 weeks or 4 weeks. Similarly, a decision analysis by Heidenreich and coworkers342 found TEE to be more cost-effective than TTE among patients with a high pretest probability of endocarditis (defined as 4%–60%)

In an effort to identify a subset of patients with suspected native valve IE who may not require TEE, one study compared a standard definition of a negative TTE (no vegetation present) with a strict definition (at least moderate ultrasound quality, normal cardiac anatomy, no valvular stenosis, at most trivial valvular regurgitation, at most mild simple pericardial effusion, absence of implanted hardware or central venous catheter, and no evidence of vegetation). In a retrospective analysis of 790 TTE/TEE pairs, 104 (13.2%) met strict negative criteria. Use of the strict definition improved sensitivity (from 43% to 98%) and negative predictive value (from 87% to 97%), at the expense of specificity (from 90% to 16%) and positive predictive value (from 53% to 22%).344

In conjunction with the physical examination, phonocardiography, and electrocardiography, the echocardiogram may play an important role in assessing the severity of acute aortic insufficiency in cases of active IE.345 In this setting, classic signs, such as a wide pulse pressure and bounding pulses, often are absent; however, there is usually a reduction in intensity of the first heart sound, and Austin Flint murmurs may be audible. Findings on the chest radiograph and electrocardiogram may be normal. The degree of mitral valve preclosure (as determined with echocardiography) correlates with the acute elevation in left ventricular end-diastolic pressure.

Modifications of the Duke criteria, to provide a floor for diagnosis of putative cases as possible IE, have added more specificity to the schema.348

A plethora of microorganisms have been implicated in IE, but streptococci and staphylococci account for 80% to 90% of the cases in which an identification is made.

Viridans streptococci remain the major cause of IE in children. The disease usually runs a subacute course with multiple nonspecific symptoms (see Table 8 0.3). More than 80% of these patients have underlying heart disease.

Viridans streptococci are the most commonly isolated pathogens in IE cases associated with mitral valve prolapse,351 and IE in young women with isolated mitral valve involvement is almost universally caused by viridans streptococci. Approximately 20% of cases that come to the physician’s attention are seen because of embolic phenomena.

With modern medical and surgical management, the cure rate should exceed 90% in nonenterococcal streptococcal IE, although complications may ensue in more than 30% of cases.

The nomenclature of the streptococci is confusing, and the terminol- ogy varies among authors. As detailed in Chapter 202, current names for the α-hemolytic streptococci other than S. pneumoniae (i.e., viridans streptococci) causing IE are S. mitis, S. sanguinis, S. mutans, Streptococcus salivarius, Abiotrophia and Granulicatella spp., and some isolates of the Streptococcus intermedius group (S. intermedius and Streptococcus anginosus). Streptococcus morbillorum now is classified as Gemella morbillorum; Streptococcus mitior now is considered to be a “genospecies” of S. mitis.

Group D streptococci are sometimes α-hemolytic, depending on the conditions and the isolate, but are not included among the viridans streptococci. Streptococci of the viridans group (not a true species) are α-hemolytic and usually nontypeable by the Lancefield system.

The streptococci most commonly isolated from cases of IE are S. sanguinis, Streptococcus bovis (we will continue to use this name here, although the human strains have been reclassified as Streptococcus gallolyticus), S. mutans, and S. mitior.81

In a series of 317 cases of streptococcal IE, the breakdown was as follows: α-hemolytic, 45%; nonhemolytic, non–group D, 21%; group D, 25%; pyogenic (groups A, B, C, G), 5%; miscellaneous, 3%; and aerococci, 1.3%

The α-hemolytic strains included S. sanguinis (16.4% of all cases of IE), non–dextran- producing S. mitior (13.2%), dextran-positive S. mitior (7.3%), and an unclassified group (7.9%).

By contrast, group D streptococci constituted 25% of all cases of IE within six regions of France representing 16 million inhabitants.353

S. mutans, a normal member of the oral microbiota, is microaerophilic, pleomorphic, and fastidious.

S. mutans first was isolated in 1924 by Clark from dental caries lesions of humans and first was reported in 1928 to cause IE. The central importance of this organism in dental caries has been amply documented.

S. bovis is a normal inhabitant of the gastrointestinal tract of humans and many animal species.

In addition, S. bovis has been subdivided further into S. gallolyticus subsp. gallolyticus, S. gallolyticus subsp. pasteurianus, and Streptococcus infantarius.358 It is important to differentiate S. bovis from the other members of group D (the enterococci), because the respective therapeutic approaches to infection with these organisms are different (see later discussion)

The association of bacteremia due to S. bovis with carcinoma of the colon and other lesions of the gastrointestinal tract suggests that a colonoscopy should be performed if this organism is isolated from blood cultures.362,363 Interest- ing to note, this association appears to be higher with S. gallolyticus subsp. gallolyticus.358

Enterococci are normal inhabitants of the gastrointestinal tract and occasionally of the anterior urethra. All enterococci are in Lancefield group D

Enterococci are responsible for 5% to 18% of the cases of IE, and the incidence seems to be increasing.7,365,366,367 The disease usually runs a subacute course and affects older men (mean age, 59 years) after genitourinary manipulation or younger women (mean age, 37 years) after obstetric procedures. The mean duration of nonspecific symptoms, such as malaise, fatigue, anorexia, and weight loss, was 140 days in one review. More than 40% of the patients have no underlying heart disease, although more than 95% develop a heart murmur during the course of the illness. Classic peripheral manifestations are uncommon (<5% of the cases). Bacteriuria with enterococci is a helpful diagnostic clue and was found in 4 of 15 patients in one study.364

With the increasing use of third-generation cephalosporins, which are relatively inactive against enterococci in vitro, and other contributing factors (e.g., use of indwelling urinary catheters), an alarming increase in enterococcal bacteremias has been documented during the past 2 decades.367–369 Most enterococcal bacteremias are health care associated, are often polymicrobial (42% in one large series370), and are associated with serious underlying disorders.

Factors that suggest IE in patients with enterococcal bacteremia include (1) community acquisition, (2) preexistent valvular heart disease, (3) cryptogenic source, and (4) absence of polymicrobial bacteremia.370

Antibiotic usage patterns, the aging of the population, and more invasive procedures in hospitalized adults all portend a continued increase in serious enterococcal infections, including IE, in the future

Before 1945, S. pneumoniae was responsible for approximately 10% of the cases of IE, but the prevalence has decreased to approximately 1% to 3% currently.371 The course usually is fulminant and often (in approximately one-third of cases) is associated with perivalvular abscess formation or pericarditis or both. Left-sided involvement is the rule, and there is a predilection for the aortic valve (approximately 70% of cases).

Many patients with pneumococcal IE are alcoholics (approximately 40%), and concurrent meningitis is present in about 70% of cases.371–373 The overall mortality rate is approximately 50% (60%–65% in children374), with death usually caused by rapid valvular destruction and hemodynamic compromise,375 although indolent presentations of pneumococcal IE with a favorable outcome have been described.376

IE due to nutrition- ally deficient streptococci is almost always indolent in onset and associated with preexisting heart disease.378

β-Hemolytic Streptococci Group B streptococci (Streptococcus agalactiae) are normal inhabitants of the mouth, vagina, and anterior urethra in 5% to 12% of the general population.

Although the organism has long been recognized as a cause of bacteremia and meningitis in neonates, serious S. agalactiae infections in adults also have been emphasized.382,383 Risk factors for group B streptococcal sepsis and IE in adults include diabetes mellitus, carcinoma, alcohol- ism, hepatic failure, elective abortion, and injection drug use.383–385

As with S. bovis, occasional cases occur in association with villous adenomas of the colon.386 More than 90 cases of group B streptococcal IE have been reported.384–388 Underlying heart disease is common, the male-to-female ratio is 1.4 : 1, the mean age is approximately 54 years, and left-sided involvement predominates. The overall mortality rate is almost 50%.

A similar clinical picture with a destructive process, left-sided predominance, frequent complications, and high mortality (approximately 40%) has been observed in the 47 cases of group G streptococcal IE reported in the literature.389,390 Most human infections with Streptococcus suis have presented as meningitis (with a striking predilection to cause deafness as a sequela) and sepsis with accompanying arthritis or endophthalmitis, but two cases of IE due to serotype 2 have been described.391 A history of pig or raw pork contact was a feature in both patients. Several cases of IE due to Streptococcus canis, a zoonotic group G streptococcal species associated with dogs, have also been reported.392

Approximately 50% of S. anginosus strains carry the group F antigen.395 IE caused by S. anginosus may result in virulent intracardiac complications (e.g., myocardial abscess, purulent pericarditis) more typical of S. aureus infections.397

Gemella IE due to Gemella haemolysans also has been reported.398 This organism now is placed in genus V of the family Streptococcaceae. Gemella should be suspected if blood cultures reveal a variable morphology (with some organisms resembling diphtheroids) and an indeterminate Gram stain. The antimicrobial susceptibility of Gemella spp. is similar to that of the viridans streptococci.

S. aureus is now the most common cause of IE in most of the industrial- ized world.10

This species is the causative agent in most cases of acute IE, but only 10% to 12% of patients with SAB have IE.402,403

The organism may attack normal heart valves (defined as those having no clinically detectable cardiac disease) in approximately one-third of the patients. The course frequently is fulminant when it involves the mitral or aortic valve, with widespread metastatic infection, and results in death in approximately 40% of patients.404–407

Traditiona lly, most cases of S. aureus IE were believed to be community acquired.409 In the late 1990s, however, a small report of S. aureus IE from Duke University suggested a demographic shift among patients with this infection.410 Over half of cases were associated with health care contact, and many were associated with intravascular catheters.

Myocardial abscesses (with conduction disturbances), purulent pericarditis, and valve ring abscesses are more common in staphylococcal

. Peripheral foci of suppuration (e.g., lung, brain, spleen, kidney) are common and affect more than 40% of these patients.404,407,408 These extravascular sites of involvement may offer clues to an early diagnosis, especially in narcotic addicts.261,262

IE in narcotic addicts usually is due to S. aureus, but the disease tends to be less severe, with mortality rates of 2% to 6%.261,262 The lower mortality is related directly to the preponderance of cases affecting the tricuspid valve, a syndrome that responds to antimicrobial therapy in most cases.409

Injection of newer psychoactive substances, including synthetic cannabinoids and synthetic cathinones, was associated with higher incidence of S. aureus IE and cavitating pulmonary lesions compared with findings in those who injected only opiates.414

Although S. epidermidis was traditionally an important agent in prosthetic valve IE (see Chapter 81) and in infants with IE related to umbilical venous catheters in neonatal intensive care units,415 studies from the ICE-PCS have confirmed that it also is an emerging cause of native valve IE.

Separation of IE from uncomplicated bacteremia due to S. epidermidis (implicated in approximately 50% of cases of native valve coagulase- negative staphylococcal IE) can be difficult.

IgG antibodies to a novel 30-kDa cloned protein, termed staphylococcal secretory antigen, were demonstrated in patients with S. epidermidis IE but not in patients with uncomplicated S. epidermidis bacteremia or IE due to other pathogens.419

Extensive laboratory evaluation420 revealed that most S. epidermidis IE isolates are distinct and do not represent common-source outbreaks, despite the frequent shift to a small-colony variant by many strains in vivo421 and the description of polyclonal S. epidermidis IE.422

A growing number of reports of IE caused by the coagulase- negative Staphylococcus lugdunensis have been published.425–428 This organism tends to cause a substantially more virulent form of IE than coagulase-negative staphylococci, with high morbidity rates despite almost uniform in vitro susceptibilities to most antibiotics, including penicillins and cephalosporins.425–428 These strains frequently are mis- identified as S. aureus because they often are yellow pigmented and yield complete hemolysis on blood agars.

However, experience from the large, contemporary, and multinational ICE-PCS demonstrated that health care contact, and not injection drug use, was the most common risk factor for enteric gram-negative IE

In this definitive study, more than half of the patients with IE due to non-HACEK gram-negative bacilli had health care–associated infection, whereas injection drug use was rare (4%). Prosthetic valves and implanted endovascular devices were frequently associated with non-HACEK gram-negative bacillary IE. Patients with cirrhosis438 also seem to be at an increased risk for the development of gram-negative bacillary IE

The duration of illness is usually less than 6 weeks, most patients are 40 to 50 years old, and men and women are affected equally.439 In gram-negative septicemia, the bloodstream usually is cleared by therapy with appropriate antimicrobial agents. In contrast, in IE due to gram- negative bacilli, persistent bacteremia is common, even with high levels of antimicrobial activity. CHF is common, and the prognosis is poor. Older series reported a mortality rate of 60% to 83% for IE due to gram-negative bacilli.439 However, contemporary experience indicates a substantially better prognosis, with in-hospital mortality rates of 24%.430 This improved mortality rate is perhaps due in part to high rates of cardiac surgery (51%)

In the early postoperative period after prosthetic valve replacement, sustained gram-negative bacteremia does not imply IE,440 and other foci of infection (e.g., sternal wound, pneumonia, urinary tract, intravenous catheters) should be sought carefully.

Tradi ti onally, Salmonella spp. were important causes of gram-negative bacterial IE among the Enterobacteriaceae. These organisms have an affinity for abnormal cardiac valves, usually on the left side of the heart.439,441 Although many serotypes have been implicated, most cases are caused by Salmonella enterica serotypes Choleraesuis, Typhimurium, and Enteritidis. Valvular perforation or destruction, atrial thrombi, myocarditis, and pericarditis are common, and the outlook is grave. Salmonellae also may produce endarteritis in aneurysms of major vessels (see later discussion)

Although historically regarded as a rare cause of endocarditis because of its poor endothelial cell–binding capacity, E. coli now appears to predominate among the Enterobacteriaceae as a cause of IE.430

Approximately 12 cases of IE due to Campylobacter fetus have been reported since the first case in 1955.442

The first case of Pseudomonas-induced IE was recognized in 1899; more than 200 cases have been reported since then.256,413,433–438 Although historical reports of pseudomonal IE (95%) were primarily associated with injection drug use,413,433–436 more contemporary reports confirm health care contact as the current primary risk factor.17,443 The male- to-female ratio is 2.5 : 1, and the mean age is 30 years. Major embolic phenomena, inability to sterilize valves, neurologic complications (53%), ring and annular abscesses, splenic abscesses, bacteremic relapses, and rapidly progressive CHF are common. Ecthyma gangrenosum, the necrotizing cutaneous lesion characteristic of Pseudomonas bacteremia, occasionally has been noted, especially in cases of IE due to Pseudomonas (Burkholderia) cepacia.444

Because of the poor prognosis and frequent complications,256 early surgery is recommended by many authorities for left-sided pseudomonal IE.334