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Following the establishment of a diagnosis of IE using clinical, microbiological, and echocardiographic methods, antibiotics should be administered in a dose designed to give sustained bactericidal serum concentrations throughout much of or the entire dosing interval. Certain general principles have been accepted, which provide the framework for the current recommendations for treatment of IE (Table 37–5). Guidelines for outpatient parenteral antibiotic therapy for IE in adults as well as general guidelines for outpatient parenteral antibiotic therapy in all age ranges have been published.77,78 Pediatric outpatient parenteral antibiotic therapy has been demonstrated to be successful, to have a relatively low risk of complications, and to have a low rehospitalization rate mostly related to issues with vascular access.79 Patients selected for outpatient therapy should have responded clinically to inpatient therapy, with negative blood cultures, no evidence of intracardiac complications, and stable hemodynamic parameters. Patients’ families need to be compliant and capable of managing the technical aspects of intravenous therapy. Such patients require careful, regular monitoring in association with a home health-care service and prompt access to medical care.48
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The American Heart Association has issued treatment guidelines for children48 and, more recently, updated specific treatment guidelines based on the microbiologic etiologic agent.65 General therapeutic considerations are summarized in Tables 37–6 to 37–9.37,48,65 All dosing is listed as milligram of antimicrobial per kilogram of patient body weight. It is important to remember that the total dose should never exceed the maximum adult dose.
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The great majority of S. aureus isolates produce a β-lactamase and, therefore, are highly resistant to penicillin G and are termed methicillin-susceptible S. aureus (MSSA). The drugs of choice for native valve MSSA are semisynthetic, β-lactamase-resistant penicillins, such as nafcillin or oxacillin (Table 37–6). The addition of gentamicin for the first 3–5 days is optional, as it may increase the killing of the staphylococci and facilitate clearance of bacteremia, although it may increase rates of nephrotoxicity and ototoxicity. In patients without a history of type 1 penicillin-allergic reactions, a first-generation cephalosporin such as cefazolin is indicated with or without gentamicin for the first 3–5 days. In patients with MSSA and allergies to β-lactams, vancomycin is the drug of choice with or without gentamicin for the first 3–5 days. However, it must be noted that some evidence suggests than vancomycin is an inferior drug in the treatment of MSSA IE, predominantly because of its slow bactericidal activity and poor tissue penetration.80
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Coagulase-negative staphylococci are usually methicillin resistant (MRSA). Because of cross-resistance, cephalosporins should not be used in these patients. Vancomycin is usually given for at least 6 weeks with or without gentamicin for the first 3–5 days.
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Staphylococcal prosthetic valve IE (PVE) is associated with high mortality and requires aggressive management. Treatment for MSSA PVE is with nafcillin or oxacillin, in combination with rifampin for 6–8 weeks and gentamicin during the first 2 weeks. For MRSA PVE, vancomycin is used in combination with rifampin for 6–8 weeks and gentamicin is added during the first 2 weeks. In order to minimize resistance to rifampin, this medication should be added only after antibiotics active against staphylococci, such as a β-lactam or vancomycin and an aminoglycoside, have been started and the infection burden of bacteria is significantly reduced. In some cases, MRSA resistant to aminoglycosides (reported to be decreasing in frequency81) can be treated with fluoroquinolones, depending on the results of susceptibility testing. Daptomycin is a lipopeptide antibiotic that is bactericidal and has been shown to be effective in treatment of staphylococcal endocarditis in adults.82 However, experience with daptomycin in children is limited, and thus a safe pediatric dose has not been established.83 Staphylococcal PVE has been reported to have a very high mortality in adults, even with aggressive medical therapy.84 For this reason, early surgical valve replacement is often considered. S. aureus PVE has been reported to cause a high incidence of intracerebral hemorrhage in adults,85 and thus the risks of continuing anticoagulation need to be carefully considered.
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Viridans Group Streptococci, Streptococcus Bovis, and Other Nonenterococcal Streptococci
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The treatment for endocarditis caused by viridans streptococci is based on the in vitro penicillin minimum inhibitory concentration (MIC) (Table 37–7). Streptococci with a penicillin MIC ≤0.12 μg/mL are considered highly susceptible and are usually treated with penicillin G or ceftriaxone for 4 weeks. Comparable cure rates can be achieved with a combination of penicillin or ceftriaxone with low-dose gentamicin for 2 weeks. A cure rate of 98% has been reported with these regimens in adults,86,87 but there are no published data on the efficacy of ceftriaxone for the treatment of IE in children. Cefazolin or other first-generation cephalosporins may be substituted for penicillin in patients whose penicillin hypersensitivity is not of the immediate type. Vancomycin is recommended for patients allergic to β-lactams.
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When IE is caused by streptococcal strains with a penicillin MIC >0.12 μg/mL and <0.5 μg/mL, combination therapy with penicillin for 4 weeks and low-dose gentamicin for the first 2 weeks of treatment is recommended. In patients allergic to β-lactams, a 4-week course of vancomycin is recommended. When native valve or PVE IE is caused by streptococcal strains with a penicillin MIC >0.5 μg/mL or nutritionally variant streptococci (now classified as Abiotrophia species), the regimen for penicillin-resistant enterococcal IE is recommended (Table 37–8).
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For highly penicillin-susceptible streptococci PVE (MIC ≤0.12 μg/mL), penicillin G for 6 weeks and gentamicin for 2 weeks are usually indicated. When PVE is caused by relatively penicillin-resistant streptococci (MIC (>0.12–0.5 μg/mL), penicillin G is recommended for 6 weeks and gentamicin for 4 weeks.
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IE caused by enterococci is usually associated with Enterococcus faecalis and occasionally with Enterococcus faecium. Enterococci are increasingly resistant to most classes of antibiotics, making treatment difficult (Table 37–8). Because of a defective bacterial autolytic enzyme system, cell-wall-active agents are bacteriostatic against enterococci and should not be given alone to treat IE. When used in combination with gentamicin, penicillin G and ampicillin facilitate the intracellular uptake of the aminoglycoside, resulting in a bactericidal effect against enterococci. Before embarking on therapy, susceptibility of the enterococcal isolate should be determined for penicillins, vancomycin, and aminoglycosides. For strains with intrinsic high-level resistance to penicillin (MIC >16 μg/mL), vancomycin is indicated. Vancomycin is synergistic with aminoglycosides, particularly gentamicin. When high-level resistance to aminoglycosides is detected (500–2000 μg/mL for gentamicin), combination with cell-wall-active agents is no longer synergistic and therefore not recommended. Limited data are available to guide therapy in these difficult cases; however, some experts will attempt high-dose ampicillin combined with imipenem or ceftriaxone for 8–12 weeks.
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IE caused by vancomycin-resistant enterococci (VRE) is difficult to treat. Most vancomycin-resistant strains of E. faecalis and some vancomycin-resistant strains of E. faecium are susceptible to achievable concentrations of ampicillin. In such cases, the recommended therapy is ampicillin or penicillin combined with gentamicin. Even when enterococci are considered resistant to ampicillin, higher doses can be used in order to achieve sustained plasma levels of >100–150 μg/mL with some treatment efficacy and little toxicity. In 1999, the FDA approved quinupristin/dalfopristin (QD) to treat infections associated with vancomycin-resistant E. faecium bacteremia when no alternative treatment is available. However, QD alone is unlikely to be curative in VREF IE because it is not usually bactericidal against E. faecium. Endocarditis models suggest that the association of QD with ampicillin may be beneficial. It is important to note that E. faecalis is not susceptible to QD. In 2000, the FDA approved linezolid to treat infections associated with vancomycin-resistant E. faecium, including cases with bloodstream infection. However, linezolid is bacteriostatic against VRE and therefore cannot be recommended for VRE IE. Newer agents such as daptomycin, telavancin, and dalbavancin may be useful in such cases based on experimental models, but clinical experience is lacking. Unfortunately, case reports of enterococcal resistance to daptomycin are already emerging.88
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HACEK organisms, including Haemophilus spp. (Haemophilus parainfluenzae, H. aphrophilus, and H. paraphrophilus), Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae are not common in children. These organisms have fastidious growth characteristics, and thus standard culture incubation for 2–3 weeks is recommended for cases in which IE is suspected and the initial blood cultures are negative. Third-generation cephalosporins are recommended for the treatment of HACEK IE (Table 37–9), with a duration of 3–4 weeks for native valves and 6 weeks for PVE.89 HACEK isolates are typically susceptible in vitro to fluoroquinolones, aztreonam, and trimethoprim–sulfamethoxazole. However, since clinical data are still lacking, these agents should be reserved as an alternative therapy in patients who cannot tolerate β-lactams.
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Other Gram-negative bacteria are an infrequent cause of IE in children and are most often nosocomially acquired. Treatment of organisms such as P. aeruginosa, E. coli, and Serratia marcescens should be individualized, based on antimicrobial susceptibility of the specific isolate.48 Empiric therapy with an extended-spectrum penicillin/β-lactamase inhibitor or cephalosporin together with an aminoglycoside is recommended until final culture testing is completed. Total duration of therapy should be 6 weeks and should be implemented in consultation with an infectious disease specialist.
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The incidence of fungal IE has increased significantly in the past decade, in most cases caused by Candida or Aspergillus species. Although current recommendations strongly favor a combined medical–surgical approach, the introduction of new fungicidal agents may reduce that need. Any documented or suspected case of fungal IE requires an infectious disease consultation.
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A mainstay of antifungal drug therapy is liposomal amphotericin B for at least 6–8 weeks. This agent is much less toxic than routine amphotericin B, which produces multiple side effects, including fever, chills, phlebitis, headache, anorexia, anemia, hypokalemia, renal tubular acidosis, nephrotoxicity, nausea, and vomiting. Depending on the isolate, some experts recommend the addition of 5-fluorocytosine or rifampin to amphotericin B, as these drugs may act synergistically to potentiate fungal killing. In patients who are unable to undergo surgery, after an initial course of amphotericin B, an azole is often used for long-term suppressive therapy. The role of newer antifungals such as posaconazole, micafungin, and capsofungin in the treatment of fungal IE remains unclear, despite their increased use, as reports of efficacy of these agents are limited.
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As a result of the substantial issues in treatment decisions, consultation with an infectious disease specialist is recommended. The primary considerations for therapy are directed against staphylococci, streptococci, enterococci, and the HACEK organisms (Table 37–9). An initial approach is to use ceftriaxone and gentamicin. A β-lactamase-resistant penicillin such as ampicillin–sulbactam should be added if there is a high suspicion of staphylococcal IE. Vancomycin should be substituted in patients who are allergic to penicillin and when suspicion of MRSA is high. If clinical improvement occurs, some authorities recommend discontinuation of treatment with the aminoglycoside after 2 weeks. The other agent(s) should be continued for a full 6 weeks of treatment. Patients who are at risk of unusual causes of IE such as Coxiella, Bartonella, Legionella, and Brucella can be empirically started on doxycycline and ciprofloxacin; however, these pathogens require targeted therapy, which should be undertaken in consultation with an infectious diseases specialist.
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Valve replacement has become an important adjunct to medical therapy in the management of IE and is now used in at least 25% of the cases. The generally accepted indications for surgical intervention during active IE are listed in Table 37–10. Of particular importance to pediatric patients with palliated congenital heart disease is development of aortopulmonary shunt obstruction and infected prosthetic material such as in right ventricle to pulmonary artery conduits. The hemodynamic status of the patient, not the activity of the infection, is the critical determining factor in the timing of cardiac valve replacement. Surgery should not be delayed because a full course of antibiotic therapy has not been completed or the patient is still bacteremic. Indeed, the incidence of reinfection of a prosthetic valve after surgery is below 1%. Thus, when CHF is diagnosed in patients with aortic valve IE or persists despite therapy in mitral valve IE, surgery is indicated. Although not systematically studied, most experts recommend continuation of antibiotic therapy postoperatively for 2–6 weeks when surgery is undertaken with active IE.90
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Most patients with PVE (except those with late disease caused by penicillin-sensitive viridans streptococci) require valve replacement. Similarly, valve replacement is necessary in a significant proportion of patients with IE on native valves after a medical cure, particularly with aortic valve involvement, which is more likely to be hemodynamically significant.
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Medical therapy alone can be considered even in the face of the listed risk factors if there are significant comorbid conditions such as central nervous system bleeding. The morbidity and mortality of surgery must be carefully considered when patients are at high risk of bypass complication.
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Antimicrobial prophylaxis before selected dental and invasive surgical and diagnostic procedures has become standard and routine in most countries, despite the fact that no prospective study has been performed that proves that such therapy is clearly beneficial. Studies have shown that amoxicillin prophylaxis results in a decrease in procedure-related bacteremia in a general population of pediatric patients.91 However, only one-half of all patients who develop IE have a cardiac disorder that would have prompted IE prophylaxis in the first place.37 Maintenance of meticulous dental hygiene is of equal importance to antibiotic prophylaxis in the prevention of IE, and compliance with dental hygiene is difficult in the pediatric population. In addition, it is advisable to instruct all patients to avoid gingival trauma with toothpicks and high-pressure water irrigation devices.
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The guidelines for antimicrobial prophylaxis for IE formulated by an expert committee of the American Heart Association are the regimens most widely used by clinicians in the United States. The guidelines were significantly revised in 2007 as the committee concluded that (1) IE is much more likely to result from frequent exposure to random bacteremia than to medical procedures, (2) only an extremely small number of cases of IE might be prevented by antibiotic prophylaxis even if 100% effective, (3) the risk of antibiotic-associated events exceeds the benefit or prophylaxis, and (4) proper maintenance of oral health and hygiene is more important than antibiotic prophylaxis for dental procedure in reducing the risk of IE. The procedures with the highest risk of bacteremia were refined, and prophylaxis is now recommended only for patients with the highest risk of an adverse outcome after an episode of IE.92
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Table 37–11 outlines the conditions associated with the highest risk for IE based on the new American Heart Association guidelines. Certain procedures and conditions are known to present the highest risk of bacteremia, and therefore antibiotic prophylaxis is recommended. This encompasses all dental procedures that involve manipulation of gingival or periapical region of teeth or perforation of oral mucosa. This also includes surgical procedures in the setting of an active infection, invasive respiratory tract procedures, and procedures where antibiotics would be given to prevent wound infections (Table 37–12). However, there is no evidence of the effectiveness of prophylaxis during these procedures to prevent IE. Routine prophylaxis solely to prevent IE is no longer recommended for GI or GU procedures. For example, clinicians must often use judgment in selecting dose and duration of antimicrobial therapy in elderly or obese patients or in those with underlying renal disease. Furthermore, there are sometimes instances in which the risk of prophylactic therapy may actually outweigh the risk of postprocedure endocarditis. Patients in such circumstances often have cardiac lesions of questionable or little hemodynamic consequence, have a documented or possible drug allergy, or are undergoing procedures in which the risk of bacteremia is extremely low.
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The antimicrobial regimens suggested by the American Heart Association for IE prophylaxis are listed in Table 37–13.
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