ORIGINAL STUDIES A Randomized, Double-Blind, Multicenter Study of Caspofungin Versus Liposomal Amphotericin B for Empiric Antifungal Therapy in Pediatric Patients With Persistent Fever and Neutropenia Johan A. Maertens, MD,* Luis Madero, MD,† Anne F. Reilly, MD,‡ Thomas Lehrnbecher, MD,§ Andreas H. Groll, MD,¶ Hasan S. Jafri, MD, Michael Green, MD,** Joseph J. Nania, MD,†† Michael R. Bourque, MS,‡‡ Beth Ann Wise, MSEd,‡‡ Kim M. Strohmaier, BS,§§ Arlene F. Taylor, MS,¶¶ Nicholas A. Kartsonis, MD,‡‡ Joseph W. Chow, MD,‡‡ Carola A. S. Arndt, MD, Ben E. dePauw, MD,*** and Thomas J. Walsh, MD,††† for the Caspofungin Pediatric Study Group Background: Persistently febrile neutropenic children at risk for invasive fungal infections receive empiric antifungal therapy as a standard of care. However, little is known about the role of echinocandins and liposomal amphotericin B (L-AmB) for empiric antifungal therapy in pediatric patients. Methods: Patients between the ages of 2 to 17 years with persistent fever and neutropenia were randomly assigned to receive caspofungin (70 mg/m 2 loading dose on day 1, then 50 mg/m 2 daily maximum 70 mg/d) or L-AmB (3 mg/kg daily) in a 2:1 ratio. Evaluation of safety was the primary objective of the study. Efficacy was also evaluated, with a successful outcome defined as fulfilling all components of a prespecified 5-part composite endpoint. Suspected invasive fungal infections were evaluated by an independent, treatment-blinded adjudication committee. Results: Eighty-two patients received study therapy (caspofungin 56, L-AmB 26), and 81 were evaluated for efficacy (caspofungin 56; L-AmB 25). Outcomes for safety and efficacy endpoints were similar for both study arms. Adverse drug-related event rates 95% confidence interval were similar between the caspofungin and L-AmB groups (clinical 48.2% 34.7– 62.0 versus 46.2% 26.6 – 66.6; laboratory 10.7% 4.0 –21.9 versus 19.2% 6.6 –39.4). Serious drug-related adverse events occurred in 1 (1.8%) of caspofungin-treated patients and 3 (11.5%) of L-AmB-treated patients. Overall success rates 95% CI were 46.4% 33.4 –59.5 for caspofungin and 32.0% 13.7–50.3 for L-AmB. Conclusions: Caspofungin and L-AmB were comparable in tolerability, safety, and efficacy as empiric antifungal therapy for persistently febrile neutropenic pediatric patients. Key Words: caspofungin, liposomal amphotericin B, empiric antifungal therapy, pediatric patients, fever and neutropenia (Pediatr Infect Dis J 2010;29: 415– 420) I nvasive fungal infections are an important cause of morbidity and mortality in patients with neutropenia who receive chemo- therapy for cancer and following hematopoietic stem-cell trans- plantation (HSCT). 1,2 Candida and Aspergillus are the most com- monly identified pathogens in these patients. Fever without signs of localized fungal infection is the most common clinical presen- tation. As early, definitive diagnosis is difficult, empiric adminis- tration of antifungal agents has become a standard of practice in neutropenic patients who remain persistently febrile despite broad spectrum antibacterial therapy. 3 As with adults, pediatric patients have hematologic and other malignancies that require chemotherapy and/or HSCT, which place them at risk for developing an invasive fungal infection. 4 –12 How- ever, there is a paucity of randomized prospective double-blind clinical trials of antifungal therapy conducted in pediatric patients. 13 Only 2 randomized clinical trials of empiric antifungal therapy that included pediatric patients have been reported; both studies found that a lipid formulation of amphotericin B was significantly less toxic than conventional amphotericin B in persistently febrile neutropenic chil- dren. 14,15 To our knowledge, there are no published reports of a randomized clinical trial of empiric antifungal therapy conducted exclusively in pediatric oncology patients. Caspofungin and liposomal amphotericin B (L-AmB) are antifungal agents with activity against Candida and Aspergillus spp. 16 –21 ; both have been studied as empiric antifungal therapy in predominantly adult febrile, neutropenic patients. 22,23 We there- fore investigated the safety and efficacy of caspofungin 50 mg/ m 2 /d and L-AmB 3 mg/kg/d as empiric therapy for suspected invasive fungal infections in pediatric patients (2–17 years) with persistent fever and neutropenia. METHODS This was a prospective, randomized, double-blind study conducted from June 2004 through September 2006 at 17 inves- tigator sites in the United States and Europe. The protocol was Accepted for publication December 9, 2009. From the *Acute Leukemia and Stem Cell Transplantation Unit, Department of Hematology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium; †Pediatrics Hematology-Oncology, Hospital Universitario Nin ˜o Jesus, Madrid, Spain; ‡Division of Oncology, Children’s Hospital of Philadel- phia, Philadelphia, PA; §Pediatric Hematology and Oncology, University of Frankfurt, Frankfurt, Germany; ¶Infectious Disease Research Program, Depart- ment of Pediatric Hematology/Oncology, University Children’s Hospital of Mu ¨nster, Mu ¨nster, Germany; Division of Pediatric Infectious Diseases, De- partment of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX; **Division of Infectious Diseases, Departments of Pediat- rics, Surgery & Clinical and Translational Science, Children’s Hospital of Pittsburgh, Pittsburgh, PA; ††Vanderbilt University, Nashville, TN; ‡‡Clinical Research–Infectious Diseases, Merck Research Laboratories, North Wales, PA; §§Medical Communications, Merck Research Laboratories, North Wales, PA; ¶¶Biostatistics & Research Decision Sciences, Merck Research Laboratories, North Wales, PA; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; ***Blood Transfusion and Transplant Immunology, Radboud University, Nijmegen Medical Centre, Nijmegen, Netherlands; †††Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD. Hasan S. Jafri is currently at Infectious Disease, Clinical Research and Develop- ment, MedImmune, Gaithersburg, MD. Address for correspondence: Dr Thomas J. Walsh, MD, Pediatric Oncology Branch, National Cancer Institute, CRC 1-5750, 10 Center Drive, Bethesda, MD 20892. E-mail: walsht@mail.nih.gov. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.pidj.com). Copyright © 2010 by Lippincott Williams & Wilkins ISSN: 0891-3668/10/2905-0415 DOI: 10.1097/INF.0b013e3181da2171 The Pediatric Infectious Disease Journal • Volume 29, Number 5, May 2010 www.pidj.com | 415