The Pediatric Infectious Disease Journal Issue: Volume 16(10), October 1997, pp 1002-1003 Copyright: (C) Williams & Wilkins 1997. All Rights Reserved. Publication Type: [Brief Reports] ISSN: 0891-3668 Accession: 00006454-199710000-00020 Keywords: Infants, very low birth weight, Candida, candidiasis, amphotericin B, toxicity [Brief Reports] LACK OF EVIDENCE OF AMPHOTERICIN B TOXICITY IN VERY LOW BIRTH WEIGHT INFANTS TREATED FOR SYSTEMIC CANDIDIASIS Kingo, Abbas R. M. M.D.; Smyth, John A. L.R.C.P.&S.I.; Waisman, Dan M.D. Author Information Department of Pediatrics; University of British Columbia and BC's Children's Hospital; Vancouver, Canada Accepted for publication July 2, 1997. Reprints not available. ---------------------------------------------- Outline Systemic candidiasis has been reported in 2 to 4% of infants with birth weights of Methods. VLBW infants with a diagnosis of systemic candidiasis were retrospectively identified from the computerized data base of admissions to the Special Care Nursery of British Columbia's Children's Hospital, Vancouver, Canada, between January 1, 1984, and December 31, 1993. Systemic candidiasis was diagnosed when Candida was isolated from blood, cerebrospinal fluid, suprapubic urine aspirate, aspirates of otherwise sterile body cavities (e.g. pleural fluid, peritoneal fluid) or at autopsy. Hypokalemia [serum potassium 20 mg/dl), elevated serum creatinine (>0.8 mg/dl) or reduced urine output (60 units/l or aspartate aminotransferase >60 units/l) were considered indicative of potential hepatic toxicity. Thrombocytopenia (platelet count 9/l) was considered indicative of potential bone marrow suppression. The treatment regimens and cumulative dose of amphotericin B were recorded. The use of other antimicrobial agents was also noted. Results. Twenty-two infants with systemic candidiasis were identified, 10 males and 12 females. The mean gestational age was 25 weeks (range, 23 to 36 weeks), and mean birth weight was 776 g (450 to 1479 g). Twenty-one infants were infected with Candida albicans and one with Candida parapsilosis. Eighteen infants were treated with amphotericin B; 4 were not. Reasons for nontreatment were the decision to withdraw intensive care (2 infants) and death before diagnosis (2 infants). Complete medical records were available for all. During the 10-year period the 22 infants with systemic candidiasis represented 0.3% of the total neonatal intensive care admissions and 0.9% of all VLBW infants. There was no apparent seasonal predilection. The sites of infection are summarized in Table 1. Candida was most frequently isolated from blood (18 cases) but also from cerebrospinal fluid, peritoneal fluid, pleural fluid and abscesses. Candida was isolated from multiple sites in 12 infants. Amphotericin B was given once daily as a 4- to 6-h intravenous infusion, diluted in 5 or 10% dextrose water. The initial dose was 0.25 mg/kg and the dose was increased in daily increments of 0.25 mg/kg to a maximum dose of 1 mg/kg. The mean cumulative dose of amphotericin B was 19.88 mg/kg (range, 0.06 to 107.52 mg/kg). A test dose was not given to any infant. Before the commencement of amphotericin B therapy, all infants received broad spectrum antibiotics (either ampicillin and gentamicin, or cefotaxime and vancomycin). Amphotericin B was the sole antifungal drug used except for one infant, with fungal ball urinary bladder obstruction, who also received flucytosine. Within 5 days of starting therapy 4 infants died from overwhelming candidemia and central nervous system involvement. Autopsy findings in these four infants confirmed severe multisystem involvement, including central nervous system Candida infection. During amphotericin B therapy two infants had a decreased urine output, which improved after therapy was interrupted for 24 h; both these infants had an elevated BUN before treatment. Two other infants with an elevated BUN before treatment had no evidence of renal toxicity during therapy. One infant with urinary tract obstruction resulting from "fungal balls" in the bladder had an elevated BUN before (28 mg/kg) and during (34 mg/kg) therapy. The elevated BUN did not change despite interrupting amphotericin B for 24 h (cumulative dose then was 3.22 mg/kg). Amphotericin B was restarted together with flucytosine. The BUN remained raised but gradually improved as the obstruction resolved and was normal at 6 months follow-up. Hypokalemia was observed on a single occasion in each of two infants (serum potassium 2.8 and 2.9 meq/l, respectively) and resolved without treatment. Six infants had thrombocytopenia before therapy; in all this resolved within the first week of therapy. Evidence of hepatic toxicity during amphotericin B therapy was not observed although two infants had an elevated aspartate aminotransferase before therapy (both were receiving total parental nutrition). None of the infants had fever (temperature >37.5[degrees]C). Discussion. The antifungal activity of amphotericin B is related to its binding with ergosterol and other sterols of the fungal cell membrane, which produces a disruption of its integrity and transport characteristics, resulting in the loss of intracellular potassium.4, 6 The major side effects of amphotericin B are transient nephrotoxicity, hepatotoxicity and bone marrow suppression.7 Baley et al.4 reported that 7 of 10 VLBW infants with systemic candidiasis treated with a combination of amphotericin B (1 mg/kg/day) and flucytosine (100 to 150 mg/kg/day) had severe nephrotoxicity manifested by oliguria or anuria and marked increases in blood urea nitrogen and creatinine. The deaths of 6 of the 7 infants were attributed in part to amphotericin B-induced nephrotoxicity. However, several of the infants had confounding factors such as multiple drug therapies and preexisting poor renal function. In contrast all 5 VLBW infants treated by Johnson et al.,2 with a smaller dosage of amphotericin B (0.5 to 1 mg/kg/day) and a similar dosage of flucytosine (50 to 150 mg/kg/day), tolerated therapy well and all survived. Since the report of Baley et al., the pharmacokinetics of amphotericin B in neonates has been studied and most of the treated infants have had more favorable outcomes.2, 8 In this series little evidence of toxicity was observed despite some infants having abnormalities of renal, hepatic or hematopoietic function before receiving amphotericin B. The one infant with evidence of worsening renal function was probably affected by urinary tract obstruction. The transient occurrence of oliguria in sick VLBW infants is weak evidence of renal toxicity. We believe that the transient renal and hepatic abnormalities and thrombocytopenia are more likely related to the systemic infection or other preexisting problems rather than amphotericin B toxicity. Although it is not possible to exclude amphotericin B as a contributory factor in the deaths of four infants, overwhelming disseminated Candida infection was the likely cause. Our experience supports the opinion of others who have reported that unlike adults and older children who experience fever, chills, nausea and vomiting, infants tolerate amphotericin B well.2, 9, 10 Acknowledgments. We sincerely thank Dr. Margaret Pendray and all neonatologists who supported this study. Special thanks to Ms. Vilia Sadler for compiling all the medical records used and BC's Children's Hospital Medical Records for allowing us to review the medical records. Work was supported by the Division of Neonatology. Abbas R. M. Kingo, M.D. John A. Smyth, L.R.C.P.&S.I. Dan Waisman, M.D. Department of Pediatrics; University of British Columbia and BC's; Children's Hospital; Vancouver, Canada 1. Baley JE, Kliegman RM, Fanaroff AA. Disseminated fungal infections in very low birth-weight infants: clinical manifestations and epidemiology. Pediatrics 1984;73:144-52. Full text via Find It Bibliographic Links 2. Johnson DE, Thompson TR, Green TP, Ferrieri P. Systemic candidiasis in very low-birth-weight infants ( 3. Faix RG, Kovariak SM, Shaw TR, Johnson RV. Mucocutaneous and invasive candidiasis among very low birth weight ( 4. Baley JE, Kleigman RM, Fanaroff AA. Disseminated fungal infections in very low-birth weight infants: therapeutic toxicity. Pediatrics 1984;73:153-7. Full text via Find It Bibliographic Links 5. Baley JE, Meyers C, Kliegman RM, Jacobs MR, Blumer JL. Pharmacokinetics, outcome of treatment, and toxic effects of amphotericin B and 5-fluorocytosine in neonates. J Pediatr 1990;116:791-7. Full text via Find It Bibliographic Links 6. Lebel MH, Lebel P, Mills EL. Antifungal agents for systemic mycotic infections, In: Yaffe SJ, Aranda JV, eds. Pediatric pharmacology, therapeutic principles in practice. 2nd ed. Philadelphia: Saunders, 1992;251-75. 7. Van den Anker JN, Van Popele NML, Sauer PJJ. Antifungal agents in neonatal systemic candidiasis. Antimicrob Agents Chemother 1995;39:1391-7. Full text via Find It Bibliographic Links 8. Butler KM, Rench MA, Baker CJ. Amphotericin B as a single agent in the treatment of systemic candidiasis in neonates. Pediatr Infect Dis J 1990;9:51-6. Ovid Full Text Full text via Find It Bibliographic Links 9. Ward RM, Satter FR, Dalton AS. Assessment of antifungal therapy in an 800-gram infant with candidal arthritis and osteomyelitis. Pediatrics 1983;72:234-8. Full text via Find It Bibliographic Links 10. Sanchez PJ, Siegel JD, Fishbein J. Candida endocarditis; successful medical management in three preterm infants and review of the literature. Pediatr Infect Dis J 1991;10:239-43. Ovid Full Text Full text via Find It Bibliographic Links Key words: Infants; very low birth weight; Candida; candidiasis; amphotericin B; toxicity ----------------------------------------------