Chapter 490. Infective Endocarditis

Infective endocarditis (IE) is defined as an infection of the endocardium, generally involving cardiac valves and their valvular apparatus such as the chordae tendinae, interventricular septum, mural endocardium, or intracardiac devices. IE may occur in children with or without antecedent underlying cardiac disease. The diagnosis of IE rests on a constellation of clinical features and laboratory investigations, including blood cultures and echocardiography.1 Most often, IE presents with fever, positive blood cultures, a new murmur, or vegetations by echocardiography. Vascular findings and immunologic phenomena are common. The presenting symptoms, rate of progression, morbidity, and mortality of infective endocarditis depend, in part, upon the underlying heart disease, the etiologic organism, and host factors. Whereas most infective endocarditis is accompanied by positive blood cultures, 5% to 7% are culture negative, sometimes due to administration of antibiotics before blood cultures were obtained.1 Compared to adults, children have a lower incidence and fatality rate of IE.2,3 The most common causes of bacterial endocarditis in children are viridans group streptococci and Staphylococcus aureus; other principal pathogenic agents include coagulase-negative staphylococci, Streptococcus pneumoniae, HACEK organisms (Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species), and enterococcus species.4-6 Emergence of antibiotic resistance to these common pathogens has serious ramifications for the morbidity and mortality of IE. It is therefore essential that pediatricians and pediatric cardiologists work in concert with specialists in infectious diseases in planning the treatment of IE.

Before the 1970s, rheumatic heart disease was the underlying substrate for infective endocarditis (IE) in 30% to 50% of children.2 As the prevalence of pediatric rheumatic heart disease has declined in developed countries, congenital heart lesions have become the most common form of underlying cardiac disease.4-6 Furthermore, recent series have suggested an ever greater proportion of IE cases without preexisting heart disease, largely a function of nosocomial infections due to greater instrumentation of children with indwelling intravascular catheters and intravenous drug use.2

The relative risk of IE among children with congenital heart lesions is a function of the particular lesion, as well as of host factors. The highest incidence of IE occurs in patients with uncorrected cyanotic congenital heart disease, prosthetic heart valves, or a history of prior IE.9 Compared to patients in the general population, those with prior infective endocarditis have a relative risk 150 times greater, whereas those with prosthetic cardiac valves have a relative risk 400 times greater.10 In general, lesions with high sheer stress or turbulent flow, such as aortic stenosis, seem to be at higher risk than those with low sheer stress, such as atrial septal defect. Patients with unrepaired ventricular septal defects have a higher incidence of infective endocarditis than do those whose defects have been corrected.8

Infective endocarditis is established by the interaction of a bloodstream pathogen with damaged endocardium.1 The process begins when sheer stress, for example, across a stenotic or regurgitant aortic valve, causes injury to the endocardium. Next, platelets and fibrin are deposited on the surface of the endocardium, forming nonbacterial thrombotic endocarditis. When a pathogen enters the bloodstream, bacteria adhere to the thrombotic area, proliferate, and form vegetation. Of note, bacterial species that commonly cause infective endocarditis, such as streptococci, staphylococci, and enterococci, have bacterial surface components that allow them to adhere to endothelial cells more avidly than gram-negative bacilli, which are uncommon causes of endocarditis.9 For example, the FimA protein of some viridans group streptococci allows this organism to adhere to the fibrin platelet matrix of a nonbacterial thrombotic mass.10S aureus has adhesins that allow it to attach to human extracellular matrix proteins such as fibronectin on the surface of the endothelial cell. Medical devices that become coated with endothelial cells that produce fibronectin may also be colonized. S aureus may also produce a biofilm on the surface of devices that allows it to become attached. Once a pathogen adheres to the thrombotic area, it stimulates further fibrin and platelet deposition, forming a vegetation that protects the microorganism from host defenses.14 In addition, more than 90% of organisms within valvular vegetations are inactive metabolically, reducing the efficacy of antibiotics in their eradication.12

Clinical Features and Differential Diagnosis

Infective endocarditis (IE) is readily diagnosable in children with at least 2 positive blood cultures, structural heart disease, and vegetations as identified by echocardiography. However, the diagnosis can be challenging, for example, when a patient with structural heart disease has bacteremia. To aid diagnosis and facilitate epidemiologic and clinical research efforts, the modified Duke criteria have become the gold standard for diagnosis of infective endocarditis. These criteria classify endocarditis as definite, possible, or rejected, based upon particular pathologic findings or combinations of major and minor clinical criteria.13 (See Table 490-1.) Transesophageal echocardiography is generally superior to transthoracic echocardiography in the older child or adolescent when interrogating for smaller vegetations, assessment of prosthetic cardiac valves, and assessing extension of infection into myocardial tissue.1,2 Serologic tests and polymerase chain reaction techniques may be useful in cases of culture-negative endocarditis.1

A typical history for the patient with subacute IE includes nonspecific symptoms, such as low-grade fever, malaise, fatigue, weight loss, headache, arthralgias, and myalgias. Presentation may also be fulminant, with acute symptoms and high fever. Careful daily physical examination reflects changes in cardiac structure or function, as well as embolic, vascular, or immune phenomena. Specifically, IE may cause new or changing heart murmurs, and worsening valvular regurgitation may cause congestive heart failure. Occlusion of a systemic to pulmonary artery shunt in a child with cyanotic heart disease may decrease oxygen saturation. Septic emboli may cause ischemia or hemorrhage in, for example, the kidneys, spleen, or brain. Patients with right-sided endocarditis may have septic pulmonary emboli. Mycotic aneurysms in the central nervous system or viscera are at risk for rupture. Vascular and immune phenomena include petechiae, most commonly present on the extremities, oral mucosa (eg, palate), or conjunctivae, best seen on eversion of the upper and lower eyelids. Splinter hemorrhages are nonblanching lines of maroon color under the proximal nail beds. Roth spots are retinal hemorrhages with white or pale centers composed of coagulated fibrin caused by immune complex deposition. Janeway lesions are painless hemorrhagic cutaneous lesions on the palms or soles due to a microabscess of the dermis formed by deposition of circulating immune complexes in small blood vessels. Osler nodes are painful subcutaneous lesions on the distal fingers caused by immune complex deposition. Glomerulonephritis and splenomegaly may also be caused by immune phenomena.

Diagnostic Evaluation

At least 3 blood cultures, from separate venipuncture sites, should be obtained prior to instituting antibiotic therapy when infective endocarditis (IE) is suspected.14 Because bacteremia is constant in IE, the cultures can be obtained at any time, regardless of fever spikes or shaking chills. When presentation of IE is indolent, blood cultures can be obtained over the course of a day or two. In contrast, the child with acute presentation, in whom initiation of empiric antibiotic therapy is urgent, undergoes serial blood cultures in rapid succession, for example, over the course of an hour. In patients with subacute presentation with previous antibiotic treatment, up to 6 blood cultures may be useful. The yield from blood cultures is related to the amount of blood inoculated.15 At least 5 cc per blood culture is optimal in children (in young infants, as little as 0.5 cc may be inoculated). In the larger child or adolescent, a minimum of 10 cc is ideal. In patients with suspected culture-negative endocarditis, serologies and molecular techniques such as polymerase chain reaction may help.1

Supportive laboratory criteria include elevated acute phase reactants, including the erythrocyte sedimentation rate and C-reactive protein, a normocytic, normochromic anemia (ie, anemia of chronic disease), and an elevated rheumatoid factor titer. Leukocytosis is inconsistent, although patients presenting with acute bacterial endocarditis generally have a left shift. Urinalysis may show hematuria and proteinuria in patients with immune complex glomerulonephritis.

Two-dimensional echocardiography can detect vegetations, myocardial abscesses, and valvular insufficiency. Although transthoracic echocardiography is more sensitive in young children than in adults, transesophageal echocardiography is more likely to identify vegetations in the child or adolescent with poor echo windows, for example, in the obese or muscular larger child or adolescent or for those after recent cardiac surgery or who have respiratory symptoms with pulmonary hyperinflation.2 In adult-sized individuals, transesophageal echocardiography is superior for detecting vegetations on native and prosthetic valves, involvement of the left ventricular outflow tract (eg, aortic root abscesses or involvement of the sinus of Valsalva), paravalvular leaks, and valve dehiscence in prosthetic valve endocarditis. 1

Electrocardiography should be performed daily in patients with aortic valve endocarditis to monitor conduction system disturbances.

If a vegetation or other tissue is obtained at surgery, histologic findings form an important component of the Duke criteria for definite endocarditis.13

Treatment

Intravenous antibiotics are the standard of care for definite or probable infective endocarditis.1,2 The choice of antibiotics, duration of therapy, and need for surgical intervention are determined by the specific etiologic pathogen and the site of infection (eg, native valve, prosthetic valve). Wherever possible, antibiotics should be bactericidal rather than bacteriostatic and administered intravenously. The duration of therapy is usually 4 to 8 weeks. Multiple antibiotics should be administered at approximately the same time to maximize synergism. Blood cultures should be performed daily until bacteremia has resolved for 48 hours. Absolute indications for surgical intervention include: congestive heart failure; valve obstruction, a definitive perivalvular abscess, non-candidal fungal infection; and left-sided infective endocarditis caused by gram-negative bacteria, especially pseudomonas. Relative indications include persistent bacteremia after 1 week of antibiotics; candidal endocarditis or vegetations of size greater than 10 mm. Surgical therapy is more frequently required for prosthetic valve infective endocarditis than native valve infective endocarditis.

Class I indications for surgical intervention include: congestive heart failure; fungal infective endocarditis; infection with aggressive antibiotic-resistant bacteria or those that respond poorly to antibiotics; left-sided infective endocarditis caused by gram-negative bacteria; persistent infection with positive blood cultures after 1 week of antibiotics; 1 or more embolic events during the first 2 weeks of antimicrobial therapy; or valve dehiscence, perforation, rupture, or fistula, or a large perivalvular abscess.1 Class IIa indications include an anterior mitral leaflet vegetation of size greater than 10 mm, a persistent vegetation after an embolic event, or an increase in vegetation size despite appropriate antimicrobial therapy.1 Surgical therapy is more common for prosthetic valve infective endocarditis than native valve infective endocarditis, but decisions should be individualized based upon the infective organism, presence of perivalvular infection, vegetation size, occurrence of embolism or heart failure, and noncardiac morbidities.1

Home therapy by a visiting nurse can be given after establishing an appropriate antibiotic regimen, with negative blood cultures in the patient with stable hemodynamics who is at low risk for complications and who has a suitable home environment and easy access to the medical center should complications occur.2

Complications of infective endocarditis include congestive heart failure, most often caused when a cardiac valve becomes regurgitant due to damage from the infection.1 Acute aortic regurgitation is especially poorly tolerated, acute tricuspid regurgitation is best tolerated, and mitral regurgitation is intermediate. Congestive heart failure can also follow rupture of the mitral chordae tendineae. Occasionally, flow through a cardiac valve is obstructed by a large vegetation, or congestive heart failure develops from abrupt creation of fistulous tracts or prosthetic valve dehiscence. Regardless of its etiology or timing, congestive heart failure carries a grave prognosis in patients with infective endocarditis and is usually an indication for surgery.1

Systemic embolization may have dire consequences.1 More than half of emboli travel to the brain, and among these, more than 90% occlude the middle cerebral artery. Independent risk factors for systemic embolization include vegetations on the mitral valve, particularly the anterior leaflet. Staphylococcal or fungal infective endocarditis appears to carry a higher risk of embolization independent of vegetation size, whereas large vegetations predict embolic events in infective endocarditis of streptococcal etiology. Although embolic events can occur late, the majority of emboli occur in the first 2 to 3 weeks after diagnosis and initiation of therapy. Thus, the benefit of surgical intervention in preventing embolization of a vegetation is greatest early in the course of the illness.

Periannular extension occurs when infection in the valve annulus spreads into contiguous tissue; this occurs most often in native aortic valve infective endocarditis and even more frequently in prosthetic valve infective endocarditis, where it has been reported to occur in the majority of patients.1 Periannular abscesses may evolve into fistulae that create either left-to-right shunts or pericardial shunts. Perivalvular abscess is suggested in the patient with persistent fever or bacteremia despite appropriate antibiotic therapy, the development of heart block, congestive heart failure, or a new murmur. Daily electrocardiograms are especially important to monitor for new atrioventricular block in patients with aortic valve endocarditis.

Other complications of infective endocarditis include splenic abscess secondary to an infected splenic embolus or to bacteremic seeding of a bland infarct. Mycotic aneurysms can result from septic emboli to the arterial vasa vasorum and most commonly affect arterial branch points. When they affect the intracranial arteries, the mortality rate is especially high, and symptoms can include headache, disorientation, and focal abnormalities. Mycotic aneurysms can also affect the arteries supplying the viscera and extremities. Rupture may occur well after the infection is cured.

Prognosis or Outcomes

Most patients with infective endocarditis are cured with antibiotic therapy and, occasionally, surgical management. Patients should receive an echocardiogram after treatment ends to establish a new baseline. In afebrile and asymptomatic patients, blood cultures should be repeated twice within 8 weeks after completing the antibiotic course. Because endocarditis may relapse, families should be educated to report the occurrence of fever or systemic signs and symptoms promptly. Empiric treatment with antibiotics for fever should be discouraged. Patients should also be monitored for developing or worsening congestive heart failure. Those treated with aminoglycosides should have audiograms. Because prolonged antibiotic use may be associated with delayed Clostridium difficile colitis, patients should report the occurrence of diarrhea promptly. Finally, patients who have had one episode of infective endocarditis are at much higher risk for repeated episodes, so physicians should have a low threshold for repeat blood cultures and avoidance of unnecessary antibiotics.

Prevention

The most recent American Heart Association recommendations advise use of antibiotic prophylaxis prior to dental procedures only in patients who are at highest risk for morbidity and mortality if they develop infective endocarditis.9 These include patients with prosthetic cardiac valves, previous infective endocarditis, cardiac transplantation recipients with cardiac valvulopathy, and certain forms of congenital heart disease. Congenital heart lesions requiring antibiotic prophylaxis include unrepaired cyanotic congenital heart disease, completely repaired congenital heart disease with prosthetic material or device either by surgery or catheter in the 6 months before the procedure, and repaired congenital heart disease with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device. This includes patients with: 1) prosthetic cardiac valves or prosthetic material used for cardiac valve repair; 2) previous infective endocarditis; 3) unrepaired cyanotic congenital heart disease, including palliative shunts and conduits; 4) completely repaired congenital heart defects with prosthetic materials or devices placed either by surgery or by catheter intervention during the first 6 months after the procedure; 5) repaired congenital heart disease with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device: and 6) cardiac transplantation recipients who develop cardiac valvulopathy. Amoxicillin is the preferred antibiotic for prophylaxis. For patients allergic to penicillin or amoxicillin, cephalexin or another first-generation oral cephalosporin, clindamycin, azithromycin, or clarithromycin is recommended. Prophylaxis is also recommended in these patients with invasive procedures involving incision or biopsy of respiratory tract mucosa, procedures on infected skin or muscle tissue, but not for routine genitourinary or gastrointestinal tract procedures.

• For those at highest risk, procedures that warrant antibiotic prophylaxis include the following.
• Dental procedures that involve the gingival tissues or periapical region of a tooth or that perforate the oral mucosa
• Invasive procedures of the respiratory tract that involve incision or biopsy of the respiratory mucosal, such as tonsillectomy and adenoidectomy
• Procedures on infected skin, skin structures, or musculoskeletal tissue

In addition, antibiotic prophylaxis should be administered to patients undergoing cardiac surgery with prosthetic heart valves or prosthetic intravascular or intracardiac tissues. Giving prophylactic antibiotics solely to prevent endocarditis is not recommended for patients who undergo routine genitourinary or gastrointestinal tract procedures.

Amoxicillin is the preferred antibiotic for prophylaxis because it is well absorbed and provides high, sustained serum levels. For patients allergic to penicillin or amoxicillin, cephalexin or another first-generation oral cephalosporin, clindamycin, azithromycin, or clarithromycin is recommended.

When patients are already taking an antibiotic that is recommended for infective endocarditis dental prophylaxis, an antibiotic from a different class should be selected because of the growth of resistant organisms in the oral cavity. If possible, it is best to delay a dental procedure until at least 10 days after completion of the antibiotic therapy. This might allow time for the usual oral flora to be reestablished.