Efficacy of intravenous itraconazole against experimental pulmonary aspergillosis

Abstract

The efficacy of intravenous itraconazole solubilized in hydroxypropyl-13-cyclodextrin was assessed in a rat model ofAspergillusfumigatus pneumonia. Immunosuppressed rats were infected by intratracheal inoculation ofA. fiumigatus conidia. Intravenous administration of various doses of itraconazole was started immediately after infection and continued once a day for 7 days. A 10-mg dose of intravenous itraconazole per kg was as effective on survival as 1 mg of amphotericin B per kg daily (a survival rate of 100o in 28 days), while treatment with 1 mg/kg did not increase the survival rate. The 50%o lethal dose of intravenous itraconazole given to immunosuppressed and uninfected rats for 7 days was 24.5 mg/kg/day. A microbiological assay to estimate accumulation in tissue after five daily intravenous administrations of itraconazole at 10 mg/kg showed that itraconazole and its active metabolites were present in the lungs for at least 6 h, reaching the MIC as previously described (B. Dupont and E. Drouhet, Rev. Infect. Dis. 9(Suppl. 1): 71-76, 1987; A. Espinel-Ingroff, S. Shadomy, and R. J. Gebhart, Antimicrob. Agents Chemother. 26:5-9, 1984). Intravenous itraconazole was considered to be worth evaluating in clinical trials of aspergillosis.Itraconazole is a promising agent in treatment of aspergillosis because of its in vitro and in vivo activity against Aspergillus species (6, 7) and also because of its minimal toxicity (6, 21). Treatment with oral itraconazole against aspergillosis has been evaluated in both animal models and clinical studies (2,4,6,9,14,25,26). However, since levels of itraconazole in serum show a large degree of variation among patients (24), because absorption varies between individuals and may be influenced by foods (29), decisions regarding doses and evaluation of efficacy are problematic. In addition, oral treatment is sometimes difficult for the patients because of nausea, vomiting, or decreased mental ability. Therefore, intravenous administration of itraconazole should be evaluated as one approach to improving antifungal therapies. Hostetler et al. reported that hydroxypropyl-j3-cyclodextrin made itraconazole, which had poor aqueous solubility because of its hydrophobic structures, soluble and enhanced oral itraconazole absorption, as determined by bioassay (11). We assessed the efficacy of intravenous administration of itraconazole against experimental invasive pulmonary aspergillosis by mortality in rats and studied the toxicity and levels of this agent in both serum and tissues by using immunosuppressed rats.Efficacy of intravenously injected itraconazole. Experimental invasive aspergillosis was induced in rats as described by Schmitt et al. (22) from sputum of a patient with a pulmonary aspergilloma was used for infection. The isolate was cultured on Sabouraud dextrose agar plates at 30°C for 4 days, and conidia were harvested with 0.02% Tween 80. After two washings in sterile saline, conidia were suspended in sterile saline and counted in a hemacytometer. Three days after the third...

Concentrations in plasma and safety of 7 days of intravenous itraconazole followed by 2 weeks of oral itraconazole solution in patients in intensive care units

“…The efficacy of i.v. administration of itraconazole solubilized in hydroxypropyl-␤-cyclodextrin was confirmed in a rat model with Aspergillus fumigatus pneumonia (13). For Candida infections, it is substantiated by an analysis of clinical data correlating itraconazole MICs, determined by the M27-T methodology (14), with outcome, mainly in AIDS patients receiving almost identical treatment with itraconazole oral solution at a dosage of 200 mg/day for oropharyngeal candidiasis.…”

Experimental models in antifungal chemotherapy

“…The course of disease is followed by assessment of the survival time and histopathological examination of the lungs. Voriconazole [ 1 141, pneumocandin analogues [113] and itraconazole [115] were effective in prolonging the survival of infected animals and inhibited the mycelia growth.…”

Efficacy of intravenous itraconazole against invasive pulmonary aspergillosis in neutropenic mice

“…Miyazaki et al 7 previously reported that this new formulation of ITZ was effective in a rat IPA model. In comparison to that model, infection developed more rapidly and severely in our murine IPA model, as shown by the substan- tial body weight loss in 1 day and mortality within 3 days.…”