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Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children

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Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children
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  Kinetic model of gentamicin dosing with the use of individualpatient parameters. Clin Pharmacol Ther 1977;21:362 – 9.23. Blaser J, Stone BB, Groner MC, Zinner SH. Comparativestudy with enoxacin and netilmycin in a pharmacodynamicmodel to determine importance of ratio of antibiotic peakconcentration to MIC for bactericidal activity and emergenceof resistance. Antimicrob Agents Chemother 1987;31:1054 – 60.24. Karlowsky JA, Zhanel GG, Davidson RJ, Hoban DJ. Oncedaily aminoglycoside dosing assessed by MIC reversion timewith  Pseudomonas aeruginosa . Antimicrob Agents Che-mother 1994;38:1165 – 8.25. Gerber AU, Kozak S, Segessenmann C, Fluckiger U,Bangerter T, Greter U. Once-daily  vs.  thrice-daily adminis-tration of netilmicin in combination therapy of   Pseudomonasaeruginosa  infection in a man-adapted neutropenic animalmodel. Eur J Clin Microbiol Infect Dis 1989;8:233 – 7.26. Weidemann B, Grimm H. Susceptibility to antibiotics: spe-cies, incidence and trends. In: Lorian V, ed. Antibiotics inlaboratory medicine. 4th ed. Baltimore: Williams & Wilkins,1996:987 – 9.27. Finland M, Garner C, Wilcox C. Susceptibility of   “ enterobac-teria ”  to aminoglycoside antibiotics: comparison with tetra-cycline, polymyxins, chloramphenicol, and spectinomycin.J Infect Dis 1976;134:S57 – 74.28. Vic P, Ategbo S, Turck D, et al. Efficacy, tolerance, andpharmacokinetics of once daily tobramycin for  Pseudomonas exacerbations in cystic fibrosis. Arch Dis Child 1998;78:536 – 9.29. Mattie H, Craig WA, Pechere JC. Determinants of efficacyand toxicity of aminoglycosides. J Antimicrob Chemother1989;24:281 – 93.30. Vogelman B, Gudmundsson S, Turnidge J, Leggett J, Craig WA.  In vivo  postantibiotic effect on a thigh infection inneutropenic mice. J Infect Dis 1988;157:287 – 98.31. Queiroz MLS, Bathirunathan N, Mawer GE. Influence of dosage interval on the therapeutic response to gentamicin inmice infected with  Klebsiella pneumoniae . Chemotherapy1987;33:68 – 76.32. Stoll BJ, Gordon T, Korones SB, et al. Early-onset sepsis in VLBW neonates: a report from the NICHD neonatal researchnetwork. J Pediatr 1996;129:72 – 80.33. Stoll BJ, Gordon T, Korones SB, et al. Late-onset sepsis in VLBW neonates: a report from the NICHD neonatal researchnetwork. J Pediatr 1996;129:63 – 71.34. Lundergan FS, Glasscock GF, Kim EH, Cohen RS. Once dailygentamicin dosing in newborn infants. Pediatrics 1999;103:1228 – 34. Pediatr Infect Dis J, 2002;21:240 – 8 Vol. 21, No. 3Copyright © 2002 by Lippincott Williams & Wilkins, Inc.  Printed in U.S.A.  Voriconazole in the treatment of aspergillosis,scedosporiosis and other invasive fungalinfections 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 ANDJOHN R. PERFECT, MD Objective.  To describe the safety and efficacy of voriconazole in children treated within the com-passionate release program.  Methods.  Children received voriconazole on acompassionate basis for treatment of an invasivefungal infection if they were refractory to orintolerant of conventional antifungal therapy. Voriconazole was administered as a loading doseof 6 mg/kg every 12 h iv on Day 1 followed by 4mg/kg every 12 h iv thereafter. When feasible theroute of administration of voriconazole waschangedfromivtooral(100or200mgtwiceadayfor patients weighing   < 40 or  > 40 kg, respective-ly). Outcome was assessed by investigators at theend of therapy or at the last visit as success(complete or partial response), stable infection,or failure, based on protocol-defined criteria.  Results.  Sixty-nine children (ages 9 months to15 years; median, 7 years) received voriconazole;58 had a proven or probable fungal infection. Among these 58 patients 27 had hematologic ma-lignancies and 13 had chronic granulomatousdisease as the most frequent underlying condi-tions. Forty-two patients had aspergillosis, 8 had  Accepted for publication Nov. 2, 2001.From the Immunocompromised Host Section, Pediatric Oncol-ogy Branch, National Cancer Institute, Bethesda, MD (TJW, MR, AG); Pfizer Ltd., Sandwich, UK (IL, PG, MH); Divisions of Hematology-Oncology (TD) and Infectious Diseases (JRP), DukeUniversity, Raleigh-Durham, NC; and Institute Pasteur, Paris,France (BD).Key words: Voriconazole, aspergillosis, scedosporiosis, candi-diasis. Address for reprints: Dr. Thomas J. Walsh, Immunocompro-mised Host Section, National Cancer Institute, Building 10,Room 13N240, Bethesda, MD 20892. Fax 301-402-0575; E-mailwalsht@mail.nih.gov. 240 Vol. 21, No. 3, March, 2002 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL  scedosporiosis, 4 had invasive candidiasis and 4had other invasive fungal infections. The medianduration of voriconazole therapy was 93 days. Atthe end of therapy 26 patients (45%) had a com-plete or partial response. Four patients (7%) hada stable response, 25 (43%) failed therapy and 4(7%) were discontinued from voriconazole be-cause of intolerance. Success rates were highestin patients with chronic granulomatous disease(62%) and lowest in patients with hematologicmalignancies (33%). Two patients experiencedtreatment-related serious adverse events (ulcer-ated lips with rash, elevated hepatic transami-nases or bilirubin). A total of 23 patients hadvoriconazole-related adverse events, 3 (13%) of which caused discontinuation of voriconazoletherapy. The most commonly reported adverseevents included elevation in hepatic transami-nases or bilirubin ( n    8), skin rash ( n    8),abnormal vision ( n    3) and a photosensitivityreaction ( n  3). Conclusion.  These data support the use of vori-conazole for treatment of invasive fungal infec-tions in pediatric patients who are intolerant of or refractory to conventional antifungal therapy. INTRODUCTION Invasive fungal infections are an important cause of morbidity and mortality in immunocompromised chil-dren, particularly those with hematologic malignan-cies, stem cell transplantation, inherited immunodefi-ciencies and acquired immunodeficiency. 1 – 5 Candida spp. and  Aspergillus  spp. constitute the leading causesof opportunistic fungal infections in these patients.However, less common but emerging fungal pathogens,such as  Scedosporium  spp. and  Fusarium  spp., also areincreasingly reported as causes of life-threatening my-coses. 6 – 8 Despite recent advances in antifungal therapy, mor-tality and morbidity from invasive fungal infections inimmunocompromised children remain high. For exam-ple mortality of immunocompromised children withinvasive aspergillosis may exceed 85%. 3, 4 Invasiveaspergillosis was the leading infectious cause of mor-tality in children with chronic granulomatous disease. 5 The current antifungal armamentarium to treat inva-sive mycoses is limited to amphotericin B, its lipidformulations, fluconazole and itraconazole. More re-cently the echinocandin known as caspofungin wasapproved in adults for treatment of invasive aspergil-losis refractory to or intolerant of conventional antifun-gal therapy. Each agent has its limitations of toxicity,spectrum, bioavailability and acquisition cost. 9, 10  Voriconazole is a member of a second generation of antifungal triazoles with broad spectrum antifungalactivity, oral and parenteral bioavailability and a fa- vorable safety profile in adults. 11 – 14 However, little isknown about voriconazole in treatment of fungal infec-tions in children. We therefore analyzed the antifungalactivity and safety profile of voriconazole in childrenwith invasive mycoses who were refractory to or intol-erant of conventional antifungal therapy. To ourknowledge this is the first comprehensive report of theuse of voriconazole in a large cohort of pediatric pa-tients with invasive fungal infections. METHODS Objective.  The objective of this study was to de-scribe within the compassionate use program thesafety and efficacy of open label voriconazole in theprimary treatment of invasive fungal infections causedby pathogens for which there was no licensed therapyor for the secondary treatment of invasive fungal infec-tions in children who were either refractory to orintolerant of approved systemic antifungal therapy. Inclusion and exclusion criteria.  Patientsyounger than 16 years of age were required to have aproven or probable invasive fungal infection caused bya pathogen for which there is no currently licensedtreatment or evidence of failure and/or intolerance totreatment with approved systemic antifungal agents.Patients were considered refractory if there wasclinical or radiologic evidence of progressive infectionafter   7 days of systemic antifungal therapy at ade-quate dosages. Patients were defined as having intol-erance or toxicity to treatment with an approved sys-temic antifungal agent under the following circumstances: (1) drug-related symptoms not amelio-rated by palliative interventions; or (2) deterioration inrenal function.Invasive fungal infection was required to be presentat baseline and documented within 4 weeks preceding  voriconazole therapy. A proven invasive fungal infec-tion was defined by a positive culture or histologicevidence of fungus in tissue biopsy or in blood accom-panied by clinical and radiologic findings consistentwith an invasive mycosis. Probable invasive fungalinfection was defined by a positive culture, directexamination or cytology for fungus in bronchoalveolarlavage or induced sputum plus clinical and radiologicfindings consistent with invasive fungal infection. Forprobable cerebral infections positive mycologic or his-tologic evidence at other tissue sites accompanied bytypical cerebral computerized tomography-magneticresonance imaging scan findings was required. Ap-proval by each hospital ’ s Institutional Review Board orEthics Committee and signed written informed consentwere required at baseline. Study drug administration.  Depending on tolera-bility voriconazole was administered either intrave-nously or orally (po). Patients received an iv loading dosage of 6 mg/kg every 12 h (q12h) for two doses.  Vol. 21, No. 3, March, 2002 241 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL  Intravenous loading dosages were followed by an ivmaintenance dose of 4 mg/kg/q12h. Depending on tol-erability the oral loading dose was 400 mg twice a day(bid) for two doses for patients weighing    40 kg and200 mg bid for two doses for patients   40 kg. Oralmaintenance doses could be administered at 200 mg bid for patients weighing    40 kg and 100 mg bid forpatients   40 kg. Provided that there were no treat-ment-related serious adverse events, dosage escalationwas permitted when baseline infections were refrac-tory to these initial dosages. The dosage of iv voricon-azole could be increased to 5 mg/kg q12h, and the oraldosage could be increased to 300 mg po bid (to 150 mg po bid in patients weighting   40 kg). Criteria for evaluation of safety and efficacy.  An adverse event (AE) was defined as any event thatwas not present at the onset of use of voriconazole butthat developed during its use. An attributable AE wasany event that, in the opinion of the investigator, waspossibly or probably related to voriconazole. A serious AE was defined as that which resulted in death, waslife-threatening, required (or prolonged) hospitaliza-tion, caused persistent or significant disability or inca-pacity, resulted in congenital anomalies or birth de-fects or displayed other conditions that in the judgmentof the investigators represented a significant hazard.Patients who completed or discontinued voriconazoletherapy were evaluated for efficacy at the end of therapy if they had received  90 days of therapy. Theend of therapy was defined as the point of discontinu-ation of voriconazole for successful treatment or with-drawal of study drug because of evidence of progressiveinfection. Because many patients had chronic immuno-deficiencies, which required variable times to achieve atherapeutic response, no prespecified time limit wasimposed to require discontinuation of voriconazole.Efficacy was evaluated by a global assessment of clin-ical, radiologic and microbiologic response.Responses were defined according to the following criteria: complete response, resolution of all attribut-able signs, symptoms and radiographic and or broncho-scopic abnormalities present at baseline with myco-logic eradication; partial response, major improvementin attributable signs, symptoms, radiographic and/orbronchoscopic abnormalities present at baseline; sta-ble, minor or no improvement in attributable signs,symptoms, radiographic or bronchoscopic abnormali-ties present at baseline; failure, deterioration in attrib-utable signs, symptoms, radiographic and or broncho-scopic abnormalities and/or persistent fungal infectionnecessitating alternative antifungal therapy or result-ing in death; and discontinuation, intolerance of drug because of an adverse event.Patients were excluded from analysis if there wasinsufficient mycologic or radiologic evidence to supportdefinite or probable fungal infection. They were alsoexcluded if they had fungal infections not considered tobe invasive or disseminated including dermatophyto-sis, oropharyngeal candidiasis, allergic bronchopulmo-nary aspergillosis or aspergilloma. Pharmacokinetics. Single or multiple plasma sam-ples for voriconazole high performance liquid chroma-tography (HPLC) assay were collected at steady statefrom 14 subjects. Plasma samples from a control pop-ulation of adults enrolled into the compassionate pro-tocol for voriconazole were also analyzed. These sam-ples were sent to a central laboratory and analyzed for voriconazole concentrations with the use of a fully validated HPLC assay with UV detection. 15 For furthercomparison plasma samples from healthy adult volun-teers were also analyzed. Statistics.  Differences between proportions wereanalyzed by Fisher ’ s exact test or chi square, as appro-priate. A two-sided  P  value of    0.05 was consideredsignificant. RESULTS Patient population.  Among the 69 patients en-rolled 58 had protocol-defined proven or probable inva-sivefungalinfection.Theremaining11patientsdidnotfulfill entry protocol-defined criteria for proven or prob-able invasive fungal infection. The median age was 7years (range, 9 months to 15 years). There were 35 boysand 23 girls (Table 1). The median duration of treat-ment with voriconazole was 93 days (range, 1 to 800days). Hematologic malignancies, chronic granuloma-tous disease (CGD) and other inherited immunodefi-ciencies were the most common underlying conditions(Table 2). Among the potential risk factors for invasivefungal infection, approximately one-half of the patientshad a hematologic malignancy and one-third under-went bone marrow transplantation (BMT) (Table 2). TABLE 1.  Pediatric patients with invasive fungal infectionreceiving voriconazole for emergency compassionate use  Age (yr)Mean 8.2Median 7Range 9 mo – 15 yrGenderBoys 35 (60)*Girls 23 (40)Reasons for enrollmentPrimary antifungal therapy 4 (7)Refractory to or intolerant of conventional antifungaltherapy54 (93)Failure of previous systemic antifungal therapy 40 (69)Intolerance of previous systemic antifungal therapy 3 (5)Failure and intolerance of previous systemicantifungal therapy5 (9)Not reported 6 (10)Duration of previous antifungal therapy of   30 days 39 (67) * Numbers in parentheses, percent. 242 Vol. 21, No. 3, March, 2002 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL  The majority of patients were enrolled for being refractory ( n  40; 69%), intolerant ( n  3; 5%) or both( n    5; 9%) to conventional antifungal therapy. Fourpatients (7%) were enrolled for treatment of fungalinfections for which there was no licensed compound(i.e.  Scedosporium prolificans  and  Fusarium  spp.) (Ta-ble 3). Organisms.  Aspergillus  spp. followed by  Scedospo-rium  spp. were the most common infecting organisms(Table 2). Other organisms included  Candida  spp.,  Alternaria  spp.,  Conidiobolus coronatus  and  Fusarium sp. Thirty-three (57%) patients had proven infectionand 25 (43%) had probable fungal infection. Responsetoantifungaltherapy. Overall responserates.  The overall response rate (complete    partialresponse) was 45% for the entire study population ( n  58), 43% for those with aspergillosis, 63% for thosewith scedosporiosis and 24% for those with candidiasis(Table 4). When evaluated according to site of infection,there was a 70% response of noncerebral disseminatedinfection ( n  10), followed by 55% in cerebral infection( n    11), 29% in sinus infection ( n    7) and 36% inpulmonary infection ( n  14). The overall mortality inthis study was 24 (41%) of 58 patients.  Infections caused by  Aspergillus  spp. Aspergillus fumigatus, Aspergillus flavus  and  Aspergillus nidulans were the most common species isolated in 26, 6 and 3subjects, respectively. In one subject with congenitalimmunodeficiency in addition to  A. fumigatus ,  Phialo- phora richardsia  was isolated in bronchoalveolar la- vage fluid. The overall response rate for invasive as-pergillosis was 43%. Response according to the patternof infection of invasive aspergillosis is presented inTable 4.  Infections caused by  Scedosporium  spp.  Six cases of   Scedosporium apiospermum (Pseudallescheria boydii) TABLE 2.  Underlying condition and infection of all pediatric patients evaluable for efficacy who received emergencycompassionate use of voriconazole Fungal Pathogens Total No.of InfectionsHematologicMalignancy and Aplastic AnemiaBoneMarrow/StemCell TransplantChronicGranulomatousDiseaseOther InheritedImmunodeficiency AIDS Other*Filamentous fungi  Aspergillus  spp. †  42 (72) ‡  19 (68) 14 (82) 12 (92) 5 (83) 1 (100) 5 (50)  Scedosporium  spp. 8 (14) 3 (11) 1 (8) 1 (17) 3 (30)Zygomycetes §  1 (2) 1 (3.5)  Fusarium  sp. 2 (3) 2 (7)  Alternaria  sp. 1 (2) 1 (3.5) Yeasts Candida  spp. 4 (7) 2 (7) 3 (18) 2 (20)Total 58 (100) 28 (100) 17 (100) 13 (100) 6 (100) 1 (100) 10 (100) * Other conditions included cancer, burns, near-drowning, hepatitis, hematologic disorders (Fanconi ’ s anemia, familial erythrophagocytic lymphohistiocytosis, congenitalagranulocytosis) and one child with no known immunosuppression. †  Includes one case of mixed infection with  Phialophora richardsia. ‡  Numbers in parentheses, percent. §  Includes  Conidiobolus coronatus. TABLE 3.  Relationship between antifungal efficacy of voriconazole, primary underlying condition and reason for enrollment  Variable  n  Complete  Partial ResponsesCompleteResponsePartialResponseStableResponse Discontinued FailedPrimary underlying conditionHematologic malignancy 27 9 (33)* 6 (22) 3 (11) 6 (22) 1 (4) 11 (41)CGD 13 8 (62) 2 (15) 6 (46) 2 (15) 3 (20)Bone marrow transplant Allogeneic 16 6 (38) 4 (25) 2 (13) 2 (13) 1 (6) 7 (44) Autologous 1 1 (100)Congenital 6 3 (50) 3 (50) 3 (50)Immunodeficiencies AIDS 1 1 (100)Other †  11 6 (55) 3 (27) 3 (27) 5 (45)Reasons for enrollmentPrimary therapy 4 1 (25) 1 (25) 1 (25) 2 (50)Efficacy failure ‡  40 18 (45) 9 (23) 9 (23) 5 (13) 3 (8) 14 (35)Intolerance §  3 1 (33) 1 (33) 1 (33) 1 (33)Efficacy failure and intolerance 5 3 (60) 3 (60) 2 (40)Unknown 6 3 (50) 1 (17) 2 (33) 3 (50) * Numbers in parentheses, percent. †  Other conditions included cancer, burns, near-drowning, hepatitis, hematologic disorders (Fanconi ’ s anemia, familial erythrophagocytic lymphohistiocytosis, congenitalagranulocytosis) and one child with no known immunosuppression. ‡  Defined as failure of previous antifungal therapy. §  Defined as toxicity related to previous antifungal therapy.  Vol. 21, No. 3, March, 2002 243 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL  and two cases of   S. prolificans  were treated with voriconazole. The overall response of all patients with  Scedosporium  infection was 63%. In  S. apiospermum infections, 83% had successful outcome; however, bothpatients with  S. prolificans  infection were refractory to voriconazole therapy (Table 4).  Infections caused by  Candida  spp.  The overall re-sponse of candidiasis to voriconazole was 25% ( n  4).Fungemia cleared in both cases, but both patients diedfrom respiratory failure; one died from pneumonia of undetermined cause, and the other died of progressiveBurkitt ’ s lymphoma during study drug follow-up oradministration. Of the two patients with disseminatedcandidiasis, one had a complete response and a secondwas prematurely withdrawn from study because of asuspected mycobacterial infection causing hepatic le-sions.  Efficacy and underlying condition.  Patients withCGD demonstrated a response rate of 62% in compar-ison with those with hematologic malignancies (33%;  P  0.20) and those undergoing BMT (35%;  P  0.27). Plasma concentrations.  The median plasma con-centration of voriconazole in children receiving dosagesof   4 mg/kg iv bid (1566 ng/ml) was lower than that of adult volunteers receiving 4 and 5 mg/kg bid (5671 and7404 ng/ml, respectively) (Fig. 1). These findings sug-gest that clearance of voriconazole may be greater inchildren than in adults. Safety.  Among patients with laboratory abnormali-ties in this study, eight had elevated alanine amino-transferase (ALT), nine had elevated aspartate amino-transferase (AST), five had elevated alkalinephosphatase, nine had elevated total bilirubin and twohad elevated serum creatinine. The median values andranges are summarized in Table 5.Duringthestudyperiodtherewere337AEsreportedin 52 patients. The most commonly reported AEs wererash, nausea, vomiting and an elevation of hepatictransaminases or bilirubin. As assessed by the individ-ual investigator, 23 patients had voriconazole-related AEs and 5 patients had 1 or more attributable severe AEs. Fifty-three AEs were considered treatment-related. Treatment-related AEs occurring in   5% of patients were transaminase or bilirubin elevation in 8(13.8%) patients, rash in 8 (13.8%), abnormal vision(photophobia, blurred vision) in 3 and photosensitivityreaction in 3. F IG . 1. Comparison of voriconazole plasma concentrations be-tween children enrolled on the compassionate release studyreported here and adults enrolled on therapeutic trials. Data foradult patients were obtained from two Phase III studies (150-304for 3 mg/kg iv bid regimen and 150-673 for 200 to 300 mg po bidregimen. Data for pediatric subjects were obtained from thecompassionate use study. Data for healthy adult volunteers wereacquired from the Phase I study 150-230. TABLE 4.  Relationship between efficacy of voriconazole and type of invasive fungal infection Type of FungalInfection  n  Complete  Partial ResponsesCompleteResponsePartialResponseStableResponse Intolerance FailedFilamentous fungi Aspergillosis 42 18 (43)* 7 (17) 11 (26) 3 (7) 4 (10) 17 (40)Pulmonary 12 4 (33) 1 (8) 3 (25) 2 (17) 1 (8) 5 (42)CNS 6 3 (50) 3 (50) 1 (17) 2 (33)Disseminated 7 6 (86) 3 (43) 3 (43) 1 (14)Sinus 7 2 (29) 1 (14) 1 (14) 1 (14) 4 (57)Single organ †  10 3 (30) 2 (20) 1 (10) 1 (10) 2 (20) 4 (40)Scedosporiosis ‡  8 5 (63) 2 (25) 3 (38) 1 (13) 2 (25) § Pulmonary 2 1 (50) 1 (50) 1 (50)CNS 5 3 (60) 1 (20) 2 (40) 2 (40)Disseminated 1 1 (100) 1 (100) Conidiobolus  1 1 (100) 1 (100)Fusariosis 2 2 (100) Alternariosis 1 1 (100) 1 (100) YeastsCandidiasisFungemia ¶  2 2 (100)Disseminated 2 1 (50) 1 (50) 1 (50)Total 58 26 (45) 11 (19) 15 (26) 4 (7) 4 (7) 25 (43) * Numbers in parentheses, percent. †  Includes bone, liver or skin. ‡  Scedosporium apiospermum  ( n  6) and  Scedosporium prolificans  ( n  2). §  Both cases were caused by  S. prolificans. ¶  Both patients cleared their fungemia, but one patient died from progressive Burkitt ’ s lymphoma and another from pneumonia of undetermined cause. 244 Vol. 21, No. 3, March, 2002 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL
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