Activities of fluconazole (UK 49,858) and ketoconazole against ketoconazole-susceptible and -resistant Candida albicans

Abstract

We have tompared the activities of fluconazole, and ketoconazole against ketoconazole-susceptible and -resistant strains of Candida albicans in a neutropenic-site rabbit model. Oral treatment with fluconazole resulted in much higher serum and extravascular concentrations of this antifungal agent than did comparable doses of ketoconazole. Fluconazole had no additional in vivo activity against the ketoconazole-susceptible strains; no fungicidal activity was observed with peak drug levels as high as -75 ,ug/ml in the infection sites. Significant fungistatic activity against the ketoconazole-resistant strains was observed with fluconazole treatment (80 mg/kg), but not with less fluconazole (20 mg/kg) or with ketoconazole (-67 mg/kg). In vitro susceptibility tests separated the ketoconazole-susceptible strains from the ketoconazole-resistant strains, but the results were variable when the resistant strains were tested with fluconazole.Fluconazole (UK 49,858) is a bis-triazole antifungal agent that is active when administered both orally and parenterally. Pharmacologically, the drug is characterized by excellent oral absorption, high serum and extravascular levels, and a long half-life that allows once-daily administration (8). These properties may explain why fluconazole has appeared to be more active than ketoconazole in some studies of experimental infections with Candida albicans despite its apparently lower in vitro activity (16; K. Richardson, R. J. Andrews, T. T. Howarth, M. S. Marriott, M. H. Tarbit, and P. F. Troke, Program Abstr. 25th Intersci. Conf. Antimicrob. Agents Chemother., abstr. no. 813, 1985). However, previous animal studies (10,12,15) have not shown any activity of fluconazole against strains of C. albicans which have become resistant to ketoconazole, i.e., strains obtained from patients with chronic mucocutaneous candidiasis who relapsed during prolonged oral therapy with ketoconazole (4, 13).In the present study we investigated the activities of fluconazole and ketoconazole against ketoconazole-susceptible and -resistant C. albicans strains, using semipermeable Visking chambers (molecular weight cutoff, 15,000) implanted subcutaneously in rabbits as the infection sites. The study was designed to use doses of fluconazole that yield much higher fluconazole levels than those attainable with ketoconazole to determine whether fluconazole is fungicidal or active against the ketoconazole-resistant strains. In vitro susceptibility tests were also performed to further assess the correlation with the in vivo studies. with shaking at 150 rpm, the cultures were then diluted in broth media to concentrations of _105 CFU/ml as determined by plate counts, and 1-ml aliquots were added to the drug dilutions. For each yeast strain, the dilutions were set up in triplicate; in addition, the tests were repeated one or more times on different dates. After 24 and 48 h of incubation at 37°C, the tubes were read turbidimetrically with a Coleman 295 spectrophotometer at 540 nm, using drug-free medium as a blank. The 24-a...

Chromoblastomycosis murine model and in vitro test to evaluate the sensitivity of Fonsecaea pedrosoi to ketoconazole, itraconazole and saperconazole

“…A cure-rate of 37% was obtained with KTZ; this cure-rate data is closer to that found in clinical studies, which have rendered a 41 to 50% curerate (Drouhet et al 1982, Hughes et al 1988). The in vitro findings and the murine animal model can be compared to results obtained in other studies and to clinical experiments on humans, keeping in mind, though, that they deal with two different models which have different natural evolutions.…”

“…The doses and the number of mice treated are recorded in Table I. These doses were chosen based on previous studies (Drouhet et al 1982, Radetsky et al 1986, Hughes et al 1988, Kan & Bennett 1988, The RW Johnson Pharmaceutical Research Institute Zurich 1989.…”

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

“…When susceptible strains were tested, discrepant results were the rule (29), although there are reports of spectrophotometric determination of 50% growth inhibition with very low MICs for most imidazoles (19), as we also found (Tables 1 and 2). 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).…”

“…It is noteworthy that the wide range of concentrations used allowed us to differentiate the greater in vitro activities of the imidazole derivatives (CZ, MZ, and KZ) compared with those of the newer systemic triazoles (FZ and IZ). In comparison with susceptible control strains, C. albicans ATCC 64550 (13,17,33) displayed decreased susceptibility to all of the azoles tested (Table 1), but at a very different range of concentrations.…”

“…Suitable susceptible control organisms included C. albicans ATCC 90028 (23), C. albicans ATCC 90029 (23), and C. albicans ATCC 64548 (1). One resistant strain was also used as a control in all susceptibility tests: C. albicans ATCC 64550 (C. albicans AD), which was clinically resistant to KZ; this resistance has been confirmed in vitro as well as in vivo (13,17,33).…”