AHA Scientific Statement In 2002, the American Heart Association (AHA) published Unique Features of Infective Endocarditis in Childhood, 1 which reviewed epidemiology, pathogenesis, diagnosis, clinical and laboratory findings, treatment, and prevention of infective endocarditis (IE) with particular attention to children. Since that time, otherAHA reports have focused on new recommendations for treatment of IE in adults (in 20052 ) and on major changes regarding prevention of IE (in 20073 ). This document updates these issues and other concerns regarding IE, with specific atten- tion to the disease as it affects infants and children. In particular, theimpactofincreasedsurvivalforchildrenwithcongenitalheart disease (CHD) on the epidemiology of IE is updated, and newer tools useful for diagnosis and treatment in the pediatric popula- tion are reviewed. This review emphasizes changing manage- ment perspectives and discussion of new agents that have utility for treatment of resistant organisms. In addition, proper use of the diagnostic microbiology laboratory remains critical to the diagnosis and management of children with IE, and newer diag- nostic guidelines that have improved sensitivity and specificity for confirming the diagnosis of IE will be reviewed. Because of improved infrastructure available for home intravenous therapy, an update on outpatient management, an increasingly accepted approach for stable patients who are at low risk for complica- tions, will also be discussed. Finally, since the publication of the last AHA document on pediatric IE, recommendations for prevention of IE have been modified substantially, and the most current recommendations are incorporated from the perspective of pediatric cardiovascular concerns. Classification of Recommendations In pediatrics, there are not likely to be any randomized con- trolled trials for treatment of IE, which posed a challenge for the writing group in compiling recommendations. Therefore, many of the indications are based on consensus. In cases of strong consensus that an intervention be considered as standard-of- care practice with scientific evidence, interventions were des- ignated as Class I indications. Where the wording of treatments indicates a recommendation, the standard classification is used. Strength of the recommendation is according to the ACC/AHA classification system for recommendations (Table 1). Epidemiology and Clinical Findings of IE in Children In a previous report, IE occurred less often in children than in adults and accounted for approximately 1 in 1280 (0.78 per 1000) pediatric admissions per year from 1972 to 1982 at a In a recent multicenter report,5 the annual incidence rate in the United States was between approximately 0.05 and 0.12 cases per 1000 pediatric admissions from 2003 to 2010, without a significant trend. Although the reported hos- pitalization rates for IE vary considerably among published series, both the overall frequency of endocarditis among chil- dren and a shift toward those with previous cardiac surgery appear to have increased in recent years in some reports.5 8 This may be related to improved survival among children who are at risk for endocarditis, such as those with CHD (with or without surgery) and hospitalized newborn infants. 2015 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0000000000000298 TheAmerican HeartAssociation makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on May 4, 2015, and the American Heart Association Executive Committee on June 12, 2015. A copy of the document is available at http://my.americanheart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. The American Heart Association requests that this document be cited as follows: Baltimore RS, Gewitz M, Baddour LM, Beerman LB, Jackson MA, Lockhart PB, Pahl E, Schutze GE, Shulman ST, Willoughby R Jr; on behalf of the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young and the Council on Cardiovascular and Stroke Nursing. Infective endocarditis in childhood: 2015 update: a scientific statement from the American Heart Association. Circulation. 2015;132:1487 1515. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the Policies and Development link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright- Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page. Infective Endocarditis in Childhood: 2015 Update A Scientific Statement From the American Heart Association Robert S. Baltimore, MD, Chair; Michael Gewitz, MD, FAHA, Vice Chair; Larry M. Baddour, MD, FAHA; Lee B. Beerman, MD; Mary Anne Jackson, MD; Peter B. Lockhart, DDS; Elfriede Pahl, MD, FAHA; Gordon E. Schutze, MD; Stanford T. Shulman, MD; Rodney Willoughby, Jr, MD; on behalf of the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young and the Council on Cardiovascular and Stroke Nursing Before the 1970s, 30% to 50% of US children with IE had underlying rheumatic heart disease.9 Because the prevalence of rheumatic heart disease has declined in developed coun- tries, including the United States, it has now become relatively unusual for patients with IE from the developed world to have underlying rheumatic heart disease. In the past 2 decades, CHD has become the predominant underlying condition for IE in children from the developed world >2 years of age. In fact, there has been an increase in cases of IE associated with CHD because most patients with CHD survive much longer than they did several decades ago. Early surgical correction of lesions that were major risk factors for IE in the past has also changed the substrate for this disease. Although congenital heart defects, such as aortic valve abnormalities, ventricular septal defect, and tetralogy of Fallot, are still common under- lying conditions, an increasing proportion of children with IE have had previous corrective or palliative surgery for complex cyanotic CHD, with or without implanted vascular grafts, patches, or prosthetic cardiac valves.10 14 Postoperative IE is a long-term risk after correction of complex CHD, especially in those with residual defects or in cases in which a surgical shunt is constructed or other prosthetic material is left in place. Increasingly, IE develops in the absence of CHD. This cir- cumstance is often associated with central indwelling venous catheters (central lines). The complexities of patient man- agement in neonatal and pediatric intensive care units have Table 1. Applying Classification of Recommendations and Level of Evidence A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1489 increased the risk of IE in children with structurally normal hearts. Currently, in approximately 8% to 10% of pediatric IE develops without structural heart disease or any other readily identifiable risk factors. In these situations, the infection usually involves the aortic or mitral valve second- ary to Staphylococcus aureus bacteremia.6,10 12 Recent initia- tives developed to reduce central line bloodstream infections will likely improve the prognosis for all critically ill children, including those with cardiac conditions, and may impact IE development further in the diverse group of vulnerable patients with central lines. Interestingly, children with congenital or acquired immunodeficiencies but without identifiable risk factors for IE do not appear to be at increased risk for endo- carditis compared with the general population. Furthermore, factors often associated with IE in adults, such as intravenous drug abuse and degenerative heart disease, are not common predisposing factors in children.7 11 IE in Children With Previous Cardiac Surgery or After Placement of Transcatheter Devices Corrective surgery with no residual defect eliminates the attrib- utable risk for endocarditis in children with ventricular and atrial septal defects or patent ductus arteriosus 6 months after surgery. However, surgery itself, including such elements as central vas- cular catheters, intravenous alimentation, and days the patient resides in the intensive care unit, may be important risk fac- tors for the development of IE. Approximately 50% of children with IE complicating CHD have had previous cardiac surgery, particularly palliative shunt procedures or complex intracardiac repairs. Morris et al12 reviewed cumulative incidences of endo- carditis for a number of congenital cardiac lesions in a follow- up series of Oregon residents. The highest annualized risk for IE was found in children who had had repair or palliation of cyanotic CHD. The greatest risk among those patients was for those who had either undergone surgery for obstruction to pul- monary blood flow or had prosthetic aortic valve replacement. In a follow-up of the series of Oregon residents, the highest inci- dence of IE in postoperative patients has been in the cohort with aortic valve stenosis, and this has increased over time, with a Endocarditis may manifest as a late complication, with presentation years after congenital heart surgical repair, and may be associated with a fulminant course or antibiotic failure.14,15 The incidence of IE in the first postoperative month is low for most defects and increases with time after surgery. An exception to this trend is that when prosthetic valves or conduits are used in surgical repairs and hemodynamic prob- lems persist, the risk of IE is high even in the immediate post- operative period (first 2 weeks after surgery).12 Two recently published studies showed a 25% incidence of previous cardiac surgery in patients with congenital heart disease who required surgery during active IE.16,17 Russell et al18 reported 34 patients who met indications for surgical management of IE (of whom 37% had prior cardiac surgery) from a 21-year single-center review through 2011 at Children s Memorial Hospital, Chicago, IL. Five had opera- tive mortality, and all deaths occurred in infants, with a mean age of 2.5 months. The infective organisms were identified in 86% of cases, with the most common being S aureus (n=8) and viridans streptococci (n=6). The Ross operation was per- formed successfully in 5 children with severe aortic valve dis- ease. Ten of the 34 patients required reoperations at a later time. The increasing prevalence of transcatheter placement of devices such as septal or vascular occluders and coils pro- vides another potential risk factor for IE, particularly in the early postdeployment period before endothelialization has Although a long-term study of transcatheter closure of atrial septal defects19 showed no cases of IE, several case reports of endocarditis related to transcatheter device treat- ment of atrial and ventricular septal defects and patent ductus arteriosus do suggest that residual defects after device place- ment may be a factor in the risk for IE.20 23 IE in Newborn Infants In a recent multicenter review, 7.3% of cases of pediatric IE (108 of 1480) were diagnosed in the first month of life.24 Improved and widely available imaging technology, particu- larly echocardiography, and increased clinical awareness have greatly facilitated the diagnosis of IE in this patient group. The incidence of neonatal IE has increased in the past 2 decades in large measure because of the increasing use of invasive tech- niques to manage neonates with multiple complex medical problems, even those with structurally normal hearts. Central venous catheters designed to be in place for prolonged peri- ods of time, such as peripherally inserted central catheters and tunneled central venous catheters, provide a portal of entry for surface bacterial despite the most meticulous management. As a result of the indwelling lines, infections frequently involve right-sided heart structures. It has been estimated that fewer than one-third of cases of neonatal endocarditis occur in the presence of congenital cardiac disease.24 26 A recent review showed that 31% of infants who died of IE were premature.24 The most common infecting organisms were S aureus, coagu- lase-negative staphylococcus strains, Gram-negative bacterial species, and Candida species. The clinical manifestations of IE in the neonate are vari- able and nonspecific and may be indistinguishable from sep- ticemia or from congestive heart failure associated with other In infants, septic emboli from IE are common, resulting in foci of infection outside the heart (eg, osteomy- elitis, meningitis, or pneumonia). Neonates with IE often have feeding difficulties, respiratory distress, tachycardia, and hypotension. As with older children, neonates also may have a new or changing heart murmur. Many neonates with IE also have neurological signs and symptoms (eg, seizures, hemipa- resis, or apnea). However, although arthritis and arthralgia are common findings in older children with IE, arthritis is rarely described in neonates. Osler nodes, Roth s spots, Janeway lesions, and splinter hemorrhages are also not mentioned in published cases of IE in neonates. Pathogenesis Early histopathologic studies in humans and decades-long investigations that have included an animal model of experi- mental endocarditis have confirmed 2 critical histopathologic findings: (1) Damaged or denuded endothelium is necessary for initial pathogen colonization of a cardiac nidus; and (2) Gram-positive cocci, the predominant pathogens in both native and prosthetic value infections, express multiple adhesins that serve as virulence factors through their ability to enhance host cell/substrate attachments that are important in both the initia- tion and propagation of endocardial infection. (Adhesins are discussed further in a separate section.) Denuded cardiac endothelium can occur when there is tur- bulence caused by abnormal cardiac structures, in particular stenotic or regurgitant valves, that results in high-velocity jets of blood. Once the endothelium is damaged, the host response includes platelet and fibrin deposition, leading to so-called nonbacterial thrombotic endocarditis (NBTE), at the wound site. NBTE serves as an excellent nidus for subsequent bac- terial or fungal colonization in a patient with bacteremia or fungemia. The prevailing notion is that activities of daily living, such as chewing food, toothbrushing, and flossing, account for most bloodstream seeding of an NBTE site. There are additional mechanisms involved in endocardi- tis pathogenesis. Right-sided endocarditis can occur when there are intravenous catheters, illicit intravenous drug use, or cardiovascular implantable electronic device leads that dwell in the right side of the heart. Damage to the endothe- lium occurs by 2 mechanisms. One involves direct damage produced by the foreign body rubbing directly against the endothelial surface. The other is via an indirect effect, such as when a foreign device interferes with normal tri- cuspid valve function and causes regurgitant jets of blood. Bacteremia may be caused by entry of organisms at the skin site of percutaneous catheters or leads, via the catheter lumen, or in contaminated infusate. Microorganisms carried by the bloodstream enter the right side of the heart, poten- tially causing IE on preexisting NBTE. IE can also occur as a result of direct infection of an indwelling device. This occurs at the time of device placement into a cardiac locus (eg, valves, leads, other types of devices) and is an example of surgical site infection. These infections can occur despite the administration of antibiotic prophylaxis at the time of placement of cardiovascular devices such as heart valves, pacemaker leads, or left ventricular devices. Adhesins Virulence factors that are involved in bacterial adherence, so- called adhesins, have received the bulk of recent investigative attention. Advances in molecular biological techniques have been crucial in characterizing these cell surface structures, with attention specifically to staphylococcal, streptococcal, and enterococcal species, which account for the large majority of IE cases. These adhesins attach to either host cell structures or extracellular molecules that bind to host cells or to extracel- lular matrix. The availability of an experimental animal model of endocarditis has been a pivotal aspect of these pathogenesis investigations. It has served as the ultimate evaluation of in vitro molecular techniques to obtain mutant and recombinant isolates that are developed to examine the effects of a single purported virulence factor expressed by a wild-type strain. Considering the fact that Gram-positive cocci typically express multiple adhesins, the ability to demonstrate the role of a single adhesin in infection pathogenesis is remarkable. For example, this approach demonstrated pilus involvement in attachment to collagen by Streptococcus gallolyticus. This was the first time that a virulence factor was demonstrated in an animal model of Interestingly, strains that expressed pil1 did not adhere to either fibronectin or fibrinogen but did form biofilm in vitro. A nonpathological Lactococcus lactis strain that by recombinant techniques expressed Pil1 in vitro was examined with its parent strain that did not express Pil1 in a rat model of experimental endocarditis. The results suggested that Pil1 was important in vivo as a virulence factor; 82% of rats challenged with the Pil1+ strain developed experimental endocarditis, in contrast to the animals that received the Pil1 strain (36%, The big 3 pathogens (viridans group streptococci [VGS], S aureus, and Enterococcus species) that account for the large majority of endocarditis cases have been the primary focus of pathogenesis studies.31 Adhesins of S aureus, which have been referred to as MSCRAMMs (microbial surface com- ponents recognizing adhesive matrix molecules), are surface molecules involved in staphylococcal attachment to collagen, thrombospondin, laminin, fibrinogen, and fibronectin.32 These interactions with host proteins not only may be important in the initial adherence of bacteria to a site of endothelial damage but also may be operative in bacterial persistence and engulf- ment by the host cell (endothelial cells, platelets). Similarly, there have been several bacterial surface structures identified in strains of VGS and Enterococcus species that appear criti- cal in endocarditis pathogenesis. Study of pathogenic mechanisms in IE is pivotal as we consider potential advances in infection treatment and preven- tion in the future. This knowledge serves as a foundation for the development of novel clinical tools that include therapeu- tics and vaccines. Indeed, identification of a virulence factor resulted in development of a vaccine that reduced the risk of endocarditis development in an animal model.33 Pathogenesis of IE on Prosthetic Material Because perivalvular infection that involves the sewing ring is commonplace among patients with prosthetic valve endocardi- tis, particularly mechanical valves, the pathogenic mechanisms reviewed previously in this section apply to prosthetic valve endocarditis. In addition, biofilm formation can be operative in infection of prosthetic valves, similar to infection of a broad array of indwelling cardiovascular and noncardiovascular devices.34 A mature biofilm represents a unique and complex environ- ment for organisms to attach to and thrive on a device surface. Both antimicrobial agents and immune cells have difficulty in penetrating biofilm, and because of metabolic changes of infecting organisms in biofilm, the ability of antimicrobial agents to kill biofilm-associated organisms is greatly reduced. Because of this, infection relapse at a prosthetic valve site is thought to be increased. Oral/Dental Considerations The oral mucosa and tooth surfaces of children who are beyond infancy are populated by a variety of pathogenic and Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1491 nonpathogenic bacteria, which are representative of hun- dreds of strains of aerobic and anaerobic species.,35,36 This oral flora, in both health and disease, is different from adults and less diverse, but it becomes more like that of adults as the child ages, including increases in the percentage of VGS ( -hemolytic streptococci), Prevotella, and Actinomyces spe- In health, the child s oral flora has a variety of VGS, Neisseria species, Haemophilus species, and Staphylococcus species. In older children, species responsible for periodontal diseases (eg, Capnocytophaga) can be found along with oth- ers known to cause IE (eg, Aggregatibacter actinomycetem- This is particularly relevant with regard to the formation of plaque on the teeth of children at risk for IE. Dental plaque biofilm formation begins soon after a tooth surface is cleaned, and in the absence of oral hygiene, this bio- film thickens and evolves to include a more pathogenic bacte- rial flora largely isolated from the immune system. In contrast to plaque in adults, plaque bacteria on the visible surfaces of the teeth (supragingival) in children are similar to those in the gingival crevice (subgingival space), where there are more Gram-negative and anaerobic species than other sites in the oral The host response to plaque is gingival inflammation and enlargement (gingivitis). Gingivitis can result in an increased depth to this shallow gingival crevice between the tooth surface and the gingival crevicular mucosa that is more difficult to clean with a toothbrush and floss. In the absence of disease, the cre- vicular mucosa serves as a barrier to bacterial invasion. As in adults, however, the child s gingival crevice is most likely the source of virtually all transient bacteremia that occur from the mouth, whether from office-based dental procedures or routine activities of daily living such as toothbrushing. Gingival inflam- mation, however, may lead to thinning and ulceration, allowing dense colonies of bacteria and bacterial byproducts ready access to the increased gingival capillary circulation. Bacteremia may then result from minimal gingival manipulation. Children have a much lower prevalence and severity of gingivitis and periodon- titis than adults, and data from bacteremia studies in adults may not be representative of children. Bacteremia From Dental Procedures Dental procedures are a frequent source of bacteremia, par- ticularly from VGS.40 48 Multiple clinical studies of chil- dren over the past 40 years focused on the impact of 1 of the following risks for development of bacteremia: class of prophylactic antibiotic drug49 ; nature and invasiveness of ; indices of oral hygiene and dis- ; timing of blood culture draws before, dur- ing, and after the dental procedure45,48,56 ; various methods of microbial analysis and identification44,57 ; and the impact of these variables on surrogate measures of risk for IE, such as the incidence, duration, nature, and magnitude of bactere- Clearly, these surrogate measures are also influenced by multiple host factors. These variable risks are associated with a wide range (0% 97%) in the incidence of bacteremia in children after various dental procedures and other manipulations of the gingiva, for example, tooth extractions (0% 96%)41,44,45,48 50,53,57 60 ; teeth cleaning and electric toothbrushing (0% 78%)42,45,47,55,61 63 ; res- ; dental injections (16% 97%)52,64 ; and other manipulations (13% 44%).42,44,46,51 53 Of the more than 100 oral bacterial species recovered from blood cultures in children after dental procedures, the number and variety of species reflect the spectrum of oral flora in health and disease (Table 2). They also reflect the varied microbiological meth- odologies used in these studies (eg, culture-based rather than molecular), with the recognition that many bacterial species clearly enter the bloodstream but are not cultivable and there- fore not recorded.44,49,57 Of greatest importance is the subset of bacterial species reported in blood cultures after dental proce- dures that are known to cause IE.66 Finally, the varied method- ologies and results make it impossible to differentiate among procedures with regard to their risk for causing bacteremia. The collective published data from adult and pediatric stud- ies suggest that the vast majority of dental office visits result in some degree of risk for bacteremia, and the emphasis has therefore changed from a focus on specific dental procedures to a focus on gingival manipulation of any kind.3 The role of duration of bacteremia as a risk factor for IE is uncertain. Older guidelines and some pediatric bacteremia studies reported positive blood cultures for only short peri- ods (10 15 minutes) after tooth extraction(s),56,67 but the vast majority of studies did not include blood draws beyond that time frame. A study of teenagers and adults demonstrated that blood cultures can remain positive for upwards of an hour after a dental procedure,48 and a pediatric study reported that blood cultures can remain positive for >45 minutes.46 The incidence of positive blood cultures drops sharply after the procedure such that the period of risk rarely exceeds 30 minutes. A few studies report the magnitude of bacteremia in chil- dren after dental procedures,43,44,47,49,56,57 often using cell lysis filtration or centrifugation rather than conventional broth- based methods. Cell lysis methods can be problematic, being time consuming, expensive, less sensitive for some oral bacte- rial species, and slower in detection, and having an increased risk of contamination. Results from different studies reflect the difficulty of determining magnitude, but the collective results suggest that the magnitude from dental procedures is low. Data from a large study of adults that used broth-based meth- ods and molecular methodology for identification suggest that the magnitude of bacteremia resulting from toothbrushing and a dental extraction, opposite ends of the spectrum of gingival invasiveness, are both relatively low at <104 colony-forming units per milliliter of blood.68 The degree to which systemic antibiotic drugs reduce the incidence, duration, nature, or magnitude of bacteremia associated with dental procedures is controversial. Large, well-designed studies suggest that amoxicillin has a highly statistically significant impact on reducing the incidence and duration of bacteremia and changes the species identified after dental procedures in children.45 It is not clear whether this antibiotic elimination of bacteria takes place in the gingi- val crevice or the bloodstream or whether it reduces the risk for IE. Given the variability in outcomes from bacteremia stud- ies and the mounting evidence that dental office procedures are at most a rare cause of IE, there has been a steady shift in the direction away from an emphasis on antibiotic prophy- laxis and toward a focus on oral hygiene and diseases as far more important risk factors for cases of IE that result from Impact of Oral Disease and Hygiene Versus Dental Procedures on Bacteremia AHA guidelines have long proposed that maintaining oral health may be important in the overall effort to prevent IE,67,69 and there is increasing support from studies that report a fre- quent occurrence of bacteremia with toothbrushing (39% It has also been suggested that chewing food may result in bacteremia, but there are no studies to confirm this in Some studies reported no impact from oral hygiene or disease on bacteremia after dental procedures.49,51,55 Other studies of bacteremia after den- tal procedures support an association between various indices of oral hygiene and gingival and dental disease (caries) with the incidence of bacteremia from dental office-based proce- dures and from routine daily activities. Virtually all dental office procedures have the potential to create a transient bacteremia. Because children are recom- mended to have dental cleaning procedures every 6 months, this suggests that office-based bacteremia may occur upwards of twice per year. Data from bacteremia studies strongly sug- gest that the incidence of bacteremia annually from tooth- brushing and other daily activities far exceeds that of dental office procedures, perhaps by hundreds of times per year.43,68 It is unknown whether frequency of bacteremia is more impor- tant than magnitude with regard to risk for IE, but current data support the importance of a focus on maintenance of good oral hygiene, prevention of gingival and dental disease, and access to routine dental care for children at risk for IE. Cases of IE from oral bacterial pathogens in children most likely result from exposure to relatively frequent, low-grade bacteremia from these activities of daily living. Results of Clinical Studies of IE Prophylaxis for Dental Procedures There has not been a prospective, randomized, placebo- controlled study of the efficacy of antibiotic prophylaxis to prevent IE in people whose risk is from dental procedures. The few published retrospective, epidemiological studies that relate to this question have had varied outcomes with respect to benefit from antibiotic prophylaxis. When an invasive pro- cedure has occurred in close proximity to the onset of symp- toms of IE, it cannot be determined that it caused IE, because there may have been episodes of bacteremia from natural causes in the same time frame. Table 2. Bacteria Recovered From Blood After Dental Procedures* in Children ; A georgiae46 ; A gerensceriae46 ; A israelii45,47 ; ; A lingnae46 ; A meyeri56 ; A meyeri/odontolyticus45 ; A naeslundii46,56 ; ; A odontolyticus45,46,48 ; A viscosus45,46,56 ; A urinae57 ; A viridans46 ; B licheniformis57 ; B megaterium57 ; B pumilus57 ; B capillosus40 ; B distasonis48 ; B fragilis48 ; C hofmanii45,51 ; E aerofaciens45,48 ; E lentum45 ; E ventriosum40 ; F fusiforme45 ; F nucleatum45,48 ; F varium48 ; H parainfluenza40,42,44 46,48,50 ; L acidophilus48 ; L brevis47 ; L casei56 ; L paracasei56 ; L greyi47 ; M nonliquefaciens45 ; N catarrhalis45 ; N cinerea47,48 ; N flava46 ; ; N pharynges46 ; N polysaccharea53 ; N sicca/subflava48 ; P asaccharolyticus45 ; P micros45,48,56 ; P prevotii45 ; P acnes46 ; P corporis48 ; P melaninogenica45,50,61 ; P acnes43,54 ; P jensenii38 Rothia; R dentocariosa44,54 ; R mucilaginosus44 Staphylococcus; S aureus42,44,52,53,57 ; S auricularis48 ; S capitis46 48,56,57 ; S cohnii46 ; ; S haemolyticus46 48 ; S hominis46,47,53,56 ; ; S saccharolyticus48 ; S saprophyticus46 ; S schleiferi46,48 ; ; S warneri46,47,56 S anginosus group42,43,45,49,53,64 ; S anginosus48,56 ; S constellatus45,46 ; S bovis group; S bovis42,48,64 ; S gordonii46,52,57 S mutans group; S mutans42,44 46,48,51,53,54,56,57 ; S sobrinus47,56,64 S mitis group; S infantis44 ; S mitis42,44 48,51 53,56,57,64 ; S pneumoniae46,53 ; S oralis (S mitior, S sanguis II)40,44 47,49,52,57,64 S sanguinis group; S parasanguinis46,56 ; S sanguinis40,42,44 47,49,50,53,56,57,64 S salivarius group57 ; S salivarius45 48,52,53,56,57,64 ; S vestibularis47,52 ; V alcalescens61 ; V dispar56 ; V parvula40,44,48 *Dental procedures include dental extractions, restorations, dental hygiene (cleaning) procedures, toothbrushing, and other procedures. (Continued) Table 2. Continued Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1493 In 2008, the National Institute for Health and Clinical Excellence (NICE) guidelines in the United Kingdom con- cluded that the use of antibiotic prophylaxis before any invasive procedures should cease, unless requested by the patient.71 A subanalysis of data from a large, nationwide study in England72 comparing the incidence and mortality from IE in 373 chil- dren <18 years old, both before and after the NICE guidelines, reported no change in the incidence of IE.73 Although small in size, this subanalysis is the strongest study currently available concerning the efficacy of antibiotic prophylaxis for children, and it lends support to the position that antibiotic prophylaxis is ineffective and that it would be reasonable to shift the dis- proportionately large focus on antibiotic prophylaxis for dental procedures to oral hygiene and prevention of oral disease. Recommendation 1. It is reasonable to shift the disproportionately large focus on antibiotic prophylaxis to an emphasis on oral hygiene and prevention of oral disease (Class IIa; Level of Evidence B). Diagnosis Clinical Findings in Children and Adolescents The presentation generally is indolent, with prolonged low- grade fever and a variety of somatic complaints, including fatigue, weakness, arthralgias, myalgias, weight loss, rigors, and diaphoresis. Although these are nonspecific findings, the presence of this cluster of symptoms requires careful evalu- ation for IE in certain settings, such as in the patient with underlying heart disease. In contrast, on occasion, the presen- tation may be fulminant, with rapidly changing symptoms and high, spiking fevers. These children are acutely ill, and some require urgent intervention. In these children, infection caused by Streptococcus pneumoniae or S aureus is likely. The clinical findings of IE in children relate to 4 underly- ing phenomena: bacteremia (or fungemia), valvulitis, immuno- logic responses, and emboli. Valvulitis may result in changing cardiac auscultatory findings or the development of congestive heart failure. Extracardiac manifestations of IE (eg, petechiae, hemorrhages, Roth s spots, Janeway lesions, Osler nodes, or splenomegaly) are considerably less common in children than in adults. Renal abnormalities (eg, glomerulonephritis, infarct) can result from an embolic or immune complex mediated pro- cess. Emboli to the abdominal viscera, the brain, or the heart are common (especially noted in the adult literature) and may produce symptoms associated with ischemia, hemorrhage, or both. In rare cases, central nervous system mycotic aneurysms can occur; their rupture can be catastrophic. The cardiac examination in the child with IE is highly variable and depends on the type of heart disease present and the particular site of infection. Valvular lesions that produce leaflet destruction result in regurgitant murmurs. In children with cyanotic CHD who have undergone systemic-pulmonary artery shunt procedures, however, the murmur may not change. Rather, declining systemic oxygen saturation may reflect graft infection with obstruction of flow. Patients with right-sided, catheter-related intravascular infection may have few or no specific cardiovascular signs or may present with asthma-like symptoms or signs related to septic pulmonary embolization As described above, an increase in the population of chil- dren requiring a long-term central venous catheter (CVC) and of those with complex congenital heart defects and correspondingly complex surgical interventions requiring prosthetic materials has changed the epidemiology and micro- biology of IE and impacted the diagnostic approach. Duke Criteria The modifications of the Duke criteria for diagnosis of IE74 76 have been demonstrated to be helpful in diagnosing IE in chil- dren, although the number of patients in these studies has been small, and there have been questions of specificity (Tables 3 The presence of a CVC may prolong a bacteremic state, thus requiring the removal of the CVC before criteria The incorporation into the modified Duke criteria of new molecular diagnostic methods on surgical specimens (eg, polymerase chain reaction [PCR]) has been proposed to help identify organisms in culture-negative IE.80 Although the revised Duke criteria have been validated for the diagno- sis of IE in children,9 the emergence of S aureus as the most common pathogenesis has important implications. The Duke criteria identify S aureus bacteremia as a major criterion, regardless of whether the infection was nosocomial or com- munity acquired or whether a primary source of infection was present or absent.75 suggests that the presence of a CVC may skew the diagnosis of IE, because the attempt to salvage the catheter rather than remove it serves to prolong the bacteremic state and raises the question of whether S aureus bacteremia should be regarded as a major microbiological cri- teria only if cultures remain positive after removal of the CVC. Laboratory Assessment Microbiology: Blood Cultures Blood cultures should be drawn for patients with fever of unexplained origin and a pathological heart murmur, a history of heart disease, or previous endocarditis. Because bactere- mia in patients with IE usually is continuous and low grade, it does not matter whether cultures are obtained at any particular phase of the fever cycle. For children, it is ordinarily not prac- tical to obtain the large volumes recommended for adults with suspected endocarditis. Lesser amounts (eg, 1 3 mL in infants and young children and 5 7 mL in older children) are optimal, depending on the blood culture detection system. Because IE is only rarely caused by anaerobic bacteria, emphasis is usu- ally given to inoculating blood into bottles for aerobic incuba- tion. It is reasonable to obtain 3 blood cultures by separate venipunctures on the first day, and if there is no growth by the second day of incubation, to obtain 2 or 3 more (Table 3). There is usually no value in obtaining >5 blood cultures over 2 days unless the patient has received antibiotic therapy within the past 2 weeks. In patients who are not acutely ill and whose blood cultures remain negative, withholding antibiotic drugs for 48 hours or longer while additional blood cultures are obtained may be considered, to determine the cause of IE. In patients with acute IE who are severely ill and unsta- ble, 3 separate venipunctures for blood cultures should be performed over a short period such as 1 to 2 hours (Table 3) and empirical antibiotic therapy initiated. Continuous- monitoring blood culture systems such as BACTEC (Becton, Dickinson and Co, Franklin Lakes, NJ) and newer molecular identification methods are more rapid and more sensitive than more conventional methods. If fastidious or unusual organisms are suspected, the director of the micro- biology laboratory should be consulted for help in diagno- sis. Culture of arterial blood is not useful because it does not increase yield. Recommendations 1. Blood cultures should be drawn for patients with fever of unexplained origin and a pathological heart murmur, a history of heart disease, or previous endocarditis (Class I; Level of Evidence B). 2. It is reasonable to obtain 3 blood cultures by sepa- rate venipunctures on the first day, and if there is no growth by the second day of incubation, to obtain 2 or 3 more (Table 3) (Class IIa; Level of Evidence B). 3. In patients who are not acutely ill and whose blood cultures remain negative, withholding antibiotic drugs for 48 hours while additional blood cultures are obtained may be considered to determine the cause of IE (Class IIb; Level of Evidence C). 4. In patients with acute IE who are severely ill and unstable, 3 separate venipunctures for blood cul- tures should be performed over a short period such as 1 to 2 hours (Table 3) and empirical antibiotic therapy initiated (Class I; Level of Evidence C). 5. If fastidious or unusual organisms are suspected, the director of the microbiology laboratory or a consultant in pediatric infectious diseases should be consulted for help in diagnosis and especially for guidance on molecular pathogen identification and when use of serological testing is likely to be benefi- cial (Class I; Level of Evidence C). 6. Culture of arterial blood is not more useful than venipuncture because it does not increase yield over venous blood cultures, but it is acceptable if only arterial blood samples are able to be obtained (Class III, No Benefit; Level of Evidence B). Pathogenic Agents Isolated From Blood Cultures The very large majority of organisms that cause IE in chil- dren are Gram-positive cocci (Table 5), including VGS (eg, Streptococcus sanguis, S mitis group, S mutans), staphy- lococci (both S aureus and coagulase-negative staphylo- cocci), -hemolytic streptococci, and enterococci.11,13,24,81 Enterococcal endocarditis is relatively less common in children than in adults. Less frequently, other organ- isms such as the HACEK group of organisms (HACEK indicates Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species) are implicated. After the first year of life, VGS are generally the most frequently isolated organisms in patients with IE caused by underlying congenital heart disease. S aureus was the second most common cause of IE in children but is now the most common cause of IE in some series and is definitely the most common agent of acute (rapidly progressive) bacterial endo- carditis. IE may be caused by organisms that are dependent on l-cysteine or pyridoxal for growth, previously referred to as the nutritionally variant streptococci (Abiotrophia Table 3. Definitions of Terms Used in Modified Duke Criteria for Diagnosis of IE Major criteria 1. Positive blood culture for IE A. Typical microorganism consistent with IE from 2 blood cultures, as noted below (i) Viridans streptococci,* Streptococcus bovis, or HACEK group or (ii) Community-acquired Staphylococcus aureus or enterococci, in the absence of a primary focus or B. Microorganisms consistent with IE from persistently positive blood cultures, defined as: (i) 2 Positive cultures of blood samples drawn >12 h apart or (ii) All of 3 or a majority of 4 blood cultures, irrespective of the timing (iii) 1 Positive blood culture for Coxiella burnetii or antiphase-I immunoglobulin G antibody titer >1:800 2. Evidence of endocardial involvement A. Positive echocardiogram (TEE recommended in prosthetic valves, rated at least possible IE by clinical criteria, or complicated IE; TTE as the first test in other patients) for IE, defined as (i) Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation or (ii) Abscess or (iii) New partial dehiscence of prosthetic valve or B. New valvular regurgitation (worsening or changing of preexisting murmur not sufficient) Minor criteria 1. Predisposition: predisposing heart condition or IV drug use Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions Immunologic phenomena: glomerulonephritis, Osler nodes, Roth s spots, and rheumatoid factor Microbiological evidence: positive blood culture but does not meet a major criterion as noted above or serological evidence of active infection with organism consistent with IE HACEK indicates Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species; IE, infective endocarditis; IV, intravenous; TEE, transesophageal echocardiography; and TTE, transthoracic echocardiography. *Includes nutritionally variant strains (Abiotrophia species). Excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis. Modified from Durack et al74 (copyright 1994, Elsevier) and Li et al75 (copyright 2000, Oxford University Press) with permission from the publishers. Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1495 and Granulicatella species). The laboratory must subculture positive blood culture bottles on special media supplemented with l-cysteine or pyridoxal phosphate to isolate these organisms. VGS, Abiotrophia or Granulicatella species, or enterococci are most associated with native valve endocar- ditis and endocarditis occurring >60 days after cardiac sur- gery. IE produced by these organisms usually is subacute in presentation. IE associated with indwelling vascular catheters, prosthetic material, and prosthetic valves frequently is caused by S aureus or coagulase-negative staphylococci. These organisms often are implanted at the time of surgery, and infection manifests within 60 days after cardiac surgery, but coagulase-negative staphylococci infection may present as late as 1 years after surgery. Among newborn infants, S aureus, coagulase-negative staphylococci, and Candida species are the most common causes of IE.9,13 Less frequently, group B Streptococcus, enteric Gram-negative rod species, and S pneumoniae cause IE in this population. Although catheter-related bacteremias caused by Gram-negative bacilli occur relatively frequently in pediatric patients in intensive care units, IE rarely is caused by these organisms. The rarity of IE caused by Gram-negative bacilli likely is attributable to poor adhesion of Gram-negative bacilli to cardiac valves. Pediatric patients who inject drugs intrave- nously are at risk for IE, especially caused by S aureus. Fungal endocarditis in children usually is caused by Candida species, especially C albicans, although Aspergillus endocarditis also occurs. With the use of CVC in infants and children and infusions with high glucose concentrations and hyperalimentation, Candida infections of the mural or valvu- lar endocardium in infants have occasionally been recognized. Fungal endocarditis is often associated with very large friable vegetations; emboli from these vegetations frequently pro- duce serious complications. Culture-Negative Endocarditis A diagnosis of culture-negative endocarditis (CNE) is made when a patient has clinical or echocardiographic evidence of IE but persistently negative blood cultures. In most centers in the United States, the prevalence of CNE approximates 5% of IE cases in adults and children. However, in more recently published series, CNE was diagnosed in 8% to 36% of patients clinically diagnosed with endocarditis with persistently nega- tive blood cultures.79,84,85 The most common causes of CNE are current or recent antibiotic therapy or infection caused by a fastidious organism such as Abiotrophia and Granulicatella species or an HACEK organism that grows poorly in vitro. Diagnosis of fungal IE is limited by lower sensitivity of blood cultures for yeast and virtually no sensitivity for filamentous fungi. Right-sided endocarditis, in which organisms are fil- tered by the lungs, and marantic endocarditis (a noninfectious condition and a synonym for NBTE) are also more difficult to confirm by blood culture. Other less common organisms such as Bartonella spe- cies, Tropheryma whipplei, Coxiella burnetii (Q fever), and Brucella species may cause CNE. Legionella pneumophila and Mycoplasma species occasionally cause CNE, but the role of Chlamydia (now Chlamydophila) species remains Although there is less emphasis on requesting extended incubation of cultures than there was in the past, positive results may be missed unless blood cultures are held for extended ( 14 days) incubation and, in some cases, spe- cial culture methodologies that are not performed routinely are included. At times, the microbiological diagnosis can only be made by molecular confirmation of material removed at the time of surgery, including vegetations, thrombi, emboli, or valves. Frequently, patients have recently received or are cur- rently receiving antibiotic therapy. In those patients who have received <4 days of antibiotic drugs, cessation of treatment can be useful in providing a culture diagnosis after a few days. Consultation with an infectious diseases expert and with all care providers can be beneficial in making such a decision. Rates of cardiovascular surgery in the management of patients with IE have been increasing, and this may offer secondary benefits in providing material for diagnosis. Members of the writing committee stressed the impor- tance of consultation with the microbiology laboratory in all cases of CNE to optimize the chance of identification of the causative microorganism. Molecular techniques to identify 16S ribosomal RNA or DNA from tissue or PCR to detect DNA in blood specimens have identified agents of CNE on ; however, molecular methods to diagnose CNE remain suboptimal when applied to detection in blood.89 Commercial nucleic acid amplification tests (NAATs) do not currently target HACEK group organisms, Mycoplasma spe- cies, or zoonotic pathogens.90 Serological methods are often used to diagnose Bartonella species, T whipplei, C burnetii, Table 4. Duke Clinical Criteria for Diagnosis of IE Definite IE Pathological criteria Microorganisms: demonstrated by culture or histology in a vegetation, a vegetation that has embolized, or an intracardiac abscess or Pathological lesions: vegetation or intracardiac abscess present, confirmed by histology showing active endocarditis Clinical criteria as defined in Table 2 2 Major criteria or 1 Major criterion and 3 minor criteria or 5 Minor criteria Possible IE Findings consistent with IE that fall short of definite but not rejected Rejected Firm alternative diagnosis for manifestations of endocarditis or Resolution of manifestations of endocarditis with antibiotic therapy for 4 d or No pathological evidence of IE at surgery or autopsy, after antibiotic therapy for 4 d IE indicates infective endocarditis. Modified from Durack et al74 (copyright 1994, Elsevier) and Li et al75 (copyright 2000, Oxford University Press) with permission from the publishers. Brucella species, and Mycoplasma species.89 Urinary antigen tests are available for L pneumophila serogroup 1. When one examines surgical materials (vegetations, valves, grafts) for potential bacterial or fungal pathogens, it is important to note that conventional culture techniques yield very high rates of false-positive results (13% 55%) compared with prior blood cultures or NAAT-based testing of surgical materials.91,92 It is best that culture-based methods be supplemented by molecu- lar methods or histological examination of tissues for greater Histology of surgical materials contributes a major criterion to the Duke classification scheme and remains positive for months after antibiotic drugs are started.93 NAAT- based testing of surgical materials is more sensitive than culture testing but may still yield false-positive results, and this is particularly obvious when multiple agents are iden- NAAT-based testing of surgical materials may also detect organisms associated with previous episodes of IE that were treated up to 12 years before surgery and are unrelated to the current episode.95,96 There is little loss of sensitivity by NAAT when surgical specimens are obtained within 5 days of initiation of antibiotic therapy; treatment for several weeks before surgery will increase the false-negative rate.93,97 Investigational approaches to the pathogenesis of CNE include tissue-culture based growth for propagation of intra- cellular pathogens and autoimmunohistochemistry on surgi- In fact, it has been proposed that molecular techniques be added to the pathological criteria of the Duke (Treatment of CNE is discussed later, in Antibiotic Treatment, where recommendations for empirical antibi- otic treatment of patients diagnosed with CNE are contained in Table 8. Epidemiological clues that may help in narrow- ing empirical antibiotic coverage for patients diagnosed with CNE are contained in Table 9.) Recommendations 1. When pediatric patients have suspected endocardi- tis and have been treated with antibiotic drugs <4 days but have not had a prior blood culture, cessa- tion of antibiotic drugs can be useful to clarify the pathogen s identity (Class IIa; Level of Evidence C) and may be considered if the patient is clinically stable (Class IIb; Level of Evidence C). In such cases, consultation with the infectious disease specialist should be obtained. 2. Consultation with the director of the microbiol- ogy laboratory or an infectious diseases expert in all cases of CNE is recommended to optimize the chance of identification of the causative microorgan- ism (Class I; Level of Evidence C). Other Microbiological Tests Testing for antimicrobial susceptibility with determination of the minimum inhibitory concentration (MIC) of the antibi- otic for the organism is recommended in choosing the opti- mal therapy for IE. Although not routinely recommended, determination of the minimum bactericidal concentration of the antimicrobial agent chosen for treatment against the infecting organism may be considered in selected circum- stances, such as with atypical organisms, organisms resis- tant to first-line antibiotic drugs, and unexplained failure to control bacteremia. Synergy studies, with a -lactam agent and an aminoglycoside, although not always available and somewhat controversial, may be reasonable in determining optimal therapy of enterococcal or penicillin-nonsusceptible streptococcal IE. However, existence of an isolate resistant to a high level of aminoglycosides indicates a lack of potential for synergy. Recommendations 1. Testing for antimicrobial susceptibility with deter- mination of the MIC of the antibiotic drug for the organism is recommended in choosing the optimal therapy for IE (Class I; Level of Evidence B). 2. Although not routinely recommended, determina- tion of the minimum bactericidal concentration of the antimicrobial agent chosen for treatment against the infecting organism may be considered in selected circumstances, such as with atypical organ- isms, organisms resistant to first-line antibiotic drugs, and unexplained failure to control bactere- mia (Class IIb; Level of Evidence C). Table 5. Principal Pathogenic Bacterial Agents Series Organism Johnson et al81 HACEK N/A 5 4 N/A Enterococcus species N/A 7 4 N/A Values indicate percentage of patients in the series. HACEK indicates Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species; and N/A, not applicable. Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1497 3. Synergy studies, with a -lactam agent and an aminoglycoside, although not always available and somewhat controversial, may be reasonable in determining optimal therapy of enterococcal or penicillin-nonsusceptible streptococcal IE (Class IIb; Level of Evidence C). Other Supportive Miscellaneous Laboratory Tests A variety of other nonspecific laboratory findings may sup- port the diagnosis of IE in children. The anemia of IE may be hemolytic or may represent the anemia of chronic dis- ease. Chronic low-grade hemolysis also may be caused by a prosthetic valve in the absence of IE. Leukocytosis is not a consistent feature of IE, but immature forms may be pres- ent on peripheral blood smears. Acute IE is likely to mani- fest leukocytosis. Thrombocytopenia can occur, particularly in neonates with IE. Hypergammaglobulinemia and elevated acute-phase reactants (eg, erythrocyte sedimentation rate and C-reactive protein) are present in a large proportion of patients. Hematuria may occur and be accompanied by red blood cell casts, proteinuria, and renal insufficiency in patients who develop immune complex glomerulonephritis, but this is less common in children than adults. In patients with immune complexes, there may also be hypocomple- mentemia. Rheumatoid factor is present in a substantial pro- portion of IE patients whose duration of illness is >6 weeks. Other supportive and useful tests include the ECG, which can indicate the presence of complicating rhythm disorders such as ventricular ectopy and conduction disorders such as com- plete heart block. The presence of either of these findings, and in particular heart block, may signal a serious or even life-threatening IE complication. Echocardiography The standard diagnostic method for identifying the intracar- diac manifestations of IE is 2-dimensional echocardiography although neither sensitivity nor specificity is 100%. Unlike the situation in adults, transthoracic echocardiography (TTE) is usually sufficient for children (especially if they weigh <60 kg) to fully understand cardiovascular findings in definite or presumptive IE. However, transesophageal echocardiog- raphy (TEE) is superior to TTE in diagnosing paravalvular leakage or dehiscence; left ventricular outflow tract compli- cations, including root abscesses; involvement of the sinuses of Valsalva; and prosthetic valve endocarditis, even in chil- TEE is reasonable to consider for infants and children in whom TTE views may be limited. This includes those who have had chest wall disruptions from previous surgery or from trauma, who have had placement of intracardiac prosthetic material, or who have congenital or acquired anomalies of the thoracic cage. Although information in pediatric patients is not well developed, data from series in adult patients suggest that intracardiac echocardiography (ICE) may also be useful in selected circumstances such as potential pacemaker-lead infections and post percutaneous prosthetic valve implanta- tions. Patients with chronic lung disease of various patho- geneses may also have limited acoustic windows via TTE, which would make TEE the preferred approach. Narducci et recently reviewed their experience with the use of ICE in the diagnosis of IE involving implantable electronic devices (pacemakers and leads). Limited data confirm the utility of ICE as a diagnostic tool in such cases and perhaps its supe- riority as a diagnostic tool for this clinical circumstance. ICE added incremental value to TEE and other methodologies in particularly in patients with a probable diagnosis of IE based on the Duke criteria but in whom the TEE was negative.100 To date, these data have not been rep- licated specifically in a pediatric series, although at least 1 case report has been published advocating ICE superiority in a pediatric case of pacemaker-related IE.101 ICE has not been demonstrated thus far to be of additional value in the diagnosis of shunt-related IE in childhood. For this condition, definitive studies demonstrating enhanced accuracy for any particular modality are needed. Echocardiography is particularly important for serial stud- ies in a patient with known or suspected IE. Not only is objec- tive documentation of progressive changes in cardiac function crucial, but identification of other important complications of IE by echocardiography can have direct bearing on decision making with regard to early surgical intervention, which can be critical for successful outcome.102 The limited capacity of TTE to detect complications of IE in adults,103 particularly in those with prosthetic valves, has been confirmed. Although TTE has been shown to effectively detect endocarditis in young children (up to 97% sensitivity), for those >10 years of age and weighing >60 kg, the TEE, as in adults, has been shown to be a more sensitive tool.104 Although there is limited experience with TTE for detect- ing aortic root abscesses, which can complicate native or prosthetic aortic valve IE in pediatric patients, it can be use- ful to perform TEE in patients who are at high risk for this complication. Recommendations 1. TEE is recommended for infants and children who had chest wall disruptions from previous surgery or from trauma or who have congenital anomalies involv- ing the thoracic cage (Class I; Level of Evidence B). 2. It can be useful to perform TEE in pediatric patients who are at high risk for aortic root abscesses, which can complicate native or prosthetic aortic valve IE (Class IIa; Level of Evidence C). Antimicrobial Treatment The principles of treatment of pediatric endocarditis are simi- lar to those for treatment of adult endocarditis.2 In patients who are not severely ill and whose blood cultures are still negative, or whose cultures may be positive for organisms that are frequently contaminants, it is reasonable to withhold antibiotic drugs for 48 hours while additional blood cultures are obtained. A prolonged course of therapy (at least 2 weeks and often 4 8 weeks; Table 6) has been the recommended practice for several reasons. Organisms are embedded within the fibrin-platelet matrix and exist in very high concentrations with relatively low rates of bacterial metabolism and cell divi- sion, which results in decreased susceptibility to -lactam and other cell wall active antibiotic drugs.105,106 Bactericidal rather than bacteriostatic antibiotic drugs should be chosen whenever possible. This recommendation is based on past reports of treatment failures and relapses when only bacteriostatic antibiotic drugs were given. In infants and children, one should use intravenous antibiotic drugs rather than intramuscular agents because of the patients small muscle mass. Outpatient (home) intravenous treatment of endocarditis may be considered in selected patients after initial treatment in the hospital and confirmation that these patients are hemodynamically stable and afebrile, have nega- tive blood cultures, and are not at high risk for complications. Additionally, patient and parent adherence to the medical plan is important. Frequent home monitoring by a home health nurse who assesses wellness, adherence to drug therapy, absence of complications (see Recommendations 4 and 5 for this section), and absence of drug toxicity are parts of the plan. Such a standard would reasonably include prompt (minutes to hours) access to medical and surgical care and cardiac follow- up should complications develop. All of the medications men- tioned in the Tables in this publication are for the intravenous route of administration unless otherwise specified. An excep- tion would be cases in which a drug is known to be 100% bioavailable when given orally, such as ciprofloxacin. Bacteremia generally resolves within several days after appropriate therapy has begun. S aureus bacteremia, however, may persist for a longer time than streptococcal bacteremia, and it may be present for 3 to 5 days with -lactam anti- staphylococcal therapy and for 5 to 10 days with vancomycin therapy. Additionally, IE caused by S aureus that is frequently associated with CVC and bacteremia may not be controlled until the catheter is removed. In a 2005 report, 12% of chil- dren with S aureus bacteremia were shown to have IE (using the modified Duke criteria75 ), and in 73% of those children with bacteremia, there was a central intravascular device and multiple positive blood cultures.107 The repetition of blood cultures daily until they are sterile would allow assessment of the adequacy of treatment and document the cessation of bac- teremia. Additional blood cultures performed after comple- tion of antibiotic treatment may be considered, but this might result in isolation of a contaminant.108 Table 7 is modeled after guidelines that will be published by the AHA for treatment of IE in adults.109 The dosages and, in some cases, the preferred antibiotic drugs are specific for children. Data on effectiveness of antibiotic drugs for IE in children generally come from reviews of experience. Because these are nonexperimental, there is a lack of useful informa- tion to compare different antibiotic regimens head-to-head; therefore, these and other recommendations in the literature are based on preferred practice in adults, qualitative interpre- tation of outcomes from pediatric reviews, and expert opinion from this committee. Recommendations 1. In patients who are not severely ill (do not have respiratory or hemodynamic compromise or change in mental status) and whose blood cultures remain negative or whose cultures may be positive for organisms that are frequently contaminants, it is reasonable to withhold antibiotic drugs for 48 hours while additional blood cultures are obtained (Class IIa; Level of Evidence C). 2. A prolonged course of therapy (at least 4 weeks and often 6 8 weeks; Table 6) has been the recom- mended practice (Class I; Level of Evidence B). 3. Bactericidal rather than bacteriostatic antibiotic drugs should be chosen whenever possible (Class I; Level of Evidence A). This recommendation is based on past reports of treatment failures and relapses when only bacteriostatic antibiotic drugs were given. 4. In infants and children, one should use intravenous antibiotic drugs rather than intramuscular agents. The patients small muscle mass is one reason (Class I; Level of Evidence C). 