A Review of Infective Endocarditis Associated With Congenital Heart Disease

Authors:
Evan J. Leonard, MS, MMS, PA-C; Brandon E. Kuebler, MD; Martin M. Zenni, MD; and Christopher B. Scuderi, DO

Citation:
Leonard EJ, Kuebler BE, Zenni MM, Scuderi CB. A review of infective endocarditis associated with congenital heart disease. Consultant. 2017;57(11):363-641.

ABSTRACT: This literature review discusses the pathology, risk factors, epidemiology, clinical manifestations, and diagnostic approach to infective endocarditis (IE) in patients with congenital heart disease (CHD). The prevalence of IE in this population has increased as a result of advances in recognition of CHD, along with surgery, neonatal care, and other therapies, which have increased the number of persons who survive cardiac anatomic anomalies. The increased risk of IE in persons with CHD is related to the vulnerable exposed endocardium, as well as the potential stasis of blood flow within the heart.

KEYWORDS: Congenital heart disease, infective endocarditis, ventricular septal defect, atrial septal defect, tetralogy of Fallot, Staphylococcus aureus, viridans group streptococci, enterococci, atypical bacteria

Infective endocarditis (IE) is a bacterial infection that is typically caused by Staphylococcus or Streptococcus species and can be fatal if untreated. The exposed endocardium of persons with congenital heart disease (CHD) is more susceptible to abscess formation and the development of difficult-to-treat infections, which may become vegetative lesions, which in turn may become septic emboli.

The diagnosis of IE in persons with CHD can be elusive compared with that of IE in unaffected persons. IE typically presents more insidiously in persons with CHD. The scarring and/or prosthetic material associated with surgical correction of the heart defect can make it more difficult to distinguish many of the objective findings typically associated with IE. Patients with CHD require special consideration during clinical assessment, including a low threshold to evaluate them for signs and symptoms of IE. Health care providers must be aware of the potential for IE, its unique presentation, and the potential difficulty of diagnosis in patients with CHD.

Understanding the risk factors for and the process by which bacteremia and seeding of the vulnerable endocardium occurs in a patient with CHD is key to identifying the pathogen and subsequently determining the best empiric antibiotic therapy.

IE in the Congenitally Malformed Heart

Persons with CHD have structural heart changes (native or postoperative) that create turbulence and sheer force in blood flow that disrupt the endocardium, leaving the heart vulnerable by exposing subendocardial collagen and extracellular matrix. (Click here for a Consultant360 exclusive sidebar on the genetics of CHD by Evan J. Leonard, MS, MMS, PA-C.) During the healing process, production of tissue factor, deposition of fibrin, and platelet adherence lead to hemostasis and scar formation. The resultant inflammation causes endothelial cells to express β1 integrins, which bind circulating fibronectin to the endothelial surface and promote scar formation.¹ Pathogenic organisms may settle in and infect the endocardium in these scarred areas, in suture lines, or along the rings of implanted heart valves. With sequestration and limited blood supply to a damaged area, formation of vegetation and/or abscess may occur, resulting in IE on native or prosthetic valves.¹

Staphylococcus aureus is pervasive, with fibronectin-binding proteins on its surface. When integrins are exposed, they provide a self-adhesive surface for circulating staphylococci. Staphylococcus species may also infect normal undamaged endocardium. Once adherent, S aureus internalizes and escapes host defenses. Antibiotic treatment may cause acute bacterial endocarditis and spread to distant organs by liberating septic emboli or bacteria.¹

Some viridans group streptococci have a type 1 fimbrial subunit that is a major adhesion protein to fibrin platelet aggregates.² Microbial invasion of the endocardium may cause vegetation formation that may erode into the myocardium and produce an abscess. These friable vegetations have the capability of causing emboli, which may cause distal abscess formation, septic infarcts, and mycotic aneurysms.³

IE is categorized as acute or subacute. Acute IE is a tumultuous, destructive infection frequently involving a highly virulent organism such as Staphylococcus or Pseudomonas and has high morbidity and mortality, even when identified and treated aggressively. Subacute IE is characterized as being more temporally “benign” with a typically more indolent course, often greater than 6 weeks, and usually involves a less-virulent organism such as Streptococcus infecting an anatomically scarred heart. Subacute IE typically presents insidiously, often eluding diagnosis for weeks or months, and may cause fever of unknown origin.¹

CHD occurs in up to 75 of 1000 live births.⁴ Of these, ventricular septal defect (VSD) accounts for 28.3%; pulmonary stenosis for 9.5%; patent ductus arteriosus for 8.7%; mixed valvular disease, such as VSD with pulmonary stenosis, for 6.8%; atrial septal defect (ASD) for 6.7%, aortic stenosis for 4.5%; and coarctation of the aorta for 4.2% (Figure).⁵ Overall, CHD affects the sexes equally, but specific diseases affect the male and female populations in different ratios.⁶

Risk Factors

Numerous risk factors for IE have been identified in patients with CHD. Careful review of patients’ living environment, age, lifestyle, occupational or recreational risk, animal or livestock exposure, and intravenous (IV) drug use is important.

The presence of cyanotic CHD confers the highest risk for IE. Among the most common cyanotic heart lesions are tetralogy of Fallot, truncus arteriosus, tricuspid valve abnormalities, total anomalous pulmonary venous connections, pulmonary atresia, and hypoplastic left heart syndrome. Rushani and colleagues found that in 34,279 children with CHD who had IE, 34% had cyanotic CHD.⁷ Considering that the vast majority of congenital heart abnormalities are noncyanotic, the finding that the much smaller population with cyanotic CHD has the highest risk for IE is quite notable.

Elder and Baltimore found that IE represented 0.05 to 0.12 per 1000 pediatric admissions.⁸ Children younger than 30 days represented 7.3% of the 1480 cases, and that less than one-third of these neonates had CHD. Cyanotic patients had more than 6 times the rate of IE compared with those with acyanotic CHD. The authors also found that the risk of IE was significantly higher in patients with functionally 1 ventricle, because these patients undergo multiple surgeries and have varying degrees of cyanosis. The authors also followed the cases of aortic surgery patients for 10 years and found the incidence for IE was 26% in the prosthetic valve cohort vs 5% in the native valvuloplasty group. Following cardiac surgery, the highest risk for IE was in patients with aortic stenosis.⁸

Another major predictor for IE is the age of the patient. Children younger than 3 years are at a significantly higher risk for IE than children aged 6 to 18 years.⁷ The frequency of IE is equivalent among the male and female populations; thus, gender is less important than age at diagnosis. IE in the adult population with CHD tends to have a male preponderance, possibly explained by the higher rate of risky behavior among men.⁷ Adolescents with CHD have associated lifestyle-related risk factors for IE. Any opportunity for bacteria to enter the bloodstream should be avoided, including tattoos and body piercings, particularly of the tongue or other mucous membranes.⁹

The risk for IE in CHD is greatly elevated in patients in the postsurgical period, in persons who use IV drugs, in persons with occupations associated with microbial exposure (eg, veterinarian, rancher, sewage worker, plumber, farmer), and in persons who sustain animal scratches or bites, skin lacerations, penetrating wounds, or compound fractures. In these cases, Staphylococcus species are the most common infectious agent.¹

Johnson and colleagues¹⁰ compared a cohort of patients younger than 20 years who presented with IE to one institution from 1980 to 2011 with a cohort who presented from 1950 to 1979. In the more recent cohort, 47 patients presented with 53 episodes of IE, of whom 36 (77%) had CHD and 24 had undergone cardiac surgery before their first IE episode of IE. No differences were identified in patient demographics, history of CHD, or infecting organisms between the 2 cohorts, but 1-year mortality was significantly lower in the modern cohort (4%) vs the historical cohort (38%). When the 2 cohorts were combined, 17 of the 97 patients seen over the entire 60-year period had prosthetic valves at IE diagnosis, possibly indicating that the number of patients with CHD was higher than reported.

Other risk factors associated with IE in the pediatric population include indwelling central venous catheters,¹¹ neoplasms, prematurity, connective tissue disorders, and diabetes mellitus.¹²

Poor dentition is a risk factor for IE in CHD, with viridans streptococci identified in a large percentage of patients undergoing dental extraction.² A careful dental examination with promotion of dental hygiene should be routine in such patients. Appropriate treatment of gingival disease and removal of infected or decayed teeth should be advocated, with appropriate antibiotic prophylaxis. Some authors have suggested that simply brushing and flossing the teeth and chewing food places those with CHD at higher risk of contracting IE than does undergoing dental procedures.^1,2

NEXT: Etiology of IE and Clinical Manifestations

Etiology of IE

The microbiologic findings in IE in CHD patients are similar to those in the overall IE patient population (Table 1).¹⁰ Staphylococcus species are particularly pathologic and can adhere to damaged and even minimally abnormal endocardium. Streptococcus species also commonly infect damaged endocardium. Streptococci must be strongly considered in the CHD population when community-acquired IE is suspected.

Staphylococci are responsible for the majority of cases of IE worldwide, with S aureus causing 80% to 90% of those infections. Other infectious staphylococci identified are Staphylococcus epidermidis, Staphylococcus saprophyticus, and Staphylococcus capitis. S aureus has the capability of destroying the endocardial surface, frequently causing fulminant disease, particularly when it involves left-sided cardiac valves. This can lead to subsequent valvular destruction, heart failure, perivalvular extension with conduction disturbances, embolization, and metastatic infection. Staphylococci may infect and destroy previously healthy valves, while streptococci are typically associated with previously damaged heart valves.^1,3,4,13

Murdoch and colleagues found similar etiologies for IE among all age groups and all subgroups, including IV drug users, patients with prosthetic valves, patients with CHD, and patients with intracardiac devices.¹³ They reported S aureus as the most common pathogen, identified in 31% of 2781 hospitalized patients with IE, followed by infection with viridans streptococci, identified in 17% of patients. They also identified a high prevalence of atypical organisms, with 27 cases of Coxiella burnetii infection (Q fever), as well as 1 case of Tropheryma whipplei infection. Bacteria in the HACEK group (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella species) were found to be relatively uncommon in North America. Community-acquired infections accounted for approximately 71% of all cases of IE, with the proportion of health care–associated cases of IE being the highest in North America at 37%.¹³

Fortún and colleagues identified 45 cases of IE in patients with CHD.¹⁴ The most frequent heart conditions among the patients were VSD (31%), tetralogy of Fallot (19%), and ASD (11%). IE was found to be community-acquired in 62% of the patients; Streptococcus species were the most frequently identified pathogens (33%), followed closely by Staphylococcus species (32%).¹⁴ They also reported that 13% of patients had fungal IE, with Candida being the primary agent, along with 1 case of Aspergillus fumigatus IE.¹⁴ Fungal IE survival rates are less than 20%, not only because of the difficulty in diagnosis and treatment, but also because patients usually have a predisposing risk factor such as CHD, as well as possibly having neutropenia, asplenia (as in heterotaxy syndrome), or endovascular/intracardiac devices. Fungal infections are typically associated with large, bulky vegetations that can obstruct valve orifices that may embolize to large blood vessels such as the femoral artery.

The common causative agents in native valve IE, α-hemolytic viridans streptococci, are responsible for 30% to 65% of cases in older children and adults. They are a natural part of the oral flora and include Streptococcus sanguinis, Streptococcus bovis, Streptococcus mutans, and Streptococcus mitis. S bovis is part of the natural flora of the gastrointestinal (GI) tract, its presence is strongly suggestive of a GI malignancy, polyp formation, or diverticular disease.¹⁵ Streptococcus pneumoniae often results in an acute, fulminant illness, which leads to severe valvular damage, perivalvular extension, embolic complications, pericarditis, and meningitis with a high mortality rate (25%-30%).

Group A streptococci rarely cause IE in adults, but in children with CHD, they can cause devastating disease. Streptococcus pyogenes is the causative agent in childhood pharyngitis, scarlet fever, impetigo, cellulitis, erysipelas, fasciitis, and myositis, thus it can easily infect a congenitally malformed heart. Group B streptococci (eg, Streptococcus agalactiae) are chiefly responsible for infections in neonates and parturient women. Group B species tend to have a higher virulence than group A species.¹⁵

Enterococcus species cause 5% to 18% of IE cases, with the vast majority of infections with Enterococcus faecalis (80%) or Enterococcus faecium (10%).¹⁵ These microbes are natural residents of the GI and genitourinary (GU) tracts and may enter the blood after manipulation of the colon, urethra, or bladder, as well as a GI tract rupture due to diverticular disease or intestinal ulceration. The isolation of S saprophyticus indicates a possible GU source of infection. In patients who are immobilized or who have paraplegia or quadriplegia, a sacral ulcer can introduce enterococcus into the bloodstream due to its close proximity to the anus. These organisms are able to form a biofilm in the heart, as well as develop a resistance to vancomycin.¹⁵

Gram-negative bacteria cause only 1% of IE cases but are noteworthy given their high virulence and the difficulty in isolating the organism. The fastidious gram-negative rods of the HACEK group reside in the oropharynx and, because of their growth requirements (eg, carbon dioxide), they may take 3 to 4 weeks to grow in culture. Of this group, Haemophilus species are the most common etiologic agent, typically forming large, friable vegetations that often embolize.¹⁵

Atypical bacterial agents include Pseudomonas, Rickettsia, and Bartonella species; the vast majority of patients with pseudomonal IE are IV drug users.¹⁵ Rickettsial organisms, such as C burnetii, may be the culprits in cases of IE in patients who have had contact with cattle, sheep, or goats. The aortic valve is involved in 80% of cases of C burnetii IE; however, the organism is very difficult to culture, and any clinical suspicion should warrant a serologic antibody titer.¹⁵ Infections with Bartonella species in persons with CHD have been increasing in North America and Europe, most likely due to the increased survival rate of neonates born with CHD.¹⁶

Brucella species have been implicated in a small number of cases.¹⁵ These organisms are usually ingested in unpasteurized milk products, and infection is an occupational hazard for veterinarians, shepherds, and livestock handlers, especially those with CHD. IE is the most common cause of brucellosis deaths, and surgery is usually required to achieve a cure.

Blumental and colleagues¹⁷ described what is possibly the first reported case of viral IE, in a 4-month-old boy with trisomy 21 and ASD who had undergone cardiac surgery; culture results eventually revealed the culprit to be the enterovirus coxsackievirus B2. Although this case study has received criticism for not directly showing virions within the endocardium, it does suggest a possible etiology when all others have been ruled out.

In as many as 20% of cases of IE, blood cultures are negative for pathogens.¹⁵ The primary reasons are inadequate technique, involvement of a highly fastidious organism, involvement of a nonbacterial organism (ie, fungus, virus), or the previous use of prophylactic antibiotics, resulting in internal decolonization.¹⁵

Clinical Manifestations

When considering IE in patients with CHD, physical examination findings may be misleading. Discerning a CHD-related pathologic murmur or a subtle change in an existing murmur from a vegetation and valve insufficiency resulting from IE may be difficult. Pediatric patients may be afebrile and only mildly symptomatic at the time of presentation. Electrocardiography (ECG) is poorly sensitive and rarely diagnostic in CHD patients.

The classic initial signs and symptoms of subacute IE include but are not limited to fever (temperature > 38°C), night sweats, anorexia, arthralgias, fatigue, and weight loss over the course of 3 to 8 weeks. However, patients with S aureus or atypical bacterial infection may present with severe, more fulminant disease characterized by acute-onset high fever (temperature > 40°C), cardiac failure, signs of infectious sepsis (eg, calor, hypotension, tachycardia), and neural deficits due to possible septic emboli from intracardiac vegetations.

The archetypal signs of IE consist of fever, new murmur or worsening of an existing murmur, hematuria (glomerulonephritis), splenomegaly, subungual splinter hemorrhages, Osler nodes, Janeway lesions, conjunctival hemorrhage, Roth spots, and, rarely, cutaneous purpura fulminans or erythema nodosum. However, the pathognomonic Janeway lesions, splinter hemorrhages, and Osler nodes occur uncommonly in adults with CHD and even less so in children with CHD.¹⁵

In an international prospective cohort study of 2781 adults with IE, among the most common presenting symptoms were fever, an elevated C-reactive protein (CRP) level, an elevated erythrocyte sedimentation rate (ESR), and hematuria; 48% of the cohort had a new murmur, 20% had worsening of an existing murmur, and 11% had splenomegaly.¹³

In their study of children with IE, Luca and colleagues reported that fatigue, malaise, fever, exertional dyspnea, chest pain, and cough were the most common presenting symptoms; these children also frequently presented with anorexia, headache, and weight loss. Additionally, 31% of the pediatric patients had neurologic symptoms such as dizziness, paralysis, and paresthesia.¹⁸ These findings highlight the importance of understanding the comorbidities of patients at risk for or with IE (eg, age, congenital malformations, immune status, diabetes, etc), which may present quite differently depending on demographics.

Al-Senaidi and colleagues’ report of an 8-year-old girl with a 2.5-month history of fever, anorexia, weight loss, and a pruritic, erythematous, bilateral, lower-extremity rash demonstrates the unique nature of IE in the pediatric CHD population.¹⁹ At presentation, she was tachycardic with a temperature as high as 40°C , as well as a mild nonproductive cough. Her weight of 16.3 kg was below the third percentile. She multiple dental caries, a hyperdynamic precordium with a thrill, a grade 4/6 systolic murmur, and nontender hepatosplenomegaly. On hospital day 8, she developed erythema nodosum on the lower extremities. Transesophageal echocardiography (TEE) eventually confirmed a VSD with vegetation just outside of the congenital lesion.¹⁹

NEXT: Diagnosis, and Prognosis

Diagnosis

The Duke criteria are generally used to confirm suspicion of IE (Table 2).¹³ A diagnosis of definite IE requires either 2 major criteria, 1 major and 2 minor criteria, or 5 minor criteria. 

The major criteria are as follows¹³:

• Positive blood cultures for microorganisms consistent with IE (ie, viridans streptococci, S bovis, HACEK organisms, S aureus, enterococci) from a minimum of 2 separate samples, drawn 12 hours apart, or from all of 3 or most of 4 or more cultures with the first and last sample drawn at least 1 hour apart.

• The presence of a vegetation or abscess on transthoracic echocardiography (TTE) or TEE. The echocardiogram must demonstrate at least 1 of the following: an oscillating intracardiac mass on a valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; abscess; or partial dehiscence of a prosthetic valve, including new valvular regurgitation.

The minor Duke criteria are as follows: a predisposing heart condition or IV drug use; temperature above 38°C; vascular phenomena (ie, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhage, Janeway lesions); immunologic phenomena (ie, glomerulonephritis, Osler nodes, Roth spots, positive rheumatoid factor); and microbiologic evidence (positive blood culture finding but does not meet major criteria, or serologic evidence of active infection with an organism consistent with IE).¹³

While the major Duke criteria for IE are often present in children, the minor Duke criteria are seldom seen in children with IE.¹³ In a small child, a TTE is sufficient, but in adolescents or pediatric patients weighing 60 kg or more, TEE should be performed.²⁰ Typical echocardiographic findings in IE are vegetation, abscess, aneurysm, fistula, leaflet perforations, or prosthetic valvular dehiscence.¹⁵

Urinalysis should be done routinely in IE patients in order to screen for renal complications. If immune-complex–mediated glomerulonephritis is present, urinalysis results usually are abnormal. Proteinuria is the most frequent finding (50%-80% of cases).¹⁵ Microscopic hematuria is seen in approximately 50% of cases.¹⁵ Gross hematuria indicates the presence of focal or diffuse glomerulonephritis or a potential embolic renal infarction. Glomerulonephritis due to IE typically presents with urinary red blood cell casts and dysmorphic red blood cells.¹⁵

When clinical suspicion warrants, or if blood cultures are negative, individual serology tests should be ordered, such as with enzyme-linked immunosorbent assay, polymerase chain reaction, or specific immunoglobulin antibodies. In the case of fungal IE, Candida species will grow on culture but Aspergillus species will not. The advent of rapid microbial detection systems has shortened the wait for culture results, in some cases to less than 1 hour.²¹ Some systems can rapidly identify (within a few hours) the antibiotic susceptibility of the organism, as well.²²

Other diagnostic findings that are helpful but not part of the Duke criteria are elevated CRP and/or ESR levels,⁴ neutrophilic leukocytosis, ECG changes (eg, atrioventricular or bundle branch blocks), thrombocytopenia, and elevated creatine kinase-MB (CK-MB) fraction or troponin levels. Unless they represent a new finding, the ECG changes may prove helpful in patients with CHD, in many of whom a dysrhythmia already is present, typically a right or left bundle branch block. Similarly, in the neonate with a septal defect, the CK-MB fraction may already be elevated due to the exposed endocardium.¹⁵

Prognosis

The prognosis for patients with CHD and IE is typically good, unless staphylococci or some other virulent, fastidious organisms are present. The location and size of the vegetation, as well as the timing of surgical procedures, also affect prognosis. Typically, the larger the vegetation, the higher the risk for severe emboli or mycotic aneurysm formation.

Indications for surgical procedures in adults include the presence of large vegetations and vegetations at high risk for embolization; abscess; persistent bacteremia despite adequate and appropriate antibiotic therapy; major conduction abnormalities; congestive heart failure; and severe valvular insufficiency. The timing of surgery is variable, but increasing evidence is confirming the notion of the earlier the better, especially in cases of staphylococcal and fungal IE. Surgery may be required for prosthetic valve IE to remove the infected valve ring.

Early surgical debridement for larger vegetations in staphylococcal and fungal IE is recommended. The EASE (Early Surgery Versus Conventional Treatment in Infective Endocarditis) trial demonstrated the significant benefit of early surgery in patients at high risk for emboli and with large vegetations.²³ Indications for surgery in patients with left-sided, native-valve IE are heart failure, uncontrolled infection, and the prevention of embolism.²⁴

Genetic testing and vaccinations for IE prevention are in development, and in a population that has a significantly higher risk for community-acquired IE, persons with CHD will be more safeguarded against this potentially deadly infection. Due to the vulnerability of patients with CHD and their potential to present with subtle or equivocal signs and symptoms such as fatigue, fever, anorexia, and weight loss, it is of utmost importance to include IE in the differential diagnosis. 

Evan J. Leonard, MS, MMS, PA-C, is an assistant professor at the Nova Southeastern University Physician Assistant Program in Jacksonville, Florida.

Brandon E. Kuebler, MD, is an assistant professor in the Department of Pediatrics, Division of Pediatric Cardiology, at the UF College of Medicine in Jacksonville, Florida.

Martin M. Zenni, MD, is an associate professor in the Department of Medicine, Division of Cardiology, and is the medical director of Nuclear Cardiology at the UF College of Medicine in Jacksonville, Florida.

Christopher B. Scuderi, DO, is an associate professor in the Department of Community Health and Family Medicine at the UF College of Medicine and medical director of UF Health Family Medicine and Pediatrics–New Berlin in Jacksonville, Florida.

References:

1. Habib G, Hoen B, Tornos P, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Eur Heart J. 2009;30(19):2369-2413.
2. Farbod F, Kanaan H, Farbod J. Infective endocarditis and antibiotic prophylaxis prior to dental/oral procedures: latest revision to the guidelines by the American Heart Association published April 2007. Int J Oral Maxillofac Surg. 2009;38(6):626-631.
3. Mitchell RN. Heart. In: Kumar V, Abbas AK, Aster JC, eds. Robbins Basic Pathology. 10th ed. Philadelphia, PA: Elsevier; 2017:chap 11.
4. McNeil JC, Ligon JA, Hulten KG, et al. Staphylococcus aureus infections in children with congenital heart disease. J Pediatric Infect Dis Soc. 2013;2(4):​337-344.
5. Marian AJ, Brugada R, Roberts R. Cardiovascular diseases caused by genetic abnormalities. In: Fuster V, Walsh RA, Harrington RA, et al, eds. Hurst’s the Heart. Vol 2. 13th ed. New York, NY: McGraw-Hill; 2011:chap 82.
6. Brown DW, Fulton DR. Congenital heart disease in children and adolescents. In: Fuster V, Walsh RA, Harrington RA, et al, eds. Hurst’s the Heart. Vol 2. 13th ed. New York, NY: McGraw-Hill; 2011:chap 83.
7. Rushani D, Kaufman JS, Ionescu-Ittu R, et al. Infective endocarditis in children with congenital heart disease: cumulative incidence and predictors. Circulation. 2013;128(13):1412-1419.
8. Elder RW, Baltimore RS. The changing epidemiology of pediatric cardiology. Infect Dis Clin North Am. 2015;29(3):513-524.
9. Sable C, Foster E, Uzark K, Bjornsen K, et al; American Heart Association Congenital Heart Defects Committee of the Council on Cardiovascular Disease in the Young, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease. Best practices in managing transition to adulthood for adolescents with congenital heart disease: the transition process and medical and psychosocial issues: a scientific statement from the American Heart Association. Circulation. 2011;​123(13):1454-1485.
10. Johnson JA, Boyce TG, Cetta F, Steckelberg JM, Johnson JN. Infective endocarditis in the pediatric patient: a 60-year single-institution review. Mayo Clin Proc. 2012;87(7):629-635.
11. Rosenthal LB, Feja KN, Lavasseur SM, Alba LR, Gersony W, Saiman L. The changing epidemiology of pediatric endocarditis at a children’s hospital over seven decades. Pediatr Cardiol. 2010;31(6):813-820.
12. Day MD, Gauvreau K, Shulman S, Newburger JW. Characteristics of children hospitalized with infective endocarditis. Circulation. 2009;119(6):865-870.
13. Murdoch DR, Corey GR, Hoen B, et al; ICE Investigators. Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study. Arch Intern Med. 2009;169(5):463-473.
14. Fortún J, Centella T, Martín-Dávila P, et al. Infective endocarditis in congenital heart disease: a frequent community-acquired complication. Infection. 2012;41(1):167-174.
15. Haldar SM, O’Gara PT. Infective endocarditis. In: Fuster V, Walsh RA, Harrington RA, et al, eds. Hurst’s the Heart. Vol 2. 13th ed. New York, NY: McGraw-Hill; 2011:chap 86.
16. Abendah FI, Bazan JA, Davis JA, Zaidi AN, Daniels CJ, Firstenberg MS. Bartonella henselae prosthetic valve endocarditis in an adult patient with congenital heart disease: favorable outcome after combined medical and surgical management. J Card Surg. 2012;27(4):449-452.
17. Blumental S, Reynders M, Willems A, et al. Enteroviral infection of a cardiac prosthetic device. Clin Infect Dis. 2011;52(6):710-716.
18. Luca AC, Begezsan II, Iordache C. Particularities in diagnosis and treatment for infectious endocarditis in children. Rev Med Chir Soc Med Nat Iasi. 2012;116(4):1028-1032.
19. Al-Senaidi KS, Abdelmogheth A-AA, Balkhair AA. Complicated subacute bacterial endocarditis in a patient with ventricular septal defect. Sultan Qaboos Univ Med J. 2014;14(1):e130-e133.
20. Penk JS, Webb CL, Shulman ST, Anderson EJ. Echocardiography in pediatric infective endocarditis. Pediatr Infect Dis J. 2011;30(12):1109-1111.
21. Miller MJ. Rapid microbial methods: understanding the technologies and regulatory expectations for validation and implementation. National Institute for Pharmaceutical Technology and Education. http://www.nipte.org/sites/default/files/documents/Rapid%20Microbiological%20Methods%20-%20
22. Michael%20Miller.pdf. Accessed October 17, 2017.
23. Halford C, Gonzalez R, Campuzano S, et al. Rapid antimicrobial susceptibility testing by sensitive detection of precursor rRNA using a novel electrochemical biosensing platform. Antimicrob Agents Chemother. 2013;57(2):​936-943.
24. Kang D-H, Kim Y-J, Kim S-H, et al. Early surgery versus conventional treatment for infective endocarditis. N Engl J Med. 2012;366(26):2466-2673.
25. Hoen B, Duval X. Infective endocarditis. N Engl J Med. 2013;368(15):1425-1433.