Chapter 37. Endocarditis

Infective endocarditis (IE) denotes infection of the endocardial surface of the heart and implies the physical presence of microorganisms in the lesion. Although the heart valves are most commonly affected, the disease may also occur within the heart in the location of congenital septal defects or on the endocardial surface in areas of turbulent flow. Extracardiac infections of arteriovenous or arterioarterial shunts (patent ductus arteriosus), infection related to structural aortic arch anomalies, and infections of prosthetic materials such as vascular occluders and stents can also be included in this definition of similar clinical manifestations. Unfortunately, variability in the clinical presentation continues to make the diagnosis of IE clinically challenging. The Duke criteria for the diagnosis of IE have been developed1 and modified.2 These criteria have been validated in multiple studies and shown to be superior to other criteria for the diagnosis of IE in the pediatric population.3–5

Despite improvements in diagnosis and treatment, IE continues to be associated with high morbidity and mortality. There are several reasons for this persistent morbidity and mortality. Pediatric patients with IE are increasingly complex. In developed countries, the improved survival of children with congenital heart disease has led to a shift in the underlying condition for IE from rheumatic heart disease to congenital heart disease. In addition, there has been an increase in antibiotic-resistant organisms. Targeted antibiotic treatment is the ideal approach to the pharmacologic management of IE. Prevention of IE remains the standard of care, although practices in prophylaxis have been shown to vary widely. Successful management of IE is dependent on the close cooperation of cardiologists, cardiothoracic surgeons, infectious disease specialists, primary-care providers, and the patients themselves.

The true incidence of IE is difficult to determine because the criteria for diagnosis have changed and the methods of reporting vary in different series.6,7 An analysis based on strict case definitions often reveals that only a small proportion (∼20%) of clinically diagnosed cases are categorized as definite. IE occurs less commonly in children than in adults, with an estimated incidence of one case per 1280 pediatric admissions per year8 vs. approximately one case per 1000 adult hospital admissions per year. However, the incidence of IE in the pediatric population has increased in the past 20 years9 potentially, in part, because of the improved survival of higher-risk neonates.

While the incidence of IE in pediatric patients has been increasing, the disease remains relatively uncommon in children and infants, in whom it is associated primarily with nosocomial bacteremia in the setting of underlying structural congenital heart disease.10,11 The incidence of IE in unrepaired congenital heart lesions has become rare because of surgical advances, which have enabled the correction or palliation of nearly all of these defects. The most common repaired congenital heart lesions predisposing to IE in children include aortic valve stenosis, pulmonary atresia, tetralogy of Fallot, complete atrioventricular canal defect, d-transposition of the great arteries, and coarctation of the aorta.12,13 Unlike most other congenital defects, secundum atrial septal defects and pulmonary valve stenosis are not associated with an increased risk of IE.12

Nosocomial IE secondary to therapeutic modalities (intravenous catheters, hyperalimentation lines, pacemakers, dialysis shunts, etc.) is increasingly common. Nosocomial IE is usually a complication of bacteremia induced by an invasive procedure or a vascular device. IE in the absence of underlying congenital heart disease has been reported to be the cause in 8–10% of pediatric cases.4 There has been an increase in the incidence of fungal endocarditis, which appears to be related to prolonged use of broad-spectrum antibiotics, central venous catheters, and improved survival of sick premature neonates.14,15 The emerging importance of nosocomial IE in industrialized nations has influenced the microbiology of IE, with an increasing prevalence of Staphylococcus aureus and a decreasing prevalence of viridans streptococci among US tertiary-care centers.16 In children, nosocomial IE in the absence of structural heart disease most often affects the mitral or aortic valve.9,17,18S. aureus is a unique pathogen because of its virulent properties, its protean manifestations, and its ability to cause IE on architecturally normal cardiac valves.19

Presence of a prosthetic valve is an important risk factor for IE in adults, with IE occurring in 1–4% of prosthetic valve recipients in the first year following valve replacement and in approximately 1% of recipients annually thereafter.20,21 While prosthetic valves are used less frequently in children, mechanical aortic valve replacement is associated with a significant increase in the incidence of IE.12 Injection drug use is a common predisposing factor for IE in adult patients <40 years of age, with S. aureus being the predominant organism. Although less common in children, the yearly prevalence of injection drug use in children aged 12–17 years is 0.11% in comparison to 0.29% for adults between the age of 18 and 25 years.22 The incidence of IE in adult intravenous drug users may be 30 times higher than the general population.23 Tricuspid valve involvement is noted in 78%, mitral in 24%, and aortic in 8% of drug abusers with IE.24 More than one valve is involved in approximately 20% of cases, and some of these infections are polymicrobial.25,26

The endothelial lining of the heart and the cardiac valves is normally resistant to infection with bacteria and fungi. In vitro observations and studies in experimental animals have demonstrated that the development of IE requires the simultaneous occurrence of several independent events, each of which may be influenced by a host of separate factors.27–30 The valve surface must first be disrupted to produce a suitable site for bacterial attachment. Surface changes may be produced by a variety of local and systemic stresses such as turbulent blood flow in incompletely repaired congenital heart disease or local catheter-induced trauma to the endocardium or valve tissue. These alterations result in the deposition of platelets and fibrin and formation of a so-called sterile vegetation, the lesion of nonbacterial thrombotic endocarditis. Bacteria must then reach this site and adhere to the involved tissue to initiate infection. Transient bacteremia can occur when a mucosal surface heavily colonized with bacteria is traumatized. Certain strains of bacteria appear to have a selective advantage in adhering to platelets and/or fibrin and thus produce IE with a lower inoculum. The ability of these organisms to adhere to nonbacterial thrombotic endocarditis lesions is a crucial early step in the development of IE. Gould and associates showed that organisms frequently associated with IE (enterococci, viridans streptococci, S. aureus, S. epidermidis, and Pseudomonas aeruginosa) adhere more avidly to normal canine aortic leaflets in vitro than do organisms uncommon in IE (Klebsiella pneumoniae, and Escherichia coli).31 In the rabbit model of IE, S. aureus and the viridans streptococci produce IE more readily than do E. coli,32 an observation that correlates with the relative frequency with which these organisms produce IE in humans. Microbial adherence is mediated by several factors, including the presence of surface adhesins such as Fim A, the amount of dextran in the bacterial cell wall, the ability of the organism to bind to fibronectin, and the exposure of extracellular matrix proteins that may support bacterial adherence such as fibrinogen, laminin, and type 4 collagen.33–36

Following microbial adherence to damaged endothelium, the surface is rapidly covered with a protective sheath of platelets and fibrin to produce an environment conducive to further bacterial multiplication and vegetation growth. Microbial growth results in the secondary accumulation of more platelets and fibrin until a macroscopic excrescence or vegetation is present. The culmination of this process is mature vegetation consisting of an amorphous collection of fibrin, platelets, leukocytes, red blood cell debris, and dense clusters of bacteria. The surface of most vegetations consists of fibrin and scant numbers of leukocytes. Clumps of bacteria, histiocytes, and monocytes are usually found deep within the vegetation. Giant cells containing ingested bacteria may be found in some vegetations. Extremely high concentrations of bacteria (e.g., 109–1011 bacteria per gram of tissue) may accumulate deep within vegetations. Some of these bacteria exist in a state of reduced metabolic activity. Following therapy and during the process of healing, capillaries and fibroblasts appear within vegetations, but, without treatment, vegetations are avascular structures.37

Vegetations often prevent proper valvular leaflet or cusp coaptation, resulting in valvular incompetence and congestive heart failure. Vegetation growth may result in leaflet perforation, which can manifest as acute congestive heart failure.38 Patients with mitral or tricuspid valve vegetations may develop chordal rupture when infection progresses beyond the valve orifice. Extension of infection may also occur into surrounding structures such as the valve ring, the adjacent myocardium, the cardiac conduction system, or the mitral-aortic intravalvular fibrosa.39 Rarely, cavitation of periaortic abscesses may occur into the adjacent aortic wall, resulting in the formation of a diverticulum or aneurysm. Even more rarely such aneurysms may perforate into surrounding structures, resulting in aortic-atrial or aortic-pericardial fistulae.40

IE causes the stimulation of both humoral and cellular immunity as manifested by hypergammaglobulinemia, splenomegaly, and the presence of macrophages in the peripheral blood. Rheumatoid factor (anti-IgG IgM antibody) develops in approximately 50% of patients with IE of >6 weeks duration.41 Antinuclear antibodies also occur in IE and may contribute to the musculoskeletal manifestations, low-grade fever, or pleuritic pain.42 Opsonic (IgG), agglutinating (IgG and IgM), and complement-fixing (IgG and IgM) antibodies and cryoglobulins (IgG, IgM, IgA, C3, and fibrinogen), various antibodies to bacterial heat-shock proteins, and macroglobulins all have been described in IE.43–45 Circulating immune complexes have been found in high titers in virtually all patients with IE and may cause a diffuse glomerulonephritis.46 Some of the peripheral manifestations of IE, such as Osler nodes, may also result from a deposition of circulating immune complexes. Pathologically these lesions resemble an acute Arthus reaction. However, the finding of positive culture aspirates in Osler nodes suggests that these may, in fact, be caused by septic emboli rather than immune complex deposition.47

History and Physical

Children with IE typically have an indolent presentation, with generalized symptoms such as prolonged fever with rigors and diaphoresis, fatigue, arthralgias, myalgias, and weight loss.48 Occasionally, children will present acutely ill with a more fulminant course and require urgent intervention. Although the virulence of the infecting organism can influence the acuity of the presentation, the interval from onset of infection to onset of symptoms is usually short. Symptoms in staphylococcal IE may even begin within a few days of the onset of infection.

The symptoms and signs of IE are protean, and essentially any organ system may be involved (Table 37–1). Four processes contribute to the clinical picture: (1) the infectious process on the valve, including the local intracardiac complications; (2) septic or aseptic embolization to virtually any organ; (3) constant bacteremia, often with metastatic foci of infection; and (4) circulating immune complexes and other immunopathologic factors.29,49 As a result, the clinical presentation of patients with IE is highly variable and the differential diagnosis is often broad (Table 37–2). The prevalence of nonspecific symptoms may result in a delay in diagnosis or an incorrect diagnosis of another systemic illness.

In recent years, the patient with low-grade fever, malaise, and peripheral stigmata from long-standing IE is not as common a presentation as in the past, reflecting a higher incidence of nosocomial IE and more effective diagnostic modalities nowadays. Fever is usually present in the current era but may be absent (5% of the cases), especially in the setting of congestive heart failure, immunosuppressive therapy, or previous antibiotic therapy.50,51 Congestive heart failure (CHF) has been reported in 10–20% of pediatric cases of IE.52–54

Audible heart murmurs occur in a majority of children with endocarditis related to valve destruction, associated with congenital heart disease, and as nonrelated innocent murmurs. The classic “changing murmur” is less common and has been reported in 21% of pediatric IE cases.52 Although valvular regurgitation is the most important hemodynamic complication of IE, hemodynamically significant valvular obstruction requiring surgery may occur rarely, even without a prior history of valvular stenosis.55 IE in patients with congenital heart disease palliated with a systemic to pulmonary shunt can present with cyanosis caused by shunt obstruction, without a change in murmur.

The classic peripheral manifestations of endocarditis are much less common in pediatric patients than in adults. Splinter hemorrhages are linear red to brown streaks in the fingernails or toenails. These are a nonspecific finding and often seen in the elderly or in people experiencing occupation-related trauma. Petechiae from local vasculitis or emboli are found after a prolonged course and usually appear in crops on the conjunctivae, buccal mucosa, palate, and extremities. These lesions are initially red and nonblanching but become brown and barely visible in 2–3 days. Osler nodes are small, painful, nodular lesions usually found in the pads of fingers or toes and occasionally in the thenar eminence. These are 2–15 mm in size and are frequently multiple and evanescent, disappearing in hours to days. Osler nodes are rare in cases of acute IE and are not specific for IE, sometimes occurring in systemic lupus erythematosus, marantic endocarditis, hemolytic anemia, and disseminated gonococcal infection, and in extremities with cannulated radial arteries. Janeway lesions are hemorrhagic, macular, painless plaques with a predilection for the palms or soles. These persist for several days and are thought to be embolic in origin and to occur with greater frequency in staphylococcal IE. Roth spots are oval, pale, retinal lesions surrounded by hemorrhage and are usually located near the optic disk. These may also be found in anemia, leukemia, and connective tissue disorders. Splenomegaly is more common in patients with IE of prolonged duration. Splenic septic emboli are common during IE, but localized signs and symptoms of splenic involvement are absent in approximately 90% of patients with this complication.56

Signs and Symptoms of IE

Abscess in or adjacent to the valve annulus is often heralded by the appearance of first- or second-degree heart block and/or fever that persists despite appropriate therapy. Pericarditis is rare but, when present, is usually accompanied by myocardial abscess formation as a complication of staphylococcal infection. Myocarditis may occur as a result of coronary vasculitis or embolic coronary occlusion or from the effects of microbial toxins or immune complex deposition.

Major embolic episodes occur in approximately one-third of cases.52–54 Splenic artery emboli with infarction may result in left upper quadrant abdominal pain with radiation to the left shoulder, a splenic or pleural rub, or a left pleural effusion. Renal infarctions may be associated with microscopic or gross hematuria, but renal failure, hypertension, and edema are uncommon. Retinal artery embolus is rare with one reported pediatric case57 and may be manifested by a sudden complete loss of vision. Pulmonary emboli can be a complication of right-sided IE. Coronary artery emboli usually arise from the aortic valve and may cause myocarditis with arrhythmias or myocardial infarction.

Neurologic manifestations occur in 10–15% of pediatric cases, especially in staphylococcal IE.53,54 Stroke is the most common neurologic complication of IE. Patients with mitral valve IE have a greater risk of stroke than patients with aortic valve IE.58 The development of clinical neurologic deterioration during IE is associated with a two- to fourfold increase in mortality in adults. Mycotic aneurysms of the cerebral circulation occur in 2–10% of the cases. Other features include seizures, severe headache, visual changes (particularly homonymous hemianopsias), choreoathetoid movements, mononeuropathy, and cranial nerve palsies.

Patients with IE may have symptoms of uremia. In the preantibiotic era, renal failure developed in 25–35% of the patients, but presently fewer than 10% are affected. Renal disease can present as transient renal insufficiency or glomerulonephritis and is reported to occur in 2–5% of pediatric IE.53,54 Renal failure is more common with long-standing disease but is usually reversible with appropriate antimicrobial treatment alone.

Septic arthritis has been reported in a small percentage of pediatric cases of IE.52,53

Laboratory Studies

Blood Cultures

The blood culture is the single most important laboratory test performed in a diagnostic workup for IE. Bacteremia is usually continuous and low grade; therefore, cultures do not have to be drawn at the time of fever spikes or chills. Based on adult studies, in approximately two-thirds of cases all blood cultures will yield positive results.59 Two blood specimens will be sufficient to detect the etiologic agent more than 90% of the time. The sensitivity of blood cultures for the detection of streptococci is particularly susceptible to prior antibiotic therapy and is also affected by the media employed.60 Continuous monitoring blood culture systems (e.g., BACTEC and BacT/ALERT) are significantly more sensitive than conventional methods.61 Blood culture media containing neutralizing resin particles have been especially helpful in improving the detection of staphylococci from patients receiving antimicrobial therapy at the time of culture.62

On the basis of these studies, the following procedures for culturing blood are recommended. At least three blood culture sets should be obtained in the first 24 hours. More specimens may be necessary if the patient has received antibiotics in the preceding 2 weeks. Blood cultures drawn within 4 hours may yield equal results to those drawn 12–24 hours apart; however, more positive cultures are required for a diagnosis of IE when drawn at shorter intervals. In general, culture of arterial blood offers no advantage over use of venous blood. At least 1–3 mL of blood should be drawn in infants and young children and 5–7 mL in older children.

The interpretation of positive blood cultures requires consideration of the isolated organism and how likely this organism is as a cause of IE. The following organisms are considered to be likely causes of IE when isolated from two or more blood cultures: S. aureus, viridans streptococci, enterococci (if acquired in the community and not nosocomially), and Group G streptococci. False-positive results are likely to be present when organisms such as Propionibacterium spp., Corynebacterium spp., Bacillus spp., and coagulase-negative staphylococci are recovered from a single blood culture or a minority of blood culture results. However, since these organisms are also capable of causing IE, it is important to determine if there is persistent bacteremia present as opposed to contamination with skin flora. Persistent bacteremia is likely if (1) positive cultures with organisms likely to cause IE are obtained from two samples collected (12 hours apart or (2) if all of three or a majority of four or more separate blood cultures are positive and if the first and last samples are collected at least 1 hour apart.1

Other Blood Laboratory Tests

The utility of other blood tests in the diagnosis of IE is limited. Hematologic parameters are often abnormal in IE, but none is diagnostic. Anemia is frequently present, especially in subacute cases. This anemia usually has the characteristics of anemia of chronic disease, with normochromic, normocytic indices, but can present as hemolytic anemia. Thrombocytopenia and leukocytosis can be seen, sometimes with a high percentage of immature neutrophils (left shift). A significant number of patients have elevation of nonspecific acute-phase reactants such as erythrocyte sedimentation rate, C-reactive protein, procalcitonin, and immunoglobulins. A positive result on assay for rheumatoid factor is found in 40–50% of adult cases, especially when the duration of the illness is >6 weeks.40 Hematuria can develop with associated proteinuria, red blood cell casts, hypocomplementemia, and renal insufficiency.48

Circulating immune complexes and mixed-type cryoglobulins are detectable in most adult patients with IE but also constitute a nonspecific finding.63

Culture-Negative IE

Blood cultures fail to isolate an etiologic agent in 5–7% of cases.48,64 Culture-negative IE is most often associated with antibiotic use within the previous 2 weeks. If blood cultures are negative in definite or possible IE, microbiologic considerations include Bartonella, Coxiella, Brucella, Legionella, and Chlamydia species, and non-Candida fungi.65

Diagnosis of these organisms requires special culture techniques or measurement of specific antibody titers.

Imaging

Echocardiography

Since its first use in the diagnosis of IE in 1973, echocardiography has become paramount in the process of evaluating IE.66 It is of crucial importance in detecting vegetations, echogenic distinct masses from the adjacent valve with independent motion from the valve itself. Vegetations have characteristic findings of a shaggy dense band of irregular echoes in a nonuniform distribution on one or more leaflets (Figure 37–1). Echocardiography may not only confirm the presence of vegetations in the setting of bacteremia, but it also provides important hemodynamic information regarding ventricular function and an estimate of the degree of valvular regurgitation (Figure 37–2). Transthoracic echocardiography (TTE) should be performed in all patients in whom IE appears to be a reasonable diagnosis. TTE is not, however, an appropriate screening test in the evaluation of febrile patients in whom IE is unlikely on clinical grounds or in bacteremic patients with organisms that rarely cause IE, particularly if there is another obvious focus to explain the clinical syndrome.67 TTE is more reliable in the pediatric population, with a reported sensitivity of 81% for detection of vegetations. One important consideration in children with congenital heart disease is that the echocardiogram be performed in a pediatric echocardiography laboratory and evaluated by a pediatric cardiologist because of the presence of underlying cardiac structural abnormalities. Technically inadequate studies are not of any value in the detection of vegetations. Although still controversial, certain characteristics of vegetations have been suggested to be prognostic of the risk for complications such as embolization or the need for surgery.68,69 In general, decisions about surgical intervention should be based on findings on the echocardiogram along with clinical parameters.

Transesophageal echocardiography (TEE) has significantly altered the diagnostic approach to patients with suspected IE (Figure 37–3). TEE has been demonstrated to be more sensitive than TTE in adults70; however, children often have more clear echocardiographic windows by TTE, generally obviating the need for further imaging. TEE is useful in children with poor TTE imaging, with a negative TTE and a high index of suspicion for IE to more precisely define the site of infection, to evaluate prosthetic valve function, and to evaluate for perivalvular abscess.71,72

Electrocardiography

An electrocardiogram should be part of the evaluation of a patient with suspected IE, although it is usually unrevealing. The development of a new arrhythmia has been reported in 5% of cases of endocarditis in congenital heart disease.54 The presence or new appearance of heart block is important evidence of extension of infection to the valve annulus and conduction system.73 A new prolongation of the PR interval in a patient with IE is highly diagnostic of the presence of a ring abscess.

Other Imaging Modalities and Tests

Computed tomography and magnetic resonance imaging of the heart have become more prevalent in pediatrics, although the utility of these techniques in detection of IE in this population has not been evaluated. Labeled white blood cell, antibacterial antibody, and platelet studies have shown promise in experimental IE.74–76 Cardiac catheterization is not used in children, as the anatomic information provided by echocardiography in young patients is usually adequate to establish need for surgical repair or valve replacement.37

Diagnostic Criteria for Ie

IE is typically a syndrome diagnosis based on the presence of multiple findings rather than a single definitive test result. Practical and logical case definitions for IE are important for both clinicians and researchers who study this complex disease. Accurate identification and classification of patients with IE are important in defining natural history, complications, epidemiology, and treatment outcomes.

Early diagnostic criteria developed by Petersdorf and Pellitier in 1977 and von Reyn and colleagues (Beth Israel criteria) in 1982 have been supplanted by the Duke criteria,1 which were first proposed in 1994. Direct comparisons of the Duke and Beth Israel criteria have now been carried out in 11 major studies, involving nearly 1400 patients. Multiple studies have demonstrated the superiority of the Duke criteria for the diagnosis of IE in children.3,4 Modifications of the Duke criteria have recently yielded more specificity to the schema.2 The modified Duke criteria for the diagnosis of IE are provided in Tables 37–3 and 37–4.

General Guidelines

Following the establishment of a diagnosis of IE using clinical, microbiological, and echocardiographic methods, antibiotics should be administered in a dose designed to give sustained bactericidal serum concentrations throughout much of or the entire dosing interval. Certain general principles have been accepted, which provide the framework for the current recommendations for treatment of IE (Table 37–5). Guidelines for outpatient parenteral antibiotic therapy for IE in adults as well as general guidelines for outpatient parenteral antibiotic therapy in all age ranges have been published.77,78 Pediatric outpatient parenteral antibiotic therapy has been demonstrated to be successful, to have a relatively low risk of complications, and to have a low rehospitalization rate mostly related to issues with vascular access.79 Patients selected for outpatient therapy should have responded clinically to inpatient therapy, with negative blood cultures, no evidence of intracardiac complications, and stable hemodynamic parameters. Patients’ families need to be compliant and capable of managing the technical aspects of intravenous therapy. Such patients require careful, regular monitoring in association with a home health-care service and prompt access to medical care.48

The American Heart Association has issued treatment guidelines for children48 and, more recently, updated specific treatment guidelines based on the microbiologic etiologic agent.65 General therapeutic considerations are summarized in Tables 37–6 to 37–9.37,48,65 All dosing is listed as milligram of antimicrobial per kilogram of patient body weight. It is important to remember that the total dose should never exceed the maximum adult dose.

Medical Therapy

Staphylococci

The great majority of S. aureus isolates produce a β-lactamase and, therefore, are highly resistant to penicillin G and are termed methicillin-susceptible S. aureus (MSSA). The drugs of choice for native valve MSSA are semisynthetic, β-lactamase-resistant penicillins, such as nafcillin or oxacillin (Table 37–6). The addition of gentamicin for the first 3–5 days is optional, as it may increase the killing of the staphylococci and facilitate clearance of bacteremia, although it may increase rates of nephrotoxicity and ototoxicity. In patients without a history of type 1 penicillin-allergic reactions, a first-generation cephalosporin such as cefazolin is indicated with or without gentamicin for the first 3–5 days. In patients with MSSA and allergies to β-lactams, vancomycin is the drug of choice with or without gentamicin for the first 3–5 days. However, it must be noted that some evidence suggests than vancomycin is an inferior drug in the treatment of MSSA IE, predominantly because of its slow bactericidal activity and poor tissue penetration.80

Coagulase-negative staphylococci are usually methicillin resistant (MRSA). Because of cross-resistance, cephalosporins should not be used in these patients. Vancomycin is usually given for at least 6 weeks with or without gentamicin for the first 3–5 days.

Staphylococcal prosthetic valve IE (PVE) is associated with high mortality and requires aggressive management. Treatment for MSSA PVE is with nafcillin or oxacillin, in combination with rifampin for 6–8 weeks and gentamicin during the first 2 weeks. For MRSA PVE, vancomycin is used in combination with rifampin for 6–8 weeks and gentamicin is added during the first 2 weeks. In order to minimize resistance to rifampin, this medication should be added only after antibiotics active against staphylococci, such as a β-lactam or vancomycin and an aminoglycoside, have been started and the infection burden of bacteria is significantly reduced. In some cases, MRSA resistant to aminoglycosides (reported to be decreasing in frequency81) can be treated with fluoroquinolones, depending on the results of susceptibility testing. Daptomycin is a lipopeptide antibiotic that is bactericidal and has been shown to be effective in treatment of staphylococcal endocarditis in adults.82 However, experience with daptomycin in children is limited, and thus a safe pediatric dose has not been established.83 Staphylococcal PVE has been reported to have a very high mortality in adults, even with aggressive medical therapy.84 For this reason, early surgical valve replacement is often considered. S. aureus PVE has been reported to cause a high incidence of intracerebral hemorrhage in adults,85 and thus the risks of continuing anticoagulation need to be carefully considered.

Viridans Group Streptococci, Streptococcus Bovis, and Other Nonenterococcal Streptococci

The treatment for endocarditis caused by viridans streptococci is based on the in vitro penicillin minimum inhibitory concentration (MIC) (Table 37–7). Streptococci with a penicillin MIC ≤0.12 μg/mL are considered highly susceptible and are usually treated with penicillin G or ceftriaxone for 4 weeks. Comparable cure rates can be achieved with a combination of penicillin or ceftriaxone with low-dose gentamicin for 2 weeks. A cure rate of 98% has been reported with these regimens in adults,86,87 but there are no published data on the efficacy of ceftriaxone for the treatment of IE in children. Cefazolin or other first-generation cephalosporins may be substituted for penicillin in patients whose penicillin hypersensitivity is not of the immediate type. Vancomycin is recommended for patients allergic to β-lactams.

When IE is caused by streptococcal strains with a penicillin MIC >0.12 μg/mL and <0.5 μg/mL, combination therapy with penicillin for 4 weeks and low-dose gentamicin for the first 2 weeks of treatment is recommended. In patients allergic to β-lactams, a 4-week course of vancomycin is recommended. When native valve or PVE IE is caused by streptococcal strains with a penicillin MIC >0.5 μg/mL or nutritionally variant streptococci (now classified as Abiotrophia species), the regimen for penicillin-resistant enterococcal IE is recommended (Table 37–8).

For highly penicillin-susceptible streptococci PVE (MIC ≤0.12 μg/mL), penicillin G for 6 weeks and gentamicin for 2 weeks are usually indicated. When PVE is caused by relatively penicillin-resistant streptococci (MIC (>0.12–0.5 μg/mL), penicillin G is recommended for 6 weeks and gentamicin for 4 weeks.

Enterococci

IE caused by enterococci is usually associated with Enterococcus faecalis and occasionally with Enterococcus faecium. Enterococci are increasingly resistant to most classes of antibiotics, making treatment difficult (Table 37–8). Because of a defective bacterial autolytic enzyme system, cell-wall-active agents are bacteriostatic against enterococci and should not be given alone to treat IE. When used in combination with gentamicin, penicillin G and ampicillin facilitate the intracellular uptake of the aminoglycoside, resulting in a bactericidal effect against enterococci. Before embarking on therapy, susceptibility of the enterococcal isolate should be determined for penicillins, vancomycin, and aminoglycosides. For strains with intrinsic high-level resistance to penicillin (MIC >16 μg/mL), vancomycin is indicated. Vancomycin is synergistic with aminoglycosides, particularly gentamicin. When high-level resistance to aminoglycosides is detected (500–2000 μg/mL for gentamicin), combination with cell-wall-active agents is no longer synergistic and therefore not recommended. Limited data are available to guide therapy in these difficult cases; however, some experts will attempt high-dose ampicillin combined with imipenem or ceftriaxone for 8–12 weeks.

IE caused by vancomycin-resistant enterococci (VRE) is difficult to treat. Most vancomycin-resistant strains of E. faecalis and some vancomycin-resistant strains of E. faecium are susceptible to achievable concentrations of ampicillin. In such cases, the recommended therapy is ampicillin or penicillin combined with gentamicin. Even when enterococci are considered resistant to ampicillin, higher doses can be used in order to achieve sustained plasma levels of >100–150 μg/mL with some treatment efficacy and little toxicity. In 1999, the FDA approved quinupristin/dalfopristin (QD) to treat infections associated with vancomycin-resistant E. faecium bacteremia when no alternative treatment is available. However, QD alone is unlikely to be curative in VREF IE because it is not usually bactericidal against E. faecium. Endocarditis models suggest that the association of QD with ampicillin may be beneficial. It is important to note that E. faecalis is not susceptible to QD. In 2000, the FDA approved linezolid to treat infections associated with vancomycin-resistant E. faecium, including cases with bloodstream infection. However, linezolid is bacteriostatic against VRE and therefore cannot be recommended for VRE IE. Newer agents such as daptomycin, telavancin, and dalbavancin may be useful in such cases based on experimental models, but clinical experience is lacking. Unfortunately, case reports of enterococcal resistance to daptomycin are already emerging.88

Gram-Negative Ie

HACEK organisms, including Haemophilus spp. (Haemophilus parainfluenzae, H. aphrophilus, and H. paraphrophilus), Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae are not common in children. These organisms have fastidious growth characteristics, and thus standard culture incubation for 2–3 weeks is recommended for cases in which IE is suspected and the initial blood cultures are negative. Third-generation cephalosporins are recommended for the treatment of HACEK IE (Table 37–9), with a duration of 3–4 weeks for native valves and 6 weeks for PVE.89 HACEK isolates are typically susceptible in vitro to fluoroquinolones, aztreonam, and trimethoprim–sulfamethoxazole. However, since clinical data are still lacking, these agents should be reserved as an alternative therapy in patients who cannot tolerate β-lactams.

Other Gram-negative bacteria are an infrequent cause of IE in children and are most often nosocomially acquired. Treatment of organisms such as P. aeruginosa, E. coli, and Serratia marcescens should be individualized, based on antimicrobial susceptibility of the specific isolate.48 Empiric therapy with an extended-spectrum penicillin/β-lactamase inhibitor or cephalosporin together with an aminoglycoside is recommended until final culture testing is completed. Total duration of therapy should be 6 weeks and should be implemented in consultation with an infectious disease specialist.

Fungal Ie

The incidence of fungal IE has increased significantly in the past decade, in most cases caused by Candida or Aspergillus species. Although current recommendations strongly favor a combined medical–surgical approach, the introduction of new fungicidal agents may reduce that need. Any documented or suspected case of fungal IE requires an infectious disease consultation.

A mainstay of antifungal drug therapy is liposomal amphotericin B for at least 6–8 weeks. This agent is much less toxic than routine amphotericin B, which produces multiple side effects, including fever, chills, phlebitis, headache, anorexia, anemia, hypokalemia, renal tubular acidosis, nephrotoxicity, nausea, and vomiting. Depending on the isolate, some experts recommend the addition of 5-fluorocytosine or rifampin to amphotericin B, as these drugs may act synergistically to potentiate fungal killing. In patients who are unable to undergo surgery, after an initial course of amphotericin B, an azole is often used for long-term suppressive therapy. The role of newer antifungals such as posaconazole, micafungin, and capsofungin in the treatment of fungal IE remains unclear, despite their increased use, as reports of efficacy of these agents are limited.

Culture-Negative Ie

As a result of the substantial issues in treatment decisions, consultation with an infectious disease specialist is recommended. The primary considerations for therapy are directed against staphylococci, streptococci, enterococci, and the HACEK organisms (Table 37–9). An initial approach is to use ceftriaxone and gentamicin. A β-lactamase-resistant penicillin such as ampicillin–sulbactam should be added if there is a high suspicion of staphylococcal IE. Vancomycin should be substituted in patients who are allergic to penicillin and when suspicion of MRSA is high. If clinical improvement occurs, some authorities recommend discontinuation of treatment with the aminoglycoside after 2 weeks. The other agent(s) should be continued for a full 6 weeks of treatment. Patients who are at risk of unusual causes of IE such as Coxiella, Bartonella, Legionella, and Brucella can be empirically started on doxycycline and ciprofloxacin; however, these pathogens require targeted therapy, which should be undertaken in consultation with an infectious diseases specialist.

Surgical Therapy

Valve replacement has become an important adjunct to medical therapy in the management of IE and is now used in at least 25% of the cases. The generally accepted indications for surgical intervention during active IE are listed in Table 37–10. Of particular importance to pediatric patients with palliated congenital heart disease is development of aortopulmonary shunt obstruction and infected prosthetic material such as in right ventricle to pulmonary artery conduits. The hemodynamic status of the patient, not the activity of the infection, is the critical determining factor in the timing of cardiac valve replacement. Surgery should not be delayed because a full course of antibiotic therapy has not been completed or the patient is still bacteremic. Indeed, the incidence of reinfection of a prosthetic valve after surgery is below 1%. Thus, when CHF is diagnosed in patients with aortic valve IE or persists despite therapy in mitral valve IE, surgery is indicated. Although not systematically studied, most experts recommend continuation of antibiotic therapy postoperatively for 2–6 weeks when surgery is undertaken with active IE.90

Most patients with PVE (except those with late disease caused by penicillin-sensitive viridans streptococci) require valve replacement. Similarly, valve replacement is necessary in a significant proportion of patients with IE on native valves after a medical cure, particularly with aortic valve involvement, which is more likely to be hemodynamically significant.

Medical therapy alone can be considered even in the face of the listed risk factors if there are significant comorbid conditions such as central nervous system bleeding. The morbidity and mortality of surgery must be carefully considered when patients are at high risk of bypass complication.

Prevention of Ie

Antimicrobial prophylaxis before selected dental and invasive surgical and diagnostic procedures has become standard and routine in most countries, despite the fact that no prospective study has been performed that proves that such therapy is clearly beneficial. Studies have shown that amoxicillin prophylaxis results in a decrease in procedure-related bacteremia in a general population of pediatric patients.91 However, only one-half of all patients who develop IE have a cardiac disorder that would have prompted IE prophylaxis in the first place.37 Maintenance of meticulous dental hygiene is of equal importance to antibiotic prophylaxis in the prevention of IE, and compliance with dental hygiene is difficult in the pediatric population. In addition, it is advisable to instruct all patients to avoid gingival trauma with toothpicks and high-pressure water irrigation devices.

The guidelines for antimicrobial prophylaxis for IE formulated by an expert committee of the American Heart Association are the regimens most widely used by clinicians in the United States. The guidelines were significantly revised in 2007 as the committee concluded that (1) IE is much more likely to result from frequent exposure to random bacteremia than to medical procedures, (2) only an extremely small number of cases of IE might be prevented by antibiotic prophylaxis even if 100% effective, (3) the risk of antibiotic-associated events exceeds the benefit or prophylaxis, and (4) proper maintenance of oral health and hygiene is more important than antibiotic prophylaxis for dental procedure in reducing the risk of IE. The procedures with the highest risk of bacteremia were refined, and prophylaxis is now recommended only for patients with the highest risk of an adverse outcome after an episode of IE.92

Table 37–11 outlines the conditions associated with the highest risk for IE based on the new American Heart Association guidelines. Certain procedures and conditions are known to present the highest risk of bacteremia, and therefore antibiotic prophylaxis is recommended. This encompasses all dental procedures that involve manipulation of gingival or periapical region of teeth or perforation of oral mucosa. This also includes surgical procedures in the setting of an active infection, invasive respiratory tract procedures, and procedures where antibiotics would be given to prevent wound infections (Table 37–12). However, there is no evidence of the effectiveness of prophylaxis during these procedures to prevent IE. Routine prophylaxis solely to prevent IE is no longer recommended for GI or GU procedures. For example, clinicians must often use judgment in selecting dose and duration of antimicrobial therapy in elderly or obese patients or in those with underlying renal disease. Furthermore, there are sometimes instances in which the risk of prophylactic therapy may actually outweigh the risk of postprocedure endocarditis. Patients in such circumstances often have cardiac lesions of questionable or little hemodynamic consequence, have a documented or possible drug allergy, or are undergoing procedures in which the risk of bacteremia is extremely low.

The antimicrobial regimens suggested by the American Heart Association for IE prophylaxis are listed in Table 37–13.

Pearls/Special Situations

1. Antibiotic doses in children are calculated per kg but should never exceed the maximum published adult dosage.

2. Obtain an infectious disease consult in any complex case of IE or when there is any uncertainty in the diagnosis or therapy. The complications of IE can be devastating, so it is better to be overly careful.