Comparison of itraconazole and fluconazole in treatment of cryptococcal meningitis and candida pyelonephritis in rabbits

Abstract

Itraconazole and fluconazole, two new triazoles, were examined for their antifungal activity in rabbits. Fluconazole easily crossed the blood-cerebrospinal fluid barrier, and active drug was eliminated in high concentrations in the urine. On the other hand, itraconazole did not cross the blood-cerebrospinal fluid barrier in measurable amounts, and urine concentrations were variable. Despite differences in pharmacokinetics at the site of infection, both agents were equally effective ill treating cryptococcal meningitis and candida pyelonephritis in animals. By using a ketoconazole-resistant strain of Candida albicans, we showed that there was cross-resistance in vivo between these two new triazole compounds.For over 25 years, amphotericin B has provided the standard treatment for most systemic mycotic infections (13,14). However, this drug is less than ideal in many respects, especially with regard to toxicity. In the search for alternative therapies, the azole compounds represent an important development. Imidazoles, such as clotrimazole and miconazole, have proven very effective for treating superficial dermatophyte and yeast infections. An intravenous preparation of miconazole had some success against disseminated mycoses (4, 11), but lack of clinical experience has limited its use for systemic disease. Ketoconazole is the most recently licensed addition to the meager stockpile of systemic antifungal drugs. It has proven to be effective against both superficial dermatophyte and yeast infections (9, 10), and some disseminated mycoses such as paracoccidioidomycosis, blastomycosis, histoplasmosis, and coccidioidomycosis (5,19,21).In the quest for new antifungal agents with lower toxicity, broader spectrum, and better pharmacokinetic profiles, the progressive development of azole compounds has produced the triazoles. These include itraconazole and fluconazole.In this study, we compared the pharmacokinetics, in vitro activity, and in vivo efficacy of these two agents in two animal model infections: cryptococcal meningitis in cortisone-treated rabbits and candida pyelonephritis in rabbits. In the first model, we evaluated the effect of these agents on a central nervous system infection in a compromised host. In the second model, we examined the treatment of the most common pathogenic yeast in the urinary tract (6).

Patterns of in vitro activity of itraconazole and imidazole antifungal agents against Candida albicans with decreased susceptibility to fluconazole from Spain

“…Nevertheless, for the best-documented strains clinically resistant to KZ, most results indicated that the strains were cross-resistant in vitro to other azoles (17,25,33). In vivo cross-resistance to azoles has also been described for some of these KZ-resistant C. albicans strains in experimental models of animal infection (26,33). With regard to the in vitro activity of IZ against C. albicans isolates with decreased susceptibility to FZ, our results are very similar to those of Barchiesi et al (3), who showed increased MICs of IZ for most but not all strains, although in the case of FZ-susceptible strains, the IZ MICs of Barchiesi et al (3) were lower than ours.…”

Overview of medically important antifungal azole derivatives

“…In rabbits, fluconazole crossed the blood-brain barrier easily at 1 order of magnitude greater than that observed with other azole derivatives, i.e., ketoconazole, vibunazole, and itraconazole (215,216). Fluconazole is distinctive for its excellent cerebrospinal fluid penetration.…”

Effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans

“…One of these antifungal agents is the triazole fluconazole (Flu) (4,10,14,33,34,41). In vivo experimental studies suggested that Flu is active against disseminated candidiasis (8,9,29,31,32,35,37). Recently, the antifungal efficacy of Flu was demonstrated in persistently granulocytopenic rabbits when it was used for prevention or early treatment (39,40).…”