Efficacy of intravenous itraconazole against invasive pulmonary aspergillosis in neutropenic mice.
The efficacy of itraconazole (ITZ) solubilized in hydroxypropyl-beta-cyclodextrin (ITZ-IV) was examined in a murine model of invasive pulmonary aspergillosis (IPA). Immunosuppressed mice were infected by the intratracheal inoculation of Aspergillus fumigatus conidia (2 x 10(6) conidia/mouse). Their body weight rapidly decreased and they died within 6 days after infection. Intravenous administration of various doses of ITZ-IV was started 24 h after infection and was continued once a day for 4 days. ITZ-IV at daily doses of 10, 20, or 40 mg/kg was as effective as the intraperitoneal administration of amphotericin B (AMPH) at a dosage of 1 mg/kg daily in improving survival. ITZ-IV (20 mg/kg per day), as well as AMPH (1 mg/kg per day) significantly lowered the fungal burden in the pulmonary tissues. Histological improvement was seen within 2 days after the beginning of administration of ITZ-IV (20 mg/kg per day). In mice intravenously given a single dose of ITZ-IV (20 mg/kg), the blood level and pulmonary tissue level of ITZ plus its active metabolites, mainly hydroxyitraconazole (OH-ITZ), decreased gradually after the injection, but after 4 h their concentration was still between 1.4 microg/ml (ITZ) and 1.9 microg/ml (OH-ITZ), concentrations that were approximately 10 to 20 times greater than the minimum inhibitory concentration (MIC) of ITZ for challenging the strain of A. fumigatus (0.16 microg/ml). These results support the clinical usefulness of ITZ-IV for the treatment of IPA in immunocompromised patients.
Tansho
Shigeru
S
Department of Microbiology and Immunology, University of Teikyo, School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan. stansho@med.teikyo-u.ac.jp
Abe
Shigeru
S
Ishibashi
Hiroko
H
Torii
Shinichi
S
Otani
Hisaya
H
Ono
Yasuo
Y
Yamaguchi
Hideyo
H
D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy* / Q000276:immunology; D001232:Aspergillus fumigatus / Q000472:pathogenicity*; D005260:Female; D016867:Immunocompromised Host / Q000187:drug effects; D007262:Infusions, Intravenous; D007263:Infusions, Parenteral; D017964:Itraconazole / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008172:Lung Diseases, Fungal / Q000188:drug therapy*; D051379:Mice; D008813:Mice, Inbred ICR; D023421:Models, Animal; D009503:Neutropenia / Q000382:microbiology*; D016019:Survival Analysis
D000935:Antifungal Agents; D017964:Itraconazole; D000666:Amphotericin B