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J Pediatr 1996;129:72–80. cies, incidence and trends. In: Lorian V, ed. Antibiotics in 33. Stoll BJ, Gordon T, Korones SB, et al. Late-onset sepsis in laboratory medicine. 4th ed. Baltimore: Williams & Wilkins, VLBW neonates: a report from the NICHD neonatal research 1996:987–9. network. J Pediatr 1996;129:63–71. 27. Finland M, Garner C, Wilcox C. Susceptibility of “enterobac- 34. Lundergan FS, Glasscock GF, Kim EH, Cohen RS. Once daily teria” to aminoglycoside antibiotics: comparison with tetra- gentamicin dosing in newborn infants. Pediatrics 1999;103: cycline, polymyxins, chloramphenicol, and spectinomycin. 1228–34. Pediatr Infect Dis J, 2002;21:240–8 Vol. 21, No. 3 Copyright © 2002 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A. Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children THOMAS J. WALSH, MD, IRJA LUTSAR, MD, TIMOTHY DRISCOLL, MD, BERTRAND DUPONT, MD, MAUREEN RODEN, MSN, PARVIS GHAHRAMANI, PHD, MICHAEL HODGES, MD, ANDREAS H. GROLL, MD AND JOHN R. PERFECT, MD Objective. To describe the safety and efficacy of intolerant of conventional antifungal therapy. voriconazole in children treated within the com- Voriconazole was administered as a loading dose passionate release program. of 6 mg/kg every 12 h iv on Day 1 followed by 4 Methods. Children received voriconazole on a mg/kg every 12 h iv thereafter. When feasible the compassionate basis for treatment of an invasive route of administration of voriconazole was fungal infection if they were refractory to or changed from iv to oral (100 or 200 mg twice a day for patients weighing <40 or >40 kg, respective- ly). Outcome was assessed by investigators at the Accepted for publication Nov. 2, 2001. end of therapy or at the last visit as success From the Immunocompromised Host Section, Pediatric Oncol- (complete or partial response), stable infection, ogy Branch, National Cancer Institute, Bethesda, MD (TJW, MR, or failure, based on protocol-defined criteria. AG); Pfizer Ltd., Sandwich, UK (IL, PG, MH); Divisions of Hematology-Oncology (TD) and Infectious Diseases (JRP), Duke Results. Sixty-nine children (ages 9 months to University, Raleigh-Durham, NC; and Institute Pasteur, Paris, 15 years; median, 7 years) received voriconazole; France (BD). 58 had a proven or probable fungal infection. Key words: Voriconazole, aspergillosis, scedosporiosis, candi- diasis. Among these 58 patients 27 had hematologic ma- Address for reprints: Dr. Thomas J. Walsh, Immunocompro- lignancies and 13 had chronic granulomatous mised Host Section, National Cancer Institute, Building 10, Room 13N240, Bethesda, MD 20892. Fax 301-402-0575; E-mail disease as the most frequent underlying condi- [email protected]. tions. Forty-two patients had aspergillosis, 8 had Vol. 21, No. 3, March, 2002 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL 241 scedosporiosis, 4 had invasive candidiasis and 4 vorable safety profile in adults.11–14 However, little is had other invasive fungal infections. The median known about voriconazole in treatment of fungal infec- duration of voriconazole therapy was 93 days. At tions in children. We therefore analyzed the antifungal the end of therapy 26 patients (45%) had a com- activity and safety profile of voriconazole in children plete or partial response. Four patients (7%) had with invasive mycoses who were refractory to or intol- a stable response, 25 (43%) failed therapy and 4 erant of conventional antifungal therapy. To our (7%) were discontinued from voriconazole be- knowledge this is the first comprehensive report of the cause of intolerance. Success rates were highest use of voriconazole in a large cohort of pediatric pa- in patients with chronic granulomatous disease tients with invasive fungal infections. (62%) and lowest in patients with hematologic malignancies (33%). Two patients experienced METHODS treatment-related serious adverse events (ulcer- Objective. The objective of this study was to de- ated lips with rash, elevated hepatic transami- scribe within the compassionate use program the nases or bilirubin). A total of 23 patients had safety and efficacy of open label voriconazole in the voriconazole-related adverse events, 3 (13%) of primary treatment of invasive fungal infections caused which caused discontinuation of voriconazole by pathogens for which there was no licensed therapy therapy. The most commonly reported adverse or for the secondary treatment of invasive fungal infec- events included elevation in hepatic transami- tions in children who were either refractory to or .intolerant of approved systemic antifungal therapy ,(8 ؍ skin rash (n ,(8 ؍ nases or bilirubin (n and a photosensitivity Inclusion and exclusion criteria. Patients (3 ؍ abnormal vision (n younger than 16 years of age were required to have a .(3 ؍ reaction (n Conclusion. These data support the use of vori- proven or probable invasive fungal infection caused by conazole for treatment of invasive fungal infec- a pathogen for which there is no currently licensed tions in pediatric patients who are intolerant of treatment or evidence of failure and/or intolerance to or refractory to conventional antifungal therapy. treatment with approved systemic antifungal agents. Patients were considered refractory if there was INTRODUCTION clinical or radiologic evidence of progressive infection Invasive fungal infections are an important cause of after Ն7 days of systemic antifungal therapy at ade- morbidity and mortality in immunocompromised chil- quate dosages. Patients were defined as having intol- dren, particularly those with hematologic malignan- erance or toxicity to treatment with an approved sys- cies, stem cell transplantation, inherited immunodefi- temic antifungal agent under the following ciencies and acquired immunodeficiency.1–5 Candida circumstances: (1) drug-related symptoms not amelio- spp. and Aspergillus spp. constitute the leading causes rated by palliative interventions; or (2) deterioration in of opportunistic fungal infections in these patients. renal function. However, less common but emerging fungal pathogens, Invasive fungal infection was required to be present such as Scedosporium spp. and Fusarium spp., also are at baseline and documented within 4 weeks preceding increasingly reported as causes of life-threatening my- voriconazole therapy. A proven invasive fungal infec- coses.6–8 tion was defined by a positive culture or histologic Despite recent advances in antifungal therapy, mor- evidence of fungus in tissue biopsy or in blood accom- tality and morbidity from invasive fungal infections in panied by clinical and radiologic findings consistent immunocompromised children remain high. For exam- with an invasive mycosis. Probable invasive fungal ple mortality of immunocompromised children with infection was defined by a positive culture, direct invasive aspergillosis may exceed 85%.3, 4 Invasive examination or cytology for fungus in bronchoalveolar aspergillosis was the leading infectious cause of mor- lavage or induced sputum plus clinical and radiologic tality in children with chronic granulomatous disease.5 findings consistent with invasive fungal infection. For The current antifungal armamentarium to treat inva- probable cerebral infections positive mycologic or his- sive mycoses is limited to amphotericin B, its lipid tologic evidence at other tissue sites accompanied by formulations, fluconazole and itraconazole. More re- typical cerebral computerized tomography-magnetic cently the echinocandin known as caspofungin was resonance imaging scan findings was required. Ap- approved in adults for treatment of invasive aspergil- proval by each hospital’s Institutional Review Board or losis