Comparison of itraconazole and ketoconazole in the treatment of experimental candidal vaginitis

Abstract

Comparison of itraconazole (R51,211) and ketoconazole in the treatment of experimental candidal vaginitis in rats on schedules of 3 and 5 days revealed significantly superior results with itraconazole at all dosages (1.0 to 7.5 mg/kg) studied, but was particularly evident at 1.0 and 2.5 mg/kg. A single 25-mg/kg dose of itraconazole was as effective as 5 daily 5-mg/kg doses of itraconazole.The imidazole derivatives miconazole, clotrimazole, and econazole administered topically and oral ketoconazole are highly effective in the treatment of vulvovaginal candidiasis (1, 2). Itraconazole (R51,211) is a new oral imidazole ( Fig. 1) which, like ketoconazole, is thought to inhibit cell membrane ergosterol synthesis. Preliminary in vitro data suggest that this agent has considerably more activity against Candida albicans in addition to a broader spectrum of activity, which includes Aspergillus sp. (J. Van Cutsem, F. Van Gerven, R. Zamon, J. Heeres, and P. A. J. Janssen, Proc. Int. Congr. Chemother. 13th, Vienna, Austria, p. 40/32-40/39, 1983). This report relates the results of a comparison of the activities of itraconazole and ketoconazole against 58 clinical isolates of C. albicans in vitro and against experimental vaginal infections with this fungus in rats.MICs of ketoconazole and itraconazole against 58 clinical vaginal isolates of C. albicans obtained from women with candida vaginitis were measured by agar dilution with an inoculum of 5 x 104 organisms as previously described (3). All isolates were maintained on agar slants at 4°C. The 50% MICs for itraconazole and ketoconazole were 0.16 and 0.2 pg/ml, respectively, and the 90% MICs for itraconazole and ketoconazole were 2.0 and 4.8 ,ug/ml, respectively.Pseudoestrous was induced in 170 oophorectomized female Sprague-Dawley rats (175 to 200 g) by subcutaneous injection of estradiol valerate in sesame oil (0.5 mg/0.1 ml) (E. R. Squibb & Sons, Princeton, N.J.) and was maintained by similar weekly injections. At 48 h after the initial estrogen injection, rats were inoculated vaginally with 104 C. albicans GMO2 blastospores (MICs of ketoconazole and itraconazole were each 0.2 ,ug/ml) suspended in 0.1 ml of sterile phosphate-buffered saline, pH 7.2. C. albicans cells used for infection were obtained by inoculating 10 ml of sterile 1% phytone-peptone glucose broth with 100 RI of a stock blastospore suspension and then incubating the preparation for 22 h at 26°C in a shaking water bath. The resulting culture suspension was centrifuged for 10 min at 2,000 rpm at 4°C and resuspended in 1 to 2 ml of sterile phosphate-buffered saline. The number of blastospores in this suspension was counted in a hemacytometer. Thereafter, the yeast suspension was administered (0.1 ml per animal) via a short segment of butterfly tubing (1.5 in. or ca. 3.8 cm) affixed to a 1-ml tuberculin syringe. * Corresponding author.Treatment with ketoconazole or itraconazole (Janssen Pharmaceutica, Piscataway, N.J.) at dosages of 1.0, 2.5, 5.0, and 7.5 mg/kg, administered by daily gavage for either 3 or 5...

High-dose itraconazole in the treatment of severe mycoses

“…Short courses of treatment with 50 to 100 mg/day are effective in most superficial fungal infections. Responses have also been seen in some systemic mycotic infections (4,21,28,32,36). Adverse reactions at 50 to 100 mg/day are minimal.…”

“…The wider spectrum of activity and greater potency are advantages over ketoconazole (3,7,32,36,37). Itraconazole therapy has been effective in some patients who have experienced failures of prior therapy with either ketoconazole or AMB (8).…”

“…It is more potent and has a wider spectrum of activity than ketoconazole in vitro and in vivo (3,7,32,36,37). Clinical responses have been reported in patients with systemic mycoses, including coccidioidomycosis, sporotrichosis, chromoblastomycosis, and aspergillosis.…”

Overview of medically important antifungal azole derivatives

“…Itraconazole is effective in the treatment of experimental vaginal candidiasis in rats (279) and systemic candidiasis in guinea pigs (316) and rats (353 (133) and Van Cauteren et al (314). Itraconazole is an extremely weak base, lipophilic, and soluble only in a few solvent systems.…”

Placebo-controlled trial of itraconazole for treatment of acute vaginal candidiasis

“…This agent appears to be an attractive alternative for the treatment of vaginal candidiasis because of its enhanced activity against Candida species and its low incidence of untoward effects (8). In an experimental model of candidal vaginitis, itraconazole was shown to be more efficacious than ketoconazole in eradicating vaginal infection with Candida albicans (24).…”