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). Outpatient (home) intrave- nous treatment of endocarditis may be considered in selected patients after initial treatment in the hos- pital and confirmation that these patients are hemo- dynamically stable and afebrile, have negative blood cultures, and are not at high risk for complications (ie, not of young age and do not have a fungal patho- gen) (Class IIb; Level of Evidence C). 5. 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, and absence of drug toxicity is part of the plan. It is reasonable that such a standard would include prompt (min- utes to hours) access to medical and surgical care and cardiac follow-up should complications develop (Class IIa; Level of Evidence C). 6. Additional blood cultures performed after comple- tion of antibiotic treatment may be considered but might also result in isolation of a contaminant (Class Table 6. Length of Treatment of Infective Endocarditis* Native valve highly susceptible streptococci 4 wk Native valve relatively resistant streptococci 4 wk Prosthetic material, caused by viridans streptococci or Streptococcus bovis Native valve Staphylococci, susceptible to oxacillin 4 6 wk Native valve Staphylococci resistant to oxacillin 6 wk Prosthetic valve Staphylococci At least 6 wk Native or prosthetic valve enterococcus 4 6 wk Native or prosthetic valve enterococcus treated with vancomycin Native or prosthetic valve HACEK endocarditis 4 wk Native valve culture-negative endocarditis 4 6 wk Prosthetic valve culture-negative endocarditis 6 wk Enteric Gram-negative endocarditis At least 6 wk HACEK indicates Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species. *These are approximate lengths of treatment for typical episodes of infective endocarditis. Patients with complicated episodes or recurrences may require additional treatment. Recommendations are the published consensus of expert reviewers. Two weeks may be adequate for some adult patients but is not recommended for children because of lack of effectiveness data. Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1499 Table 7. Recommended Antibiotic Treatments for Pediatric Infective Endocarditis* Organism/Condition Recommended Antibiotic Drug/Daily Antibiotic Dose Alternative Antibiotic Drug Choice Unknown agent (initial empirical therapy or culture-negative endocarditis, generally after at least 48 h of attempting to culture the causative organism except in severely ill children) Native valve (community acquired) or late prosthetic valve (>1 y after surgery) infection Ampicillin/sulbactam plus gentamicin Vancomycin (plus gentamicin) With or without vancomycin For prosthetic valve endocarditis, add rifampin IV divided every 4 6 h up to 12 g daily IV divided every 6 h up to 2 g IV divided every 8 h. IV divided every 8 divided every 12 h up to 600 mg IV every 6 h up to 2 g Nosocomial endocarditis associated with vascular cannulae or early prosthetic valve endocarditis ( 1 y after surgery) Vancomycin plus gentamicin ( rifampin if prosthetic material present) ? Plus cefepime or ceftazidime IV divided every 6 h up to 2 g IV divided every 8 h divided every 8 h up to 900 mg/d divided every 8 12 h up to 6 g/d IV divided every 8 h up to 2 4 g daily Streptococci Highly susceptible to penicillin G (MBC 0.1 g/mL); includes most viridans streptococci, groups A, B, C, G nonenterococcal, group D streptococci (S bovis, S equinus) Penicillin G or ceftriaxone IV divided every 4 h up to 12 24 million U daily IV divided every 12 h or IV every 24 h up to 4 g daily (if over 2 g, divide BID) Vancomycin or first-generation cephalosporin or ceftriaxone IV divided every 8 12 h up to 2 g daily IV divided every 8 h up to 12 g daily IV divided every 12 IV every 24 h up to 4 g daily Relatively resistant to penicillin (MBC 0.2 g/mL; includes enterococci and less-susceptible viridans streptococci) Penicillin G (or ampicillin) plus gentamicin (for first 2 wk, or whole course for enterococci) IV divided every 4 h up to 12 24 million U daily IV divided every 4 6 h up to 12 g daily IV divided every 8 h. Vancomycin plus gentamicin for enterococci Ampicillin plus ceftriaxone (for aminoglycoside- resistant enterococci or aminoglycoside- intolerant patient) Ceftriaxone plus gentamicin (not for enterococcal endocarditis) IV divided every 8 12 h up to 2 g daily IV divided every 8 IV divided every 12 IV every 24 h up to 4 g daily IV divided every 4 6 h up to 12 g daily Staphylococci (S aureus or coagulase-negative staphylococci) Susceptible to 1 g/mL penicillin G (rare) Penicillin G IV divided every 4 h up to 12 24 million U daily Oxacillin or nafcillin or first-generation cephalosporin or vancomycin Oxacillin or nafcillin 200 mg kg 1 IV divided every 4 6 h up to 12 g/d IV divided every 8 h up to 12 g daily IV divided every 8 12 h up to 2 g daily (Continued) Resistant to 0.1 g/mL penicillin G Penicillinase-resistant penicillin (oxacillin or nafcillin) gentamicin 3 5 d Vancomycin or a first-generation cephalosporin IV divided every 8 h up to 12 g daily IV divided every 8 12 h up to 2 g daily for those highly allergic to -lactam antibiotic drugs Oxacillin or nafcillin 200 mg kg 1 IV divided every 4 6 h up to 12 g/d IV divided every 8 h. Adults: 3 5 mg/kg Resistant to 4 g/mL oxacillin (MRSA) Vancomycin IV divided every 8 12 h up to 2 g daily Daptomycin for right-sided endocarditis, maybe for left-sided Daptomycin 6 mg/kg IV every 24 h; <6 y: 10 mg/kg Vancomycin resistant or intolerant Daptomycin ? Daptomycin 6 mg/kg IV every 24 h; For all staphylococci plus rifampin, plus gentamicin (for first 2 wk) if prosthetic material present Gram-negative enteric bacilli Ceftazidime, cefepime, cefotaxime, or ceftriaxone plus gentamicin (or tobramycin or amikacin, depending on susceptibility) A broad-spectrum penicillin plus gentamicin (or tobramycin or amikacin) divided every 8 h up to 18 g daily Gentamicin or tobramycin 3 6 mg kg 1 IV IV divided every IV divided every 8 h up to 2 4 g daily IV divided every 6 h up to 12 g daily IV divided every 12 h IV every 24 h up to 4 g daily Gentamicin or tobramycin 3 6 mg kg 1 IV IV divided every 8 12 h up HACEK group Ceftriaxone or cefotaxime or Ampicillin-sulbactam Ampicillin (for susceptible organisms) plus aminoglycoside IV divided every 4 6 h up to 12 g daily IV divided every 6 h up to 12 g daily Gentamicin or tobramycin 3 6 mg kg 1 IV IV divided every 12 h or IV every 24 h up to 4 g daily IV divided every 4 6 h up to 12 g daily IV divided every 8 12 h up to 15 mg kg 1 Fungi Candida spp, Aspergillus spp Surgical resection plus amphotericin B with or without flucytosine IV administered over Amphotericin B followed by imidazole (eg, fluconazole, itraconazole, voriconazole) suppression if surgery cannot be performed orally divided every 6 h Amphotericin liposomal/lipid-associated (3 in a single dose daily IV administered over 3 4 h Amphotericin liposomal/lipid-associated 3 5 in a single dose daily BID indicates twice per day; HACEK, Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species; IV, intravenously; MBC, minimum bactericidal concentration; and MRSA, methicillin-resistant Staphylococcus aureus (includes resistance to oxacillin, nafcillin, and cephalosporins). Treatment is generally for 4 to 6 weeks. See Table 8. Longer therapy may be required for recurrent endocarditis, prosthetic valve endocarditis, endocarditis attributable to uncommon species. *As discussed in the text, these recommendations are based on consensus of experts and not experimental comparative studies (Class IIa; Level of Evidence C). Doses for neonates and infants not included. For cases of infective endocarditis in infants, consult infectious diseases and pediatric clinical pharmacists with special expertise in neonatal and infant clinical pharmacology. Maximum daily dose or adult dose should not be exceeded on a per kilogram basis when treating children. Possibly lifelong suppression if no surgery or relapse after surgery. Table 7. Continued Organism/Condition Recommended Antibiotic Drug/Daily Antibiotic Dose Alternative Antibiotic Drug Choice Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1501 IIb; Level of Evidence C).108 Some members of the writing group questioned whether there is value in taking blood cultures after completion of treatment unless there is evidence of return of symptoms. Streptococcal IE on Native Cardiac Valves (No Prosthetic Material) or Prosthetic Material Native Cardiac Valves This has been the most common form of IE in children for decades; some recent reports show staphylococcal IE over- taking streptococci as the most common organism.24,110,111 Penicillin-susceptible streptococci are those with an MIC of 0.1 g of penicillin per milliliter. In patients with IE caused by penicillin-susceptible streptococci who are able to tolerate a -lactam antibiotic, 2 therapeutic regimens are associated with high cure rates (Table 7) and include penicillin G and ceftriaxone. A 4-week regimen of intravenous aqueous crystalline pen- icillin G (or ampicillin if penicillin G is unavailable) achieves a high cure rate.112 This approach avoids aminoglycoside-con- taining regimens for children with impairment of renal func- tion, concurrently administered nephrotoxic drugs, or eighth cranial nerve impairment. In adult patients, 4 weeks of ther- apy with ceftriaxone given once daily also is a recommended In adults, a 4-week course of ceftriaxone therapy has a bacteriologic cure rate of 98%,113 but only limited and retrospective data on the use of ceftriaxone in the treatment of IE in children have been published. The advantage of using ceftriaxone is that children initially treated for IE in the hos- pital can be transitioned to home intravenous therapy with an antibiotic that only requires a single infusion daily. Although home treatment for part of the antibiotic course appears to be becoming a more frequently used option, this decision is rea- sonable but requires careful selection of the appropriate can- didate based on family accommodations and access to home A 2-week course of therapy with penicillin, ampicillin, or ceftriaxone combined with an aminoglycoside has become increasingly popular and results in bacteriologic cure rates of up to 98% in adults.114 This regimen is commonly used for uncomplicated cases of native valve IE but is not recom- mended for patients who have had clinical symptoms of endo- carditis for >3 months or those who have an extracardiac focus of infection, an intracardiac abscess, or a mycotic aneurysm. It is not recommended by this committee for children because of lack of data, and it should be used with caution in people at increased risk for adverse events caused by aminoglycoside therapy, such as those with renal impairment or those taking other nephrotoxic drugs. In 1 study in adults,115 single daily doses of gentamicin (3 mg/kg per day) combined with cef- triaxone (2 g/d for adults) for 2 weeks were as effective as 4 weeks of ceftriaxone alone. Although once-daily dosing of gentamicin has become an accepted practice for adult patients with infections other than endocarditis, few studies detail- ing the use of this regimen for the treatment of streptococcal endocarditis in adults have been published. Several stud- ies have demonstrated the safety and efficacy of once-daily dosing of gentamicin in children with infections other than endocarditis; however, no studies describing outcomes after the use of single daily dosing of gentamicin for the treatment of IE in children have been published. Occasionally, IE may be caused by streptococci that are relatively resistant to penicillin (MIC between 0.1 and 0.5 g/ mL). In this situation, concern about the efficacy of penicillin alone is avoided by use of a treatment regimen of 4 weeks of penicillin, ampicillin, or ceftriaxone combined with gentamicin for the first 2 weeks. Patients with IE caused by Abiotrophia, Granulicatella species, or streptococci with an MIC of >0.5 g of penicillin per milliliter should be treated with the antibiotic regimen listed for enterococci. For children who are unable to tolerate -lactam antibiotic drugs, vancomycin is an effective substitute, and current practice includes the addition of genta- micin for a 4-week course (Table 7). Caution should be exer- cised by obtaining blood levels of vancomycin and gentamicin, as well as serum creatinine levels, weekly because of the pos- sibility of nephrotoxicity with this combination. S pneumoniae accounts for 3% to 5% of cases in children (Table 5). Because of the potential for multidrug resistance and the infrequency of the syndrome of pneumococcal IE, no optimal therapy has been established for this illness.116 118 A review of pneumococcal endocarditis published in 2004 reported on 11 cases of pneumococcal IE over a 10-year period at 8 children s hospitals, and 10 of the 11 survived to the time All isolates were susceptible to ceftriaxone, and 9 were susceptible to penicillin. One was resistant to pen- icillin, and 1 demonstrated an intermediate susceptibility to penicillin. Therapy consisted of cefotaxime or ceftriaxone for 5 patients, cefotaxime plus vancomycin for 2, penicillin for 2, and clindamycin for 1, and 1 patient received many different antibiotic drugs. One patient died during cardiac surgery and had received vancomycin and cefotaxime for a pneumococ- cal isolate intermediately susceptible to penicillin. Generally, for penicillin-susceptible strains, penicillin with or without an aminoglycoside has been used. It was the consensus of the writing group that consultation with an infectious disease spe- cialist should be considered for all children with IE but espe- cially for IE caused by S pneumoniae that is not susceptible to penicillin. Recommendations 1. A 4-week regimen of intravenous aqueous crys- talline penicillin G (or ampicillin if penicillin G is unavailable) achieves a high cure rate in those with highly penicillin-susceptible streptococcal IE.112 This approach avoids aminoglycoside-containing regimens for children with impairment of renal function, concurrently administered nephrotoxic drugs, or eighth cranial nerve impairment. In adult patients, 4 weeks of therapy with ceftriaxone given once daily also is a recommended approach113 (Class I; Level of Evidence B). 2. Although home treatment for part of the antibiotic course appears to be becoming a more frequently used option, this decision is reasonable but requires careful selection of the appropriate candidate based on family accommodations and access to home healthcare providers (Class IIa; Level of Evidence B). species, or streptococci with an MIC of >0.5 g of penicillin per milliliter should be treated with the antibiotic regimen listed for enterococci (Class I; Level of Evidence C). For children who are unable to tolerate -lactam antibiotic drugs, vancomycin is an effective substitute, and current practice includes the addition of gentamicin for a 4-week course. 4. Obtaining blood concentrations of vancomycin and gentamicin, as well as renal function tests, weekly because of the possibility of nephrotoxicity with multiple nephrotoxic antibiotic drugs may be con- sidered (Class IIb; Level of Evidence C). Prosthetic Cardiac Valves or Other Prosthetic Material In cases in which endocarditis occurs in the setting of prosthetic material and is caused by a penicillin-susceptible streptococcal strain, therapy is continued for 6 weeks with penicillin, ampi- cillin, or ceftriaxone combined with gentamicin for the first 2 weeksoftherapy.Inthecaseofinfectionscausedbyastrainwith an MIC >0.1 g of penicillin per milliliter or by Abiotrophia or Granulicatella species, a combination of penicillin, ampicillin, or ceftriaxone combined with gentamicin for 6 weeks is rec- ommended. For patients unable to tolerate -lactam therapy, vancomycin for 6 weeks is combined with gentamicin for the first 2 weeks of therapy. In -lactam intolerant patients with Abiotrophia infections, therapy consists of a combination of vancomycin and gentamicin for 6 weeks. Recommendation 1. In cases in which endocarditis occurs in the setting of prosthetic material and is caused by a penicil- lin-susceptible streptococcal strain, therapy is con- tinued for 6 weeks with penicillin, ampicillin, or ceftriaxone combined with gentamicin for the first 2 weeks of therapy. In the case of infections caused by a strain with an MIC >0.1 g of penicillin per milliliter or by Abiotrophia or Granulicatella species, a combination of penicillin, ampicillin, or ceftriaxone combined with gentamicin for 6 weeks is recom- mended (Class I; Level of Evidence C). Enterococcal IE on Native Cardiac Valves or Prosthetic Material Enterococcal endocarditis is relatively rare in children. Treatment is difficult because of the relative resistance of enterococci to penicillin and ampicillin (which are not bac- tericidal for enterococci) and their variable resistance to ami- noglycosides and vancomycin.120,121 The treatment regimen for native valve IE caused by susceptible strains should be a combination therapy of penicillin G or ampicillin together with gentamicin for 4 to 6 weeks, with a longer duration of therapy in cases involving prosthetic material.2,120,122 For patients with infections caused by susceptible strains of enterococci who are unable to tolerate -lactam therapy, experts recommend vancomycin combined with gentamicin for 6 weeks for native valve IE and for a minimum of 6 weeks for infection of prosthetic material.2,122 In contrast to therapy for streptococcal IE [ Streptococcal IE on Native Cardiac Valves (No Prosthetic Material) or Prosthetic Material ], the length of treatment with an aminoglycoside is for the entire course of therapy, and in patients with normal renal function, with the aminoglycoside divided into 2 to 3 doses daily rather than given in a single daily dose. The emergence of high- level vancomycin, ampicillin, and aminoglycoside resistance in some enterococcal species has further complicated treat- ment choices. The combination of ampicillin plus ceftriaxone was reported to be effective for aminoglycoside nonsuscep- tible Enterococcus faecalis strains first in a report from Spain and recently confirmed in a multi-institutional observational Enterococci are resistant to ceftriaxone and other cephalosporins, and these drugs used alone are not an option for treatment of enterococcal endocarditis. Vancomycin- resistant enterococci may cause IE, but there are too few reports in the literature to determine the most effective treat- ment. The antibiotic drugs linezolid and daptomycin have activity against vancomycin-resistant enterococci in vitro, and successful treatment of adults with vancomycin-resistant enterococci IE has been reported. The consensus of the writ- ing group is that management of patients with enterococcal IE should always involve infectious disease consultation as the standard of care. Recommendations 1. The treatment regimen for native valve IE caused by susceptible strains of enterococcus should be a combination therapy of penicillin G or ampicillin together with gentamicin for 4 to 6 weeks, with a lon- ger duration of therapy in cases involving prosthetic material (Class I; Level of Evidence A [in adults]). 2. The consensus of the writing group is that manage- ment of patients with enterococcal IE should always involve infectious disease consultation as the stan- dard of care (Class I; Level of Evidence C). Staphylococcal Endocarditis on Native Valves or Prosthetic Material Native Valve IE Staphylococci may be coagulase positive (S aureus) or coagu- lase negative (S epidermidis and various other species) and appear to have overtaken streptococci as the most common cause of IE in children in recent years.24,110,111 This may be attributable in part to the proliferation of intravascular cath- eters, as well as the nonspecificity of the Duke criteria in children causing false-positive diagnoses.Almost all staphylo- cocci are highly resistant to penicillin G and ampicillin.125 For those few that are susceptible to penicillin, penicillin or ampi- cillin will be effective, assuming a highly qualified laboratory has performed antibiotic susceptibility tests. Staphylococci that are susceptible to -lactamase resistant penicillins are termed methicillin susceptible or MSSA and may be S aureus or coagulase-negative strains such as S lugdunensis, which is typically susceptible and acts similarly to S aureus. In some centers, S aureus resistant to -lactamase resistant penicil- lins are termed MRSA, or ORSA or NRSA to indicate that oxacillin and nafcillin are the available penicillinase-resistant Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1503 penicillins and methicillin is no longer available. The usually accepted current standard of care for methicillin-susceptible S aureus endocarditis involving a native valve or other native cardiac tissue includes a semisynthetic, -lactamase resistant penicillin (nafcillin or oxacillin) given intravenously for a minimum of 4 to 6 weeks, assuming there has been an appro- priate microbiological and clinical response to therapy. The addition of gentamicin for the first 3 to 5 days is an option and may accelerate the killing of the staphylococci, but this concept is based on extrapolation from experimental models. In patients without a history of type 1 penicillin allergic reac- tions, a first-generation cephalosporin, for example, cefazolin, is an alternative (for 4 6 weeks), with or without gentami- cin for the first 3 to 5 days.2,122 For patients unable to tolerate -lactam antibiotic drugs, vancomycin for a minimum of 6 weeks, with or without gentamicin for the first 3 to 5 days of therapy, is an alternative. Some staphylococcal strains may be methicillin resistant, and patients with IE caused by these organisms should not receive nafcillin, oxacillin, or a cephalosporin. Despite antibi- otic susceptibility results indicating that methicillin-resistant, coagulase-negative staphylococci are susceptible to cephalo- sporins, cross-resistance exists, and cephalosporins are not considered to be useful in these patients. Patients with meth- icillin-resistant staphylococcal endocarditis may be treated with vancomycin for a minimum of 6 weeks, with or without gentamicin for the first 3 to 5 days of therapy. It is the consen- sus of the writing group that patients with S aureus endocardi- tis should be cared for in a medical facility with cardiothoracic surgery capabilities and infectious diseases consultation. As with other IE cases, decisions about outpatient therapy may be individualized on the basis of clinical impression of symptom- atic recovery, cardiovascular stability, assessment of the fam- ily s ability to follow prescribed treatment, and availability of infrastructure for outpatient monitoring. Recommendations 1. We recommend the current standard of care for methicillin-susceptible S aureus endocarditis involv- ing a native valve or other native cardiac tissue, which includes a semisynthetic, -lactamase resistant peni- cillin (nafcillin or oxacillin) given intravenously for a minimum of 4 to 6 weeks, assuming there has been an appropriate microbiological and clinical response to therapy (Class I; Level of Evidence A). 2. The addition of gentamicin for the first 3 to 5 days may be considered and may accelerate the killing of the staphylococci, but this concept is based on extrapolation from experimental models. Addition of gentamicin increases the likelihood of renal and otic toxicity (Class IIb; Level of Evidence C). 3. Treatment of patients with methicillin-resistant staphylococcal endocarditis with vancomycin for a minimum of 6 weeks, with or without gentamicin for the first 3 to 5 days, is recommended except when the organism is not susceptible to vancomycin (Class I; Level of Evidence B). 4. Patients with S aureus endocarditis should be cared for in a medical facility with cardiothoracic surgery capabilities and infectious diseases consultation (Class I; Level of Evidence C). 5. As with other IE cases, decisions concerning out- patient therapy may be considered and may be individualized on the basis of clinical impression of symptomatic recovery, cardiovascular stability, assessment of the family s ability to follow prescribed treatment, and availability of infrastructure for out- patient monitoring (Class IIb; Level of Evidence C). Prosthetic Material IE Staphylococcal endocarditis on a prosthetic cardiac valve or other cardiac prosthetic material is usually caused by coagulase-negative staphylococci that are methicillin resis- tant, especially if the endocarditis develops within 1 year after cardiac surgery.126 (See details in Table 7 for treat- ment of methicillin-resistant and methicillin-susceptible staphylococcal endocarditis based on consensus of the writing group and experience in the treatment of adult IE.) Additional recommendations for the treatment of staphylo- coccal endocarditis on intracardiac prosthetic material are listed in the AHA statement on Infective Endocarditis: Diagnosis, Antimicrobial Therapy, and Management of Eradication of infection involving pros- thetic material is considered difficult at best, even when prolonged optimal antibiotic treatment is used. Despite occasional reports of successful medical treatment, which requires long-term use of multiple antimicrobial agents, in most circumstances removal of the infected material is required to achieve a satisfactory outcome.127 The antibi- otic rifampin is included as an addition to other antibiotic drugs in the treatment of staphylococcal IE, especially when there is prosthetic material. Most staphylococcal strains are susceptible to rifampin, and in experimental systems, it has good tissue penetration. The overall mortality rate associated with prosthetic valve endocarditis is relatively high but is highest for infec- tions caused by S aureus.128 Although 1 study reporting cases from the 1970s showed that many cases of pediatric IE with patches or prostheses could be treated successfully with medical management alone, surgical management is gener- Moreover, prosthetic valve infection caused by S aureus has been shown to be an independent risk factor for death.130,131 Many authorities have concluded that valve replacement surgery is preferable in most if not all patients with pros- thetic valve infection caused by S aureus. Decisions regard- ing transition to outpatient care in cases of prosthetic valve endocarditis should be individualized and should be made in consultation with pediatric infectious diseases consultants, taking into consideration the elements discussed at the end of Staphylococcal Endocarditis on Native Valves or Prosthetic Material. Recommendation 1. Valve replacement surgery may be considered and is preferable in most if not all patients with prosthetic valve infection caused by S aureus (Class IIb; Level of Evidence C). Gram-Negative IE (Including HACEK Species) The Gram-negative bacteria that most often cause IE in chil- dren are the HACEK group of fastidious coccobacilli. The consensus of experts recommending therapy for IE caused by the HACEK group is a 4-week course of ceftriaxone or another third-generation cephalosporin alone, or ampicillin Other Gram-negative bacteria, such as Escherichia coli, Pseudomonas aeruginosa, or Serratia marcescens, are rare causes of IE. Few data are available to determine a single best antimicrobial agent, and thus, treatment is individualized according to the judgment of the expert consultant and guided by identification of the organism and antimicrobial suscepti- bility testing. Because these IE cases may be nosocomially acquired, the strains may have unpredictable antimicrobial susceptibilities and may be highly resistant to antimicrobial agents, having many different antibiotic resistance elements, including extended-spectrum -lactamases. Most infectious disease specialists recommend an extended-spectrum peni- cillin (eg, piperacillin/tazobactam) or an extended-spectrum cephalosporin (eg, ceftazidime, ceftriaxone, or cefotaxime) together with an aminoglycoside132 for a minimum of 6 weeks of therapy. There are few data on the use of quinolones for treatment of endocarditis in children, but such therapy has been successful in series of adults with IE. Limited data are available describing treatment of IE caused by Gram-negative pathogens with multidrug resistance (eg, extended-spectrum -lactamase production). Recommendations 1. Therapy for IE caused by the HACEK group should be a 4-week course of ceftriaxone or another third- generation cephalosporin alone, or ampicillin plus gentamicin (Class I; Level of Evidence C). 2. For IE caused by other Gram-negative species, we recommend an extended-spectrum penicillin (eg, piperacillin/tazobactam) or an extended-spectrum cephalosporin (eg, ceftazidime, ceftriaxone, or cefo- taxime) together with an aminoglycoside,132 with choice guided by antibiotic susceptibility of the iso- late and input from an infectious diseases consultant for a minimum of 6 weeks of therapy (Class I; Level of Evidence C). Fungal Endocarditis With the exception of neonates with mural endocarditis and occasionally older children, medical therapy of fun- gal IE is usually unsuccessful. For most patients with fun- gal IE, surgery in conjunction with antifungal agents is required. Early consultation with infectious disease, car- diology, and cardiac surgery services is recommended for these patients. Amphotericin B has been the first-line antifungal agent for medical therapy, although it does not penetrate vegeta- tions well. Although the imidazoles (eg, fluconazole) do not have proven efficacy in human fungal IE, long-term suppressive therapy with these agents has been recom- mended by experts for patients with infections caused by susceptible organisms who are not able to undergo curative per day, divided every 6 hours) to amphotericin B given by mouth for Candida endocarditis caused by strains susceptible to 5-FC may provide additional benefit. Monitoring blood levels of 5-FC will minimize toxicity associated with this agent. The rationale is that the 2 drugs may act synergistically and potentiate fungal killing. The use of liposomal forms of amphotericin B is an alternative for patients with moderate to severe renal impairment or those with unacceptable infusion- related toxicities. In some centers, fluconazole or liposomal forms of amphotericin have been used successfully for native valve fungal endocarditis. Recommendations 1. For most patients with fungal IE, surgery in con- junction with antifungal agents is required. Early consultation with infectious disease, cardiology, and cardiac surgery services is recommended for these patients (Class I; Level of Evidence C). 2. The addition of 5-FC (100 150 mg/kg per day, divided every 6 hours) to amphotericin B given by mouth for Candida endocarditis caused by strains susceptible to 5-FC may be considered to provide additional benefit (Class IIb; Level of Evidence C). Monitoring of Antibiotic Blood Levels (for Children Beyond the Neonatal Period) When gentamicin is used for synergy, a reasonable dose is 3 to 6 mg/kg per day in children and is adjusted for a target peak blood concentration of 3 to 4 g/mL and a trough of <1 g/mL. A dose of up to 7.5 mg/kg per day may be required for treatment of Gram-negative rod isolates, with peak blood levels of 5 to 10 g/mL and troughs of <1 to 1.5 g/mL. The daily dose is divided into 3 doses and given every 8 hours. Currently, there is insufficient clinical experience for treat- ment of pediatric IE with single daily dosing. For vancomy- cin, a starting dose for children is 40 to 60 mg/kg per day, and only trough concentrations are used for monitoring. The target trough blood level is usually 10 to 15 g/mL, although a higher blood level, 15 to 20 g/mL, may be required to treat methicillin/oxacillin/nafcillin-resistant staphylococci with a vancomycin MIC of >1 g/mL or when there is a lack of microbiological response. Children with renal failure require dosage adjustments, and in these cases, guidance from phar- macists, infectious diseases, or renal diseases consultants is recommended. Recommendations 1. When gentamicin is used for synergy, it is reason- able to give a dose of 3 to 6 mg/kg per day (divided as an every 8-hour regimen) in children, adjusted for a target peak blood concentration of 3 to 4 g/ mL and a trough of <1 g/mL (Class IIa; Level of Evidence B). Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1505 2. Currently, there is insufficient clinical experience for treatment of pediatric IE with single daily dos- ing (of gentamicin) (Class III; Level of Evidence C). 3. Children with renal failure require dosage adjust- ments, and in these cases, guidance from pharma- cists, infectious disease specialists, or renal diseases consultants is recommended (Class I; Level of Evidence B). Culture-Negative Endocarditis The causes of CNE are discussed in LaboratoryAssessment. All cases of CNE are considered management conundrums for at least 2 reasons. First, empirical therapy is necessary, and thus, the antimicrobial regimen selected for administration may not provide adequate coverage for the undefined patho- gen. Second, empirical therapy could cause harm secondary to drug adverse events. A worst case scenario could develop in which the empirical regimen would result in clinical wors- ening and drug toxicity would develop because of an antimi- crobial agent that would not have been used if the pathogen had been defined. For these reasons, and with the information that antibiotic treatment is the main cause of CNE, the writing committee deemed it reasonable to obtain the proper number of cultures before antibiotic drugs are started or to stop antibi- otic drugs that were started fewer than 4 days earlier. Empirical treatment regimens are devised only after important epidemiological factors are considered, including the pivotal issue as to whether or not there has been recent antimicrobial exposure before obtaining blood cultures. Other key factors that are included in such a decision are the follow- ing: what specific antimicrobial agent was given (if there was prior antimicrobial exposure); determination of the route of acquisition of microbes; whether the infection was community acquired, nosocomial, or non-nosocomial health care associ- ated; what environmental exposures there had been (including injection drug use; Table 9); type of valve infected (whether native or prosthetic) and, if prosthetic, how long it had been implanted; and the clinical course of infection, whether acute, subacute, or chronic. Specific empirical regimens that are considered for use in patients with CNE are listed in Table 8. Because of the major limitations related to administration of therapy that is not specifically pathogen directed, it was the consensus of the writing group that infectious diseases consultation should be obtained in each case of CNE. An infectious diseases consul- tant will review any adverse events related to prior receipt of any drug, types of adverse events, whether there is residual organ damage related to these events or that caused by under- lying medical or surgical conditions, and the potential for clinically important drug interactions with agents other than antimicrobial agents. Recognition of the common causes of IE in specific clini- cal presentations is pivotal (Table 9). For example, in cases of native valve infection acquired in the community with a subacute clinical course, VGS, HACEK organisms, or, less likely, Enterococcus species should be considered. For an acute course of infection in the same setting, S aureus, S pneumoniae, and -hemolytic streptococci are more likely pathogens. Recommendations 1. For CNE, it is reasonable to obtain the proper num- ber of cultures before antibiotic drugs are begun or to stop antibiotic drugs that were started fewer than 4 days earlier (Class IIa; Level of Evidence C). 2. Infectious diseases consultation should be obtained in each case of CNE (Class I; Level of Evidence C). Complications and Surgical Issues In the current era, outpatient antibiotic therapy after initial diagnosis and stabilization is increasingly used. This makes it extremely important to define the patient population that is at higher risk for complications. Several factors predispose children with IE to potentially life-threatening complica- tions that may require early surgery. Risk factors are listed in Table 10. Other considerations that increase concern and the need for surveillance for complications include the size and location of the vegetation, acute onset of atrioventricular block, type of organism, occurrence of IE in an otherwise normal heart, and occurrence in children <2 years of age.10,11 The complications of IE can be classified into cardiac and extracardiac sequelae. Cardiac complications include congestive heart failure, new or progressive valvular dysfunction that is usually seen as increased regurgitation, periannular extension of infection, sinus of Valsalva rupture, myocardial dysfunction, obstruction of conduits or shunts, prosthetic valve dysfunction including dehiscence, pericardial effusion, and less commonly, septic emboli to the coronary arteries. Congestive heart failure is caused by various combinations of the above factors and is one of the more frequent complica- tions that carries a guarded prognosis. Progressive congestive heart failure usually is caused by worsening valvular regur- gitation, often accompanied by ventricular dysfunction. Poor ventricular function is associated with an increased surgical Urgent surgery in patients with moderate to severe heart failure improves the likelihood of survival and preservation of cardiac function.137 In general, for patients with IE, the degree of illness is not considered a limitation to surgical intervention because the alternative, to delay or defer surgery, can have dire consequences. Periannular extension of infection also increases the risk of congestive heart failure.138,139 The greatest risk for this complication exists in aortic valve endocarditis. Periannular infections also cause fistulous tracks into the pericardium, as well as between cardiac chambers or vascular structures. Such abscesses or fistulae usually do not respond to medi- cal management alone and require surgical treatment. Sinus of Valsalva aneurysms may occur with rupture into any of the cardiac chambers.140 Clinical signs and symptoms of extension of infection beyond valve leaflets are nonspe- cific and include persistent bacteremia or fever, recurrent emboli, heart block, worsening congestive heart failure, or new pathological murmurs in patients receiving appropriate Surgicallycreatedshuntsorintracardiacconduitsareapoten- tial source for complications of IE. Because these connections Table 8. Empirical Therapy in Culture-Negative Endocarditis* Regimen Dosage and Route Duration, wk Strength of Recommendation (Class/LOE) Comments Native valve Ampicillin-sulbactam 12 g/d IV in 4 equally divided doses 4 6 IIb/C Consensus of experts is that patients with culture-negative endocarditis should be managed with consultation with an infectious diseases specialist plus IV/IM in 3 equally divided doses 4 6 IV in 2 equally divided doses 4 6 IIb/C Vancomycin is recommended only for patients who are unable to tolerate penicillins plus IV/IM in 3 equally divided doses 4 6 plus ciprofloxacin 1500 mg/d PO or 800 mg/d IV in 2 equally divided doses Pediatric dosage: Ampicillin-sulbactam 300 IV in 4 6 equally divided doses; IV/IM in 3 equally divided doses; vancomycin 40 mg kg 1 or 3 equally divided doses; ciprofloxacin 20 30 IV/PO in 2 equally divided doses Prosthetic valve (early, 1 y) IV in 2 equally divided doses 6 IIb/C plus IV/IM in 3 equally divided doses 2 plus cefepime 6 g/d IV in 3 equally divided doses 6 plus rifampin 900 mg/d PO/IV in 3 equally divided doses 6 Pediatric dosage: Vancomycin 40 mg kg 1 IV in 2 or 3 equally divided doses; gentamicin IV/IM in 3 equally divided doses; IV in 3 equally divided PO/IV in 3 equally divided doses Prosthetic valve (late, >1 y) 6 IIb/C Same regimens as listed above for native valve endocarditis Suspected Bartonella, culture negative Ceftriaxone sodium 2 g/d IV/IM in 1 dose 6 IIa/B Patients with Bartonella endocarditis should be treated in consultation with an infectious diseases specialist plus IV/IM in 3 equally divided doses 2 with or without doxycycline 200 mg/d IV/PO in 2 equally divided doses 6 (Continued) Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1507 involve various prosthetic materials, including Gore-Tex, Dacron, or homografts, bacteriologic cure is often impossible without surgical intervention. Septic vegetations at these sites may lead to dehiscence, obstruction, or distal emboli.15,143 Extracardiac complications are the result of sepsis, immune complex mediated vasculitis, and, most importantly, embolic phenomena from septic vegetations. Embolic com- plications may involve the cerebral, pulmonary, renal, splenic, coronary, or peripheral arteries, depending on the original locus of infection. Neurological sequelae include stroke, brain abscess, hemorrhage, seizures, diffuse vasculitis, or menin- gitis, and these events may occur in up to 30% of cases.144 The incidence of stroke has been reported to be 6% in pediat- and 11% in those of all ages with CHD.146 Mycotic aneurysms may occur in any systemic artery or the pulmonary arteries but are particularly dangerous in the cere- bral circulation; surgical therapy may be used because of the risk of rupture. Numerous studies in adults102,147 have shown increased risk for embolization with vegetations >10 mm, which indicates a role for early surgical intervention in those with such large vegetations. Recently, this finding was sup- ported in a pediatric study.148 The location of the vegetation may also be a factor, with mitral valve anterior leaflet lesions having a higher rate of embolization than aortic valve vegeta- Particular organisms, namely, staphylococci, pneumococci, and fungi, also carry a high risk of embolism. Most emboli occur early in the course of the illness, but an increase in the size of the vegetation while a patient is receiving effective treatment may be predictive of The kidney and spleen may be involved during IE, with infarcts or abscesses related to emboli. The kidney may also be affected by glomerulonephritis secondary to immune complex depositions. Although mortality from IE has clearly improved in the current era, the mortality rate remains 5% to 10% for patients (including children) with this condition,24,146,151 with the risk of death clearly related to the presence of underly- ing heart disease, as shown in a review of a large pediatric In that study, the overall mortality was only 5%, but it was 48% in patients with tetralogy of Fallot and pulmonary atresia and 8% in patients who had pros- thetic valves. Recommendations 1. In general, for patients with IE, we recommend that the degree of illness not be considered a limitation to surgical intervention, because the alternative, to delay or defer surgery, can have dire consequences (Class I; Level of Evidence B). 2. Mycotic aneurysms may occur in any systemic artery or the pulmonary arteries but are particu- larly dangerous in the cerebral circulation; surgical therapy may be considered because of the risk of rupture (Class IIb; Level of Evidence B). Indications for Surgery Cardiovascular surgery is often urgently necessary and may be lifesaving in patients with IE, but decisions regarding surgical intervention are best made when individualized. Recommendations for surgical management of pediatric IE are mostly an extension of recommendations of experts for management of adult IE. The most common reasons for surgical management of IE are congestive heart failure, progressive valve dysfunction, and embolic phenomena. Prediction of an individual patient s risk for embolization Documented Bartonella, initially culture negative, determined to be positive by nonculture tests Doxycycline 200 mg/d IV or PO in 2 equally divided doses 6 IIa/B If gentamicin cannot be given, then replace it with rifampin 600 mg/d PO/IV in 2 equally divided doses plus IV/IM in 3 equally divided doses Pediatric dosage: Ceftriaxone 100 mg kg 1 IV/IM once daily; gentamicin 3 mg kg 1 IV/ IM in 3 equally divided doses; doxycycline 2 4 IV/PO in 2 equally divided doses; PO/IV in 2 equally divided doses As discussed in the text, these recommendations are based on consensus of experts and not experimental comparative studies (Class IIa; Level of Evidence C). Note: Pediatric dosage should not exceed that of a normal adult. IM indicates intramuscular; IV, intravenous; LOE, level of evidence; and PO, oral. *Dosages recommended are for patients with normal renal function. If ampicillin-sulbactam is unavailable, vancomycin is the suggested alternative (see Table 7 for empirical treatment of native valve infective endocarditis). See text and Table 7 for appropriate dosing of gentamicin. See Table 7 for appropriate dosing of vancomycin. Table 8. Continued Regimen Dosage and Route Duration, wk Strength of Recommendation (Class/LOE) Comments remains difficult, with conflicting data published regard- ing the specific value of echocardiographic determination of vegetation size or specific location as predictors.152,153 Nevertheless, left-sided heart lesions, specifically those involving the mitral valve anterior leaflet, particularly if associated with S aureus, appear to be at highest risk for However, at this time, there are no pediatric evidence-based data to indicate that prophylactic surgery to prevent a primary embolic event is definitively indicated given the immediate and long-term risks of valve replacement in childhood. Other important issues for which early surgery is used include perivalvular extension of infection, fungal endocar- ditis, persistent bacteremia despite appropriate antibiotic therapy, unstable prosthesis, ruptured sinus of Valsalva, or ventricular septal and mycotic aneurysms.156 158 The indica- tions for surgical intervention tabulated in Table 11 should be considered recommendations of experts.17 Although the clinical circumstances seem dire, even difficult aortic root complications can be treated successfully with aortic homografts or Ross procedure autografts.159,160 Depending on the degree of valve or great vessel root damage, valve- sparing operations are often possible.110,152,161 In some Late (>1 y) prosthetic valve placement Coagulase-negative staphylococci S aureus Viridans group streptococci Enterococcus species Fungi Corynebacterium species Dog-cat exposure Bartonella species Pasteurella species Capnocytophaga species Contact with contaminated milk or infected farm animals Brucella species Coxiella burnetii Erysipelothrix species Homelessness, body lice Bartonella species AIDS Salmonella species S pneumoniae S aureus Pneumonia, meningitis S pneumoniae Solid-organ transplant S aureus Aspergillus fumigatus Enterococcus species Candida species Gastrointestinal lesions Streptococcus bovis Enterococcus species Clostridium septicum HACEK indicates Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species. Table 9. Continued Epidemiological Feature Common Microorganism(s) Table 9. Epidemiological Clues in Pathogenic Diagnosis of Culture-Negative Endocarditis Epidemiological Feature Common Microorganism(s) Injection drug use Staphylococcus aureus, including community-acquired methicillin/ oxacillin/nafcillin-resistant S aureus Coagulase-negative staphylococci -Hemolytic streptococci Fungi Aerobic Gram-negative bacilli, including Pseudomonas aeruginosa Polymicrobial Indwelling cardiovascular medical devices S aureus Coagulase-negative staphylococci Fungi Aerobic Gram-negative bacilli Corynebacterium spp Genitourinary disorders, infection, and manipulation, including pregnancy, delivery, and abortion Enterococcus species Group B streptococci (Streptococcus agalactiae) Listeria monocytogenes Aerobic Gram-negative bacilli Neisseria gonorrhoeae Chronic skin disorders, including recurrent infections S aureus -Hemolytic streptococci Poor dental health, dental procedures Viridans group streptococci Nutritionally variant streptococci Abiotrophia defectiva Granulicatella species Gemella species HACEK organisms Alcoholism, cirrhosis Bartonella species Aeromonas species Listeria species Streptococcus pneumoniae -Hemolytic streptococci Burn patients S aureus Aerobic Gram-negative bacilli, including P aeruginosa Fungi Diabetes mellitus S aureus -Hemolytic streptococci S pneumoniae Early ( 1 y) prosthetic valve placement Coagulase-negative staphylococci S aureus Aerobic Gram-negative bacilli Fungi Corynebacterium species Legionella species (Continued) Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1509 circumstances, cardiological evaluation may suggest a need for early surgical therapy, performed even before steriliza- tion of blood. In a recent 15-year review of children treated for IE at the Texas Heart Institute in Houston, TX, early surgery was performed in 61% of patients, with most of these surgeries occurring within 7 days and half within 3 days of diagnosis.16 Several other studies have also shown that early surgery can be performed with low morbidity and mortality in childhood and improves the overall outcome Recent observational studies in adults have suggested that when adjusted for both selection and survi- vor biases, surgery in patients with left-sided IE, even when not considered urgent, may produce better outcomes and lower mortality than medical therapy alone.162,163 Although these data have not been replicated in specific pediatric- focused studies, the information does provide a reason- able framework for similar consideration in pediatric IE. Similarly, in prosthetic valve endocarditis, data from series in adults indicate that even aside from obvious indications for early surgery such as symptomatic heart failure, valve dehiscence, and great vessel root abscess formation, among others, surgery may benefit patients with relapsing pros- thetic valve endocarditis even if valvar function remains intact after prolonged medical therapy. Recommendations 1. Prophylactic surgery to prevent a primary embolic event is not recommended given the lack of proven benefit and long-term risks of valve replacement in childhood (Class III; Level of Evidence C). 2. Surgery may be considered for patients with relaps- ing prosthetic valve endocarditis even if valvar func- tion remains intact after prolonged medical therapy (Class IIb; Level of Evidence B). Prevention of Endocarditis For >5 decades, scientific organizations and public health- care policy groups around the world have advocated for the administration of antibiotic drugs for prophylaxis against IE. This recommendation, however, was never firmly grounded on well-designed, appropriately powered randomized clini- cal trials, and thus, scientific challenges to the concept emerged. These challenges were abetted by epidemio- logical facts that became apparent as well. 