Antifungal efficacy, pharmacokinetics and pharmacodynamics of intravenous itraconazole against invasive pulmonary aspergillosis in persistently neutropenic rabbits

A. H. Groll, D. Mickiene, R. Petraitiene, V Petraitis, K. Roussillion, M. Hemmings, S. Raskas, and T. J. Walsh

Author address: 

"˜"œlmmunocompromised Host Section, Pediatric Oncology Branch, NCI, Bethesda MD; and Center for Bone Marrow Transplantation, Department of Pediatric Hematology/ Oncology, Wilhelms- University Medical Center, Muenster, Germany

Abstract: 

Intravenous itraconazole has been approved for second line therapy of invasive pulmonary aspergillosis. However, little is known about its comparative antifungal efficacy against this disease in the state of persistent and profound neutropenia. We therefore investigated the pharmacokinetics and pharmacodynamics of intravenous hydroxypropyl-beta-cyclodextrin itraconazole in a persistently neutropenic rabbit model of invasive pulmonary aspergillosis. Twenty-four hours following endotracheal inoculation with Aspergillus jumigatus, cohorts of 4 animals each received itraconazole at dosages ranging from 0.66 to 16 mg/kg once daily as lo-minutes IV bolus for a total of 12 days. Optimal plasma sampling was performed in each individual animal after the 5th dose to obtain pharmacokinetic and pharmacodynamic parameters. Untreated animals and animals treated with standard amphotericin B deoxycholate (lmg/kg) served as controls. Responses to treatment were evaluated by survival and the residual fungal burden in lung tissue at autopsy. Intravenous itraconazole showed dose-dependent antifungal efficacy against invasive pulmonary aspergillosis. The relationship between dosage and residual fungal burden in lung tissue followed an inhibitory effect sigmoidal Emax function with an estimated ED50 of 7 mg/kg. In comparison to untreated controls, treatment with dosages of 6.6 to 12 mg/kg resulted in a reduction of the residual fungal burden in lung tissue (p
2002

abstract No: 

s49

Full conference title: 

12th International Symposium on Infections in the Immunocompromised Host
    • ISIIH 12th