Article

Pediatric pharmacology of antifungal agents

Current Fungal Infection Reports 01/2008; 2(1):49-56. DOI: 10.1007/s12281-008-0008-0

ABSTRACT Pediatric age groups display important differences in host biology, predisposing conditions, epidemiology, and presentation
of fungal infections relative to the adult population. Over the past decade, major advances have been made in the field of
medical mycology. Most importantly, an array of new antifungal agents has entered the clinical arena. Although pediatric approval
of several of these agents remains to be established, the pediatric development of antifungal agents is moving forward. Invasive
fungal infections will remain important causes for morbidity and mortality in immunocompromised pediatric patients. Although
the availability of new therapeutic options is an important advance, antifungal therapy has become increasingly complex, and
a thorough understanding of the available antifungal armamentarium is essential for the successful management of individual
patients.

1 Bookmark
 · 
107 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Posaconazole is an orally bioavailable triazole antifungal agent for the treatment and prophylaxis of invasive fungal infection. We evaluated plasma posaconazole concentration data from juvenile (younger than 18 years; n = 12) and adult (18 to 64 years; n = 194) patients who participated in a multicenter, phase 3, open-label study that assessed the efficacy and safety of posaconazole treatment for persons who were intolerant of or had invasive fungal infection refractory to standard antifungal therapies. With the exception of one juvenile patient who received 400 mg/day as a divided dose on the day of sample collection, all patients received posaconazole at 800 mg/day as an oral suspension in divided doses. Plasma samples were analyzed through a validated liquid chromatographic-tandem mass spectrometric method with a lower limit of quantitation of 1 ng/ml. Because plasma posaconazole concentrations are relatively constant at steady state, the average of all plasma concentrations (C(av)) for each patient was calculated to provide a single steady-state plasma posaconazole concentration. A blinded data review committee reviewed all treatment outcomes. Variable posaconazole plasma concentrations were observed within both the juvenile and adult populations. Mean (median [range]) C(av) values for juvenile and adult patients were 776 ng/ml (579 ng/ml [85.3 to 2,891 ng/ml]) and 817 ng/ml (626 ng/ml [0 to 3,710 ng/ml]), respectively. Overall success rates and adverse event profiles were comparable. In conclusion, posaconazole concentrations in plasma were similar for juvenile and adult patients, suggesting that clinical outcomes are expected to be similar in adults and children with refractory invasive fungal infection.
    Antimicrobial Agents and Chemotherapy 04/2007; 51(3):812-8. · 4.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The safety, tolerability, and pharmacokinetics of an oral solution of itraconazole and its active metabolite hydroxyitraconazole were investigated in an open multicenter study of 26 infants and children aged 6 months to 12 years with documented mucosal fungal infections or at risk for the development of invasive fungal disease. The most frequent underlying illness was acute lymphoblastic leukemia, except in the patients aged 6 months to 2 years, of whom six were liver transplant recipients. The patients were treated with itraconazole at a dosage of 5 mg/kg of body weight once daily for 2 weeks. Blood samples were taken after the first dose, during treatment, and up to 8 days after the last itraconazole dose. On day 1, the mean peak concentrations in plasma after the first and last doses (Cmax) and areas under the concentration-time curve from 0 to 24 h (AUC0-24) for itraconazole and hydroxyitraconazole were lower in the children aged 6 months to 2 years than in children aged 2 to 12 years but were comparable on day 14. The mean AUC0-24-based accumulation factors of itraconazole and hydroxyitraconazole from day 1 to 14 ranged from 3.3 to 8.6 and 2.3 to 11.4, respectively. After 14 days of treatment, Cmax, AUC0-24, and the half-life, respectively, were (mean +/- standard deviation) 571+/-416 ng/ml, 6,930+/-5,830 ng.h/ml, and 47+/-55 h in the children aged 6 months to 2 years; 534+/-431 ng/ml, 7,330+/-5,420 ng.h/ml, and 30.6+/-25.3 h in the children aged 2 to 5 years; and 631+/-358 ng/ml, 8,770+/-5,050 ng.h/ml, and 28.3+/-9.6 h in the children aged 5 to 12 years. There was a tendency to have more frequent low minimum concentrations of the drugs in plasma for both itraconazole and hydroxyitraconazole for the children aged 6 months to 2 years. The oral bioavailability of the solubilizer hydroxypropyl-beta-cyclodextrin was less than 1% in the majority of the patients. In conclusion, an itraconazole oral solution given at 5 mg/kg/day provides potentially therapeutic concentrations in plasma, which are, however, substantially lower than those attained in adult cancer patients, and is well tolerated and safe in infants and children.
    Antimicrobial Agents and Chemotherapy 02/1998; 42(2):404-8. · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The safety and efficacy of amphotericin B lipid complex injection (ABELCET; Enzon Pharmaceuticals, Piscataway, NJ) was assessed in 548 children and adolescents 0-20 years of age who were enrolled in the Collaborative Exchange of Antifungal Research (CLEAR) registry. To our knowledge, this is the largest series of pediatric patients treated for invasive mycoses with a single agent. All patients had cancer or had received a bone marrow, cord blood or solid organ transplant and were treated with amphotericin B lipid complex for documented or suspected fungal infection. The CLEAR database was queried for all patients 0-20 years of age from 1996 to 2000. Data gathered included demographic variables, underlying disease type, reasons for the use of amphotericin B lipid complex injection, dosing information, clinical response and renal effects. Most patients were either intolerant of or refractory to conventional antifungal therapy, and almost one-half were neutropenic at treatment onset. Of the 548 patients, 300 (54.7%) were transplant recipients and 393 (71.7%) had received one or more concomitant nephrotoxins. Candida and Aspergillus were the most commonly isolated species in patients with proven or probable infections. Response data were evaluable for 255 of the 285 patients with documented single or multiple pathogens. A complete (cured) or partial (improved) response was achieved in 54.9% of patients, with an additional 16.9% of patients having a stable outcome. Among patients with proven Aspergillus infection, the response rates (cured + improved) were 40.5 and 37.5% in transplant and nontransplant patients, respectively. When stable responses were added, the response rates were 48.6 and 71.9%, respectively. There were few clinically significant deleterious effects on renal function. There was no significant difference between the rates of new hemodialysis versus baseline hemodialysis. Elevations in serum creatinine of >1.5 x baseline and >2.5 x baseline values were seen in 24.8 and 8.8% of all patients, respectively. The safety and efficacy data from this large pediatric population support the use of amphotericin B lipid complex injection for treatment of invasive fungal infections in immunocompromised children and adolescents, including the high risk subgroup of transplant recipients. The overall response rate and safety profile in pediatric patients who were largely intolerant of or refractory to conventional antifungal therapy were consistent with earlier reported findings of smaller trials.
    The Pediatric Infectious Disease Journal 03/2005; 24(2):167-74. · 3.57 Impact Factor