Successful treatment of a staphylococcal endocarditis vegetation with tissue plasminogen activator

THE JOURNAL OF PEDIATRICS Volume 132, Number 3, Part 1 2. Kitchen WH, Doyle LW, Ford GW, Rickards AL, Lissenden JV, Ryan MM. Cerebral palsy in very low birthweight infants surviving to 2 years with modern perinatal intensive care. Am J Perinatol 1987;4:29-35. 3. Van Zeben-van der AA TM, Verloove-Vanhorick SP, Brand R, Ruys JH. Morbidity of very low birthweight infants at corrected age of two years in a geographically defined population: report from Project on Preterm and Small for gestational age infants in The Netherlands. Lancet 1989;1:253-5. 4. Veelken N, Stollhoff K, Claussen M. Development of very low birth weight infants: a regional study of 371 survivors. Eur J Pediatr 1991;150:815-20. 5. Arnold CC, Kramer MS, Hobbs CA, McLean FH, Usher RH. Very low birth weight: a problematic cohort for epidemiologic studies of very small or immature neonates. Am J Epidemiol 1991;134:604-13. 6. Veelken N, Stollhoff K, Claussen M. Development and perinatal risk factors of very low-birth-weight infants: small versus appropriate for gestational age. Neuropediatrics 1992;23:102-7. 7. Savitz DA, Blackmore CA, Thorp JM. Epidemiologic characteristics of preterm delivery: etiologic heterogeneity. Am J Obstet Gynecol 1991;164:467-71. 8. Gomez R, Ghezzi F, Romero R, Muñoz H, Tolosa JE, Rojas I. Premature labor and intra-amniotic infection: clinical aspects and role of the cytokines in diagnosis and pathophysiology. Clin Perinatol 1995;22:281-342.

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9. Eskenazi B, Fenster L, Sidney S, Elkin EP. Fetal growth retardation in infants of multiparous and nulliparous women with preeclampsia. Am J Obstet Gynecol 1993; 169:1112-8. 10. Adinolfi M. Infectious diseases in pregnancy, cytokines and neurological impairment: an hypothesis. Dev Med Child Neurol 1993;35:549-53. 11. Leviton A. Preterm birth and cerebral palsy: Is tumor necrosis factor the missing link? Dev Med Child Neurol 1993;35:553-8. 12. Touwen BCL. Examination of the child with minor neurological dysfunction. In: Clinics in developmental medicine no. 71. London: Spastics International Medical Publications; 1979. 13. Bax MCO. Terminology and classification of cerebral palsy. Dev Med Child Neurol 1964;6:295-7. 14. Kuban KC, Leviton A. Cerebral palsy. N Engl J Med 1994;330:188-95. 15. Dubowitz LM, Dubowitz V, Goldberg C. Clinical assessment of gestational age in the newborn infant. J Pediatr 1970;77:1-10. 16. Largo RH, Wälli R, Duc G, Fanconi A, Prader A. Evaluation of perinatal growth. Helv Paediatr Acta 1980;35:419-36. 17. Dales LG, Ury HK. An improper use of statistical significance testing in studying covariables. Int J Epidemiol 1978;7:373-5. 18. Leviton A, Paneth N. White matter damage in preterm newborns—an epidemiologic perspective. Early Hum Dev 1990;24:1-22. 19. Blair E, Stanley F. Aetiological pathways to spastic cerebral palsy. Paediatr Perinatol Epidemiol 1993;7:302-17.

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20. Nelson KB, Ellenberg JH. Predictors of low and very low birth weight and the relation of these to cerebral palsy. JAMA 1985;254:1473-9. 21. Spinillo A, Iasci A, Capuzzo E, Egbe TO, Colonna L, Fazzi E. Two-year infant neurodevelopmental outcome after expectant management and indicated preterm delivery in hypertensive pregnancies. Acta Obstet Gynecol Scand 1994;73:625-9. 22. Murphy DJ, Sellers S, MacKenzie IZ, Yudkin PL, Johnson AM. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 1995;346:1449-54. 23. Grether JK, Nelson KB, Emery ES III, Cummins SK. Prenatal and perinatal factors and cerebral palsy in very low birth weight infants. J Pediatr 1996;128:407-14. 24. Klebanoff MA, Shiono PH. Top down, bottom up and inside out: reflections on preterm birth. Paediatr Perinatol Epidemiol 1995;9:125-9. 25. Pinto-Martin JA, Riolo S, Cnaan A, Holzman C, Susser MW, Paneth N. Cranial ultrasound prediction of disabling and nondisabling cerebral palsy at age two in a low birth weight population. Pediatrics 1995;95:249-54. 26. Yoon BH, Romero R, Yang SH, Jun JK, Kim IO, Choi JH, et al. Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. Am J Obstet Gynecol 1996;174:143340.

Successful treatment of a staphylococcal endocarditis

vegetation with tissue plasminogen activator Robert E. Fleming, MD, Stephen J. Barenkamp, MD, and Saadeh B. Jureidini, MD A 930 gm premature infant had Staphylococcal endocarditis with a tricuspid valvular vegetation that was unresponsive to antibiotics and not amenable to resection. Infusion of tissue plasminogen activator over a 3-day period completely lysed the vegetation. The infection cleared with continued antibiotics, and the infant recovered without sequelae. (J Pediatr 1998;132:535-7)

From the Department of Pediatrics, St. Louis University School of Medicine, St. Louis, Missouri. Received for publication Mar. 25, 1997; accepted June 24, 1997. Reprint requests: Robert E. Fleming, MD, Department of Pediatrics, St. Louis University School of Medicine, 1465 South Grand Ave., St. Louis, MO 63104. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/22/84342

Despite current treatment modalities infectious endocarditis remains a serious problem in pediatric and adult patients. The mortality rate from IE is substantial in all age groups (25% to 33% for IE tPA

Infective endocarditis Tissue plasminogen activator

neonates,1,2 11% for children,3 30% for adults4). Surgical intervention has been reported in 31% to 76% of pediatric patients with IE,5,6 often for resection of the vegetation alone. We report here the 535

FLEMING, BARENKAMP, AND JUREIDINI

Fig. 1. Apical four-chamber view from two-dimensional echocardiography. A, Day 34. Large (10 × 6 mm) vegetation (V) is seen on tricuspid valve (TV). B, Day 37. Same view after thrombolytic therapy reveals that vegetation has completely resolved. LA, Left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

use of tissue plasminogen activator in a neonate to successfully treat a Staphylococcal IE vegetation that was unresponsive to antimicrobial therapy and not amenable to surgical therapy.

CASE REPORT An 815 gm male infant was born at 25 weeks gestation after preterm labor unresponsive to tocolytics. The infant was administered ampicillin, gentamicin, and surfactant and underwent ventilation. He did well initially, and antibiotics were discontinued after 3 days of negative cultures. On postnatal day 6 a percutaneous catheter was placed in the foot with the tip in the inferior vena cava at the level of the diaphragm. On day 8 the infant had hyperglycemia, hypercarbia, leukocytosis (49.2 × 109/L), and thrombocytopenia (73 × 109/L). Vancomycin and cefotaxime were instituted. Blood cultures grew Staphylococcus aureus, resistant to methicillin but sensitive to vancomycin, gentamicin, rifampin, and clindamycin. Spinal 536

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fluid was negative. Vancomycin was continued, and the central venous catheter was replaced. The infant subsequently had a grade II/VI systolic murmur at the left upper sternal border. Echocardiography (day 13) revealed a patent ductus arteriosus with left-sided volume overload and no evidence of vegetation in the cardiac chambers or great vessels. Indomethacin (0.2 mg/kg every 12 hours × 3) was administered; however, clinical signs of patent ductus arteriosus persisted. On day 18 the infant had hepatosplenomegaly and thrombocytopenia (3 × 109/L). Echocardiography demonstrated, in addition to the patent ductus arteriosus, a 5 × 5 mm pedunculated vegetation on the tricuspid valve with mild regurgitation. No other vegetations were present in the cardiac chambers or great vessels. Gentamicin and rifampin were added. Rifampin was later replaced with clindamycin when the infant had conjugated hyperbilirubinemia. Follow-up echocardiography on day 25 revealed growth of the vegetation to 6 × 6 mm and the development of surface irregularities along the ductus lumen, suggesting extension of the infection to this structure. The ductus was surgically ligated on day 26 and appeared inflamed and aneurysmal on direct inspection. Despite therapeutic antibiotic levels, blood cultures continued to grow S. aureus, thrombocytopenia persisted, and a subcutaneous nodule appeared on the right arm. Echocardiography on day 34 revealed further growth of the vegetation to 10 × 6 mm (Fig. 1, A). Because the infant’s size (930 gm) precluded surgical resection, lysis of the vegetation was considered. The platelet count at that time was 77 × 109/L. Prothrombin time and partial thromboplastin time were normal. Previous cranial ultrasonography had demonstrated a stable right subependymal hemorrhage. After potential risks of thrombolytic therapy were discussed with the parents, alteplase tPA (Activase, Genentech), 0.5 mg/kg over a 10-minute period, was administered by left subclavian catheter. This was followed by continuous infusion of 0.2 mg/kg/hr over a 3-day period (days 34 to 37). Other than prolonged bleeding from needlesticks, no complications were identified. There were no episodes of

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cyanosis or respiratory deterioration to suggest pulmonary embolism. Follow-up echocardiography on day 37 revealed complete resolution of the vegetation (Fig. 1, B) without sonographic evidence of embolization to any cardiac structure or great vessel including the distal pulmonary arteries and the course of the aorta to the iliac bifurcation. By day 39 platelet count had normalized (170 × 109/L), and C-reactive protein concentration had fallen to <0.4 mg/dl (from 4.07 mg/dl on day 21). All subsequent cultures were negative. Gentamicin was continued an additional 2 weeks and vancomycin an additional 4 weeks. Follow-up echocardiography was entirely normal and without evidence of tricuspid regurgitation. The subependymal hemorrhage continued to resolve. The infant was discharged home without medications on day 67. With the exception of retinopathy of prematurity, the physical examination was normal.

DISCUSSION The use of anticoagulation (heparin or coumadin) to attenuate vegetation growth has met with bleeding complications and disappointing results for native valve IE7 and was not initiated in our patient. Persistent sepsis despite antibiotic therapy is an indication for surgical intervention.5,6 However, the infant’s size precluded cardiac bypass. Inflow stasis under profound hypothermia was thought to present an unreasonable risk to this very preterm infant. Consideration was thus given to thrombolytic therapy. IE vegetations consist of colonizing bacteria, platelets, and fibrin. By promoting fibrin degradation, thrombolytic agents offer the theoretic possibility of reducing vegetation mass and enhancing antibiotic diffusion. In an animal model of catheter-induced IE, tPA plus antibiotics was more effective than antibiotics alone in reducing vegetation mass, eliminating electrocardiographic signs of ischemia, and decreasing the erythrocyte sedimentation rate.8 Among the thrombolytic agents, tPA has a number of clinical advantages. Although it has a high affinity

THE JOURNAL OF PEDIATRICS Volume 132, Number 3, Part 1 for fibrin, tPA has a low affinity for circulating plasminogen, reducing its systemic effects.9 The elimination half-life is short, decreasing the risk of bleeding complications.9 tPA has been successfully used in neonates to lyse vascular thrombi10 and an intracardiac thrombus.11 The continued growth of the vegetation in our patient suggested new fibrin deposition amenable to lysis. We therefore initiated treatment with tPA, following the regimen used by Van Overmeire et al.11 Within 3 days of starting the infusion, the vegetation was completely lysed without clinical or echocardiographic evidence of embolization. Complete lysis was unexpected, given the age of the vegetation (more than 2 weeks) and the likelihood of thrombus organization. Catastrophic intracranial hemorrhage was reported in an adult with unsuspected left-sided IE (diagnosed post mortem) who had received tPA, intravenous heparin, and aspirin after embolic myocardial infarction.12 Our patient treated with tPA alone demonstrated no extension of a previous subependymal hemorrhage. The successful application in this patient suggests that tPA should be considered

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in the setting of IE unresponsive to antimicrobial therapy when the operative risk is thought to be greater than the potential for hemorrhagic complication. tPA administration could potentially negate the requirement for surgical intervention in selected cases of infectious endocarditis.

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REFERENCES 9. 1. Mecrow IK, Landusans EJ. Infective endocarditis in newborn infants with structurally normal hearts. Acta Pediatr 1994;83:35-9. 2. Daher A, Berkowitz F. Infective endocarditis in neonates. Clin Pediatr 1995; 34:198-206. 3. Saiman L, Prince A, Gersony WM. Pediatric infective endocarditis in the modern era. J Pediatr 1993;122:847-53. 4. Erbel R, Liu F, Ge J, Rohmann S, Kupferwasser I. Identification of highrisk subgroups in infective endocarditis and the role of echocardiography. Eur Heart J 1995;16:588-602. 5. Nomura F, Penny DJ, Menahem S, Pawade A, Karl TR. Surgical intervention for infective endocarditis in infancy and childhood. Ann Thorac Surg 1995; 60:90-5. 6. Citak M, Rees A, Mavroudis C. Surgical

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10.

11.

12.

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management of infective endocarditis in children. Ann Thorac Surg 1992; 54:755-60. Levine HJ, Pauker SG, Salzman EW, Eckman MH. Antithrombotic therapy in valvular heart disease. Chest 1992; 102:434S-44S. Meyer MW, Witt AR, Krisnan, LK, Yokota M, Roszkowski MJ, Rudney JD, et al. Therapeutic advantage of recombinant human plasminogen activator in endocarditis: evidence from experiments in rabbits. Thrombos Haemostas 1995;13:680-2. Levy M, Benson LN, Burrows P, Bentur Y, Strong DK, Smith J, et al. Tissue plasminogen activator for the treatment of thromboembolism in infants and children. J Pediatr 1991;118:467-72. Dillon PW, Fox PS, Berg CJ, Cardella JF, Krummel TM. Recombinant tissue plasminogen activator for neonatal and pediatric vascular thrombolytic therapy. J Pediatr Surg 1993;28:1264-8. Van Overmeire B, Van Reempts PJ, Van Acker KG. Intracardiac thrombus formation with rapidly progressive heart failure in the neonate: treatment with tissue type plasminogen activator. Arch Dis Child 1992;65:443-5. DiSalvo TG, Tatter SB, O’Gara PT, Nielsen GP, DeSanctis RW. Fatal intracranial hemorrhage following thrombolytic therapy of embolic myocardial infarction in unsuspected infective endocarditis. Clin Cardiol 1994;17:340-4.

Recurrent group B streptococcal disease in infants:

Who should receive rifampin? Jane T. Atkins, MD, Gloria P. Heresi, MD, Teresa M. Coque, PhD, and Carol J. Baker, MD A preterm breast-fed infant had three episodes of type Ia/c group B streptococcus septicemia. After the second episode rifampin was given to the infant, but further Ia/c exposure to maternal breast milk ensued. We propose rifampin treatment for both the mother and infant in cases of recurrent group B streptococcus disease. (J Pediatr 1998;132:537-9)

Recurrent1-6 and maternal mastitis-associated5,7,8 group B streptococcus disease are both uncommon. In each, persistent mucosal colonization is postulated to influence pathogenesis. Some experts recGBS

From the Departments of Pediatrics and Medicine, The University of Texas Health Science Center, Houston, Texas, and the Department of Pediatrics, Baylor College of Medicine, Houston, Texas. Submitted for publication Mar. 20, 1997; accepted June 24, 1997. Reprint requests: Jane T. Atkins, MD, Department of Pediatrics, 6431 Fannin, J.F.B. 1.739, Houston, TX 77030. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/22/84341

Group B streptococcus

ommend rifampin to eradicate mucosal colonization in recurrent infant disease,2,4 but its role in GBS disease associated with maternal mastitis or breastfeeding has not been addressed. We describe a preterm breast-fed infant who 537