Management of infective endocarditis in children

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1 Management of infective endocarditis in children Ashutosh Marwah, MD* Savitri Shrivastava, MD DM FAMS FACC* INTRODUCTION Infective endocarditis (IE) continues to remain a serious disease despite advances in its recognition and treatment modalities. It is uncommon in pediatric population; however, the incidence may be on rise. 1 In the western world the epidemiology of heart disease has changed over past few decades. There has been a decline in population with rheumatic heart disease and a gradual increase in the survivors of children with congenital heart defects (CHD). Congenital heart defects now constitutes the predominant underlying cause in developed countries. But in India, the incidence of rheumatic heart disease is still very high, while the incidence of CHD is also increasing. To complicate the issues further there is a rampant use of antibiotics, and lack of laboratory facilities for proper identification of cases. 2 Incidence of IE in developed countries has been reported to be around cases per 100,000 patient years, accounting for 1/1280 pediatric admission per year. 3 The exact incidence of endocarditis remains unknown. In various published series rheumatic heart disease still contributes to greater number of patients. 4 7 The blood cultures are more often negative and there is higher mortality and morbidity due to delay in diagnosis. DIAGNOSIS OF INFECTIVE ENDOCARDITIS IN CHILDREN Correct diagnosis remains the key to successful management could not be truer for IE. Presentation in children is usually indolent, with prolonged fever, weight loss, diaphoresis, and myalgias. The manifestations are secondary to ongoing bacteremia, valvulitis, embolic and immunological phenomenon. The cardiac involvement may result in new or changing murmur, electrocardiography (ECG) abnormalities, and congestive failure. The peripheral manifestation such as Roth spots, Janeway lesions, Osler s nodes, and renal abnormalities are * Fellowship in Pediatric Cardiology, Department of Pediatric and Congenital Heart Diseases, Escorts Heart Institute & Research Center, New Delhi. Correspondence: Dr. Ashutosh Marwah, Fellowship in Pediatric Cardiology, Department of Pediatric and Congenital Heart Diseases, Escorts Heart Institute & Research Center, Okhla Road, New Delhi ashu_marwah@yahoo.com caused by circulating immune complexes. The vegetations may embolize, and produce symptoms of ischemia or hemorrhage of the organ involved. There may be metastatic abscess secondary to septic emboli, and mycotic aneurysms may be seen in the brain. On occasion endocarditis may present as acute illness with spiking temperatures, and rapid worsening of patients condition due to cardiac decompensation secondary to cardiac lesion. These children often require urgent surgical interventions. In patients with palliated congenital heart defects there may not be much change in the murmurs but a declining oxygen saturation and congestive cardiac failure may be indirect pointers towards endocarditis. Recently proposed modified criteria have been shown to be superior to previous criteria in adult population and are outlined in the Tables 1 and 2. 8 The sensitivity of these criteria in Indian population remains to be tested. In absence of positive blood cultures and limited availability of echocardiography (ECHO) a large number of patients may be missed. LABORATORY ASSESSMENT Blood Culture In patients with known cardiac lesion blood cultures are indicated in all patients with fever of unexplained origin. The bacteremia is usually continuous, it is not necessary to obtain cultures only during fever, but it is important to send adequate volumes of blood (1 3 ml in infants and 5 7 ml in older children). At least 3 blood cultures are obtained by separate venepunctures on first day and 2 more cultures may be obtained if there has been no growth by 48 hours. According to the American College of Cardiology (ACC) guidelines it is not necessary to send anaerobic cultures as it is rare to have anaerobes as the etiological agent. 9 A large number of patients in our country receive antibiotics before they present at tertiary care centers. This results in more number of negative cultures. Sometimes withholding antibiotics for 3 4 days before sending blood culture helps in improving the yield, but such a practice is hard to follow even at best of institutes. In published series the blood culture positivity has been reported to be between 47% and 67%. 6,7 Fastidious organism such as coxiella. HACEK group, chlamydia, etc. may not grow on routine cultures, and require special serological tests for exact diagnosis. A false positive blood culture is also not so uncommon in clinical setting. Blood samples should be taken with strict aseptic technique to avoid contamination by normal skin commensals such as coagulase negative staphylococci and prevent over treatment. Bacteremia in hospitalized patients does not always result in endocarditis; however, any persistent and unexplained bacteremia should be investigated properly. Approximately 12% patients with staphylococcal bacteremia develop endocarditis. Whereas almost 50% patients with prosthetic valves with associated staphylococcal bacteremia develop endocarditis. Recent guidelines have included staphylococcal bacteremia as major criterion. 10 JICC Vol 1 Issue ICC

2 Marwah and Shrivastava Table 1 Definitions of terms used in the Duke s criteria for the diagnosis of infective endocarditis. Major criteria 1. Positive blood culture for infective endocarditis A. Typical micro-organism consistent with infective endocarditis from 2 separate 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. Micro-organisms consistent with infective endocarditis 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 separate cultures of blood (with first and last sample drawn 1 h apart). 2. Evidence of endocardial involvement A. Positive echocardiogram for 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 pre-existing murmur not sufficient). Minor criteria 1. Predisposition predisposing heart condition or i.v. drug use. 2. Fever temperature 38.0 C. 3. Vascular phenomena major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions. 4. Immunologic phenomena glomerulonephritis, Osler nodes, Roth s spots, and rheumatoid factor. 5. 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 infective endocarditis. 6. Echocardiographic findings consistent with infective endocarditis but do not meet a major criterion as noted above. *Includes nutritionally variant strains (Abiotrophia species). Excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis. HACEK indicates Haemophilus species, Actinobacillus (Haemophilis) actinomycetemcomitans, Cardiobacterium hominis, Eikenella species, and Kingella kingae. Table 2 Duke s clinical criteria for diagnosis of infective endocarditis. Definite infective endocarditis Pathological criteria Micro-organisms: 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 1 2 major criteria, or 1 major criterion and 3 minor criteria, or 5 minor criteria Possible infective endocarditis Findings consistent with infective endocarditis 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 infective endocarditis at surgery or autopsy, after antibiotic therapy for 4 d Echocardiography Cross-sectional ECHO has become an essential tool for diagnosing and management of endocarditis. Echocardiographic findings have been included as major criteria in recent Duke s criteria. 8 Echocardiography can detect the site of infection, the extent of cardiac involvement, and cardiac function, and the size of vegetation, large vegetation being suggestive of fungal or staphylococcal endocarditis. Associated problems such as pericardial effusion, abscess formation, valve/patch dehiscence can also be detected. Large mobile vegetation on left-sided structures may lead to early surgery to prevent embolization. Transthoracic echocardiography (TTE) has been reported to have sensitivity of 81% in pediatric population. 11 It remains the investigation of choice in most clinical setting. However, a trans-esophageal echocardiography (TEE) has been shown to be superior to TTE in adults for detection of vegetations on native and prosthetic valves. 12 No similar comparisons are available in children. TEE may be used in patients with poor imaging windows or patients already on ventilators. Echocardiography may be used to monitor the progress of the patients. Cardiac size, worsening of valve incompetence, increase in size of vegetation or development of myocardial abscess can all be monitored. Though ECHO may be able to pick up vegetations in culture negative endocarditis, absence of vegetation does not JICC Vol 1 Issue ICC

3 Management of infective endocarditis in children exclude the diagnosis of endocarditis. Also, one must remember old vegetations, sterile mass, ruptured chordae, or a normal anatomical variation may be confused for active endocarditis. 13,14 Molecular Techniques Fastidious organisms such as coxiella, legionella, chlamydia, etc. are often difficult to culture by routine methods. Techniques such as polymerase chain reaction (PCR) with signal amplification alone or in combination with sequence analysis allow a rapid and reliable identification of the causative agent. 15 PCR may also help in differentiating commensals after isolating different bacteria in different samples. Though the technique offers a great advantage over the routine cultures but it has its limitations. It is not able to give any anti-microbial sensitivity pattern. There is risk of contamination leading to false positive results. Presence of PCR inhibitors may lead to false negative results. Another disadvantage in our country is the cost and nonavailability of these tests for routine use. Histological and Immunological Methods Demonstration of microbial organism on a pathological specimen (resected valve/vegetation) remains the reference standard for diagnosis of endocarditis. It may be possible to culture the organism from the vegetation or identify the agent using immunohistological techniques. Coxiella burnetti may be easily identified by serological testing with enzyme-linked immunosorbent assay (ELISA). Miscellaneous Investigations Other investigations include a hemogram showing polymorphic response and anemia of chronic illness. There may be raised erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Urine microscopy may show RBC casts and proteinuria. TREATMENT OF INFECTIVE ENDOCARDITIS IN CHILDREN Antibiotic Treatment Recommendations for antibiotic treatment in adults have been made by American Heart Association (AHA). The Tables 3, 4 and 5 give guidelines for children based on the AHA recommendations. 9 Streptococcal Infective Endocarditis on Native Cardiac Valves or Prosthetic Material Viridans group of streptococci remain the commonest cause of IE in community. In patients with organisms susceptible to penicillin (minimum inhibitory concentration [MIC] < 0.1 μg/ml), a 4-week regimen of crystalline penicillin G achieves a high cure rate. 16 In adults ceftriaxone given or 4 weeks has been recommended but experience in pediatric population is limited. 17 A 2-week course of penicillin or ceftriaxone in combination with gentamycin also results a 98% cure rate in adults. This regimen is recommended for children with uncomplicated endocarditis of < 3 months duration. 18 It is also inappropriate for children at risk of adverse effects caused by gentamycin therapy. Once daily use of gentamicin is popular in adults, however such a practice is not recommended for children with IE. In patients with streptococci relatively resistant to penicillin (MIC > 0.5 μg/ml) use of penicillin, or ampicillin, or ceftriaxone in combination with gentamycin for first 2 weeks has been recommended. For patients sensitive to penicillin vancomycin has been recommended. 19 Patients with endocarditis of prosthetic cardiac valves with penicillin susceptible strains should be treated for 6 weeks. Patients sensitive to penicillin should receive vancomycin for 6 weeks along with gentamycin for the first 2 weeks. 9 Enterococcal Endocarditis Enterococcal endocarditis is rare in children. The treatment for native valve endocarditis is penicillin plus gentamycin for 6 weeks, or vancomycin plus gentamycin for 6 weeks in patients sensitive to penicillin. The aminoglycoside should be given for entire 6 weeks and in patients with normal renal function aminoglycoside should be administered in 2 or 3 divided doses rather than single daily dose. 20 Enterococci are resistant to cephalosporins and these drugs are not recommended for treatment of enterococcal endocarditis. Vancomycin resistant isolates of enterococci are often multi-drug resistant and difficult to treat. Linezolid has resulted in cure rates of about 77% in patients with vancomycin-resistant enterococcal infections. Use of double β-lactum antibiotic combinations such as imepenem and ampicillin, or cephalosporin plus ampicillin has also been recommended for treating high level resistant strains. Surgery may offer the best cure for some of these patients Staphylococcal Endocarditis Both coagulase positive and coagulase negative staphylococci can cause infective endocarditis in susceptible patient. Most staphylococci are resistant to β-lactum antibiotics. Endocarditis due to staphylococci susceptible to β-lactamase resistant penicillin (the methicillin susceptible staphylococci) should be treated for 6 weeks using oxacillin or nafcillin. Gentamycin may be added for 3 5 weeks to achieve rapid cure. First generation cephalosporin such as cefazolin can be used as an alternative for first 3 5 days of the therapy. 20 Patients not able to tolerate penicillin should receive vancomycin for minimum of 6 weeks. Methicillin resistant staphylococci are seen often in community. Patient with endocarditis due to methicillin resistant strains should be treated with combination of vancomycin and gentamycin for a minimum 6 weeks. 9 Prosthetic Valve Endocarditis Treatment of prosthetic valve endocarditis is often difficult. In patients with early onset staphylococcal or fungal endocarditis one should always consider replacement of the infected material. The timing of surgery should be individualized. Experience in adults shows lower mortality if infected valves are replaced early. 24 Infection caused by gram-negative organisms requires treatment for 6 8 weeks based on in vitro culture sensitivity. Diptheroids are best treated with penicillin/gentamycin/ vancomycin and gentamycin for at least 6 weeks. 25 JICC Vol 1 Issue ICC

4 Marwah and Shrivastava Table 3 Regimens for therapy of native valve infective endocarditis caused by viridans group streptococci, Streptococcus bovis or enterococci.* Organism Antimicrobial agent Dosage, per Kg/24 h Frequency of administration (h) Duration (wk) Penicillin-susceptible Penicillin G** or 200,000 U i.v. q streptococci (MIC 0.1 μg/ml)** ceftriaxone 100 mg i.v. q 24 4 Penicillin G** or 200,000 U i.v. q ceftriaxone mg i.v. q 24 2 gentamicin 3 mg i.m. or i.v. q 8 2 Streptococci relatively Penicillin G** or 300,000 i.v. q resistant to penicillin ceftriaxone mg i.v. q 24 4 (MIC > μg/ml) gentamicin 3 mg i.m. or i.v. q 8 2 Enterococci, ## nutritionally variant viridans Penicillin G** + 300,000 U i.v. q streptococci or high-level penicillin- gentamicin 3 mg i.m. or i.v. q 8 # 4 6 resistant streptococci (MIC > 0.5 μg/ml) For treatment of patients with prosthetic cardiac valves or other prosthetic materials, see text. MIC indicates minimum inhibitory concentration of penicillin. *Dosages suggested are for patients with normal renal and hepatic function. Maximum dosages per 24 hours penicillin 18 million units; ampicillin 12 g; ceftriaxone 4 g, gentamicin 240 mg. The 2-week regimens are not recommended for patients with symptoms of infection > 3 months in duration, those with extracardiac focus of infection, myocardial abscess, mycotic aneurysm, or infection with nutritionally variant viridans streptococci (Abiotrophia sp.). **Ampicillin 300 mg/kg/24 h in 4 6 divided dosages may be used as alternative to penicillin. Studies in adults suggest gentamicin dosage may be administered in single daily dose. If gentamicin is administered in 3 equally divided doses per 24 hours, adjust dosage to achieve peak and trough concentrations in serum of 3.0 and < 1.0 μg of gentamicin per ml, respectively. Studies in adults suggest that 4 weeks of therapy is sufficient for patients with enterococcal infective endocarditis with symptoms of infection of < 3 months duration; 6 weeks of therapy is recommended for patients with symptoms of infection of > 3 months duration. # Adjust gentamicin dosage to achieve peak and trough concentrations in serum of 3.0 and < 1.0 μg of gentamicin per ml, respectively. ## For enterococci resistant to penicillins, vancomycin, or aminoglycosides, treatment should be guided by consultation with specialist in infectious diseases (cephalosporins should not be used to treat enterococcal endocarditis regardless of in vitro susceptibility). Table 4 Treatment regimens for therapy of infective endocarditis caused by viridans group streptococci, Streptococcus bovis, or enterococci in patients unable to tolerate a β-lactam.* Organism Antimicrobial agent Dosage, per Kg/24 h Frequency of administration (h) Duration (wk) Native valve (no prosthetic material) Streptococci Vancomycin 40 mg i.v. q Enterococci** or nutritionally variant Vancomycin + 40 mg i.v. q viridans streptococci gentamicin 3 mg i.m. or i.v. q 8 6 Prosthetic devices Streptococci Vancomycin + 40 mg i.v. q gentamicin 3 mg i.m. or i.v. q 8 2 Enterococci** or nutritionally variant Vancomycin + 40 mg i.v. q viridans streptococci gentamicin 3 mg i.m. or i.v. q 8 6 *Dosages suggested are for patients with normal renal function. Maximum daily dose per 24 hours of gentamicin is 240 mg. **For enterococci resistant to vancomycin or aminoglycosides, treatment should be guided by consultation with specialist in infectious diseases. Dosage of gentamicin should be adjusted to achieve peak and trough concentration in serum of 3.0 and < 1.0 μg of gentamicin per ml, respectively. Prosthetic valve endocarditis caused by streptococci or enterococci should be treated on the guidelines discussed earlier. Culture Negative Endocarditis A lot of patients in our country receive or self-medicate themselves before presenting to a tertiary care center. If cultures are negative after careful evaluation therapy should be initiated with ceftriaxone and gentamycin. Beta-lactamse resistant penicillin should be added to the regimen if staphylococcal infection is suspected. Vancomycin should be added if methicillin resistant staphylococcal infection is suspected. A team approach in consultation with infectious disease specialist is helpful in optimizing the treatment of culture negative endocarditis. 9,26 ROLE OF SURGERY Patients with IE with congestive heart failure should be evaluated for surgical causes. Despite higher surgical mortality rates in patients with congestive heart failure (CHF) the mortality is JICC Vol 1 Issue ICC

5 Management of infective endocarditis in children Table 5 Treatment regimens for endocarditis caused by staphylococci.* Organism Antimicrobial agent Dosage, per Kg/24 h Frequency of administration (h) Duration Native valve (no prosthetic materials) Methicillin-susceptible Nafcillin or oxacillin 200 mg i.v. q wk with or without gentamicin** 3 mg i.m. or i.v. q d β-lactam allergic Cefazolin with or without 100 mg i.v. q wk gentamicin** or 3 mg i.m. or i.v. q d vancomycin 40 mg i.v. q wk Methicillin-resistant Vancomycin 40 mg i.v. q wk Prosthetic device or other prosthetic materials Methicillin-susceptible Nafcillin or oxacillin or 200 mg i.v. q wk cefazolin mg i.v. q wk rifampin # + 20 mg po q 8 6 wk gentamicin** 3 mg i.m. or i.v. q 8 2 wk Methicillin-resistant Vancomycin + 40 mg i.v. q wk rifampin # + 20 mg po q 8 6 wk gentamicin** 3 mg i.m. or i.v. q 8 2 wk *Dosages suggested are for patients with normal renal and hepatic function. Maximum daily doses per 24 hours: oxacillin or nafcillin 12 g; cefazolin 6 g; gentamicin 240 mg; rifampin 900 mg. **Gentamicin therapy should be used only with gentamicin-susceptible strains. Dosage of gentamicin should be adjusted to achieve peak and trough concentrations in serum of 3.0 and < 1.0 μg of gentamicin per ml, respectively. Cefazolin or other first-generation cephalosporin in equivalent dosages may be used in patients who do not have a history of immediate type hypersensitivity (urticaria, angioedema, and anaphylaxis) to penicillin or ampicillin. # Dosages suggested for rifampin is based upon results of studies conducted in adults and should be used only with rifampin-susceptible strains. lower in patients who undergo timely surgery, as compared to those managed on medical therapy alone. The incidence of reinfection of implanted valves is about 2 3% as compared to mortality without surgery, which can approach 51% on medical management alone. 27,28 Surgery is also indicated in cases of valve dehiscence, periannular abscess formation, or a fistulous tract into pericardium. Other indication for surgery is presence of large vegetation 10 mm which are at the risk of systemic embolization. The greatest risk of embolization is in first 2 weeks of therapy. Fungal infection or infection with aggressive antibiotic resistant bacteria, persistent culture positivity after 1 week of antibiotics, or one or more embolic events during first 2 weeks may also warrant surgery. In children with endocarditis of shunts or prosthetic conduits likelihood of cure with antibiotics alone is low and surgical intervention is often needed CARE AT COMPLETION OF TREATMENT In patients completing the treatment an ECG should be obtained to establish a new baseline for subsequent comparisons. A thorough dental referral should be done to remove any infected teeth and proper dental hygiene advised; all indwelling catheters should be removed. A relapse may occur despite successful treatment. Fresh cultures should be obtained before initiating treatment of relapse. Every effort should be made to identify and treat the cause of relapse. Congestive heart failure may worsen during follow-up and may need aggressive decongestive therapy or valve replacement. Late onset complications of antibiotic toxicity should be looked into and treated. REFERENCES 1. Baltimore RS. Infective endocarditis. In: Pediatric Infectious Diseases: Principles and Practice Jenson HB, Baltimore RS, eds. Norwalk, conn: Appleton and Lange, Kothari SS, Ramakrishna S, Bahl VK. Infective endocarditis an Indian perspective. Indian Heart J 2005;57: Van Hare GF, Ben-Shachar G, Liebman J, et al. Infective endocarditis in infants and children during the past 10 years. A decade of change. Am Heart J 1984;107: Moreillon P, Que YA. Infective endocarditis. Lancet 2004;363: Tornos P, Iung B, Permanyer-Miralda G, et al. Infective endocarditis in Europe: lessons from euro heart survey. Heart 2005;91: Garg N, Khandpal B, Garg N, et al. Characteristics of infective endocarditis in a developing country clinical profile and outcome in 192 Indian patients, Int J Cardiol 2005;98: Choudhury R, Grover A, Varma J, et al. Active infective endocarditis observed in an Indian hospital Am J Cardiol 1992;70: Durack DT, Lukes AS, Bright VK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 1994;96: JICC Vol 1 Issue ICC

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