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

Abstract

Two groups of recent clinical isolates of Candida albicans consisting of 101 isolates for which fluconazole MICs were <0.5 g/ml (n ‫؍‬ 50) and >4.0 g/ml (n ‫؍‬ 51), respectively, were compared for their susceptibilities to fluconazole, clotrimazole, miconazole, ketoconazole, and itraconazole. Susceptibility tests were performed by a photometer-read broth microdilution method with an improved RPMI 1640 medium supplemented with 18 g of glucose per liter (RPMI-2% glucose; J. L. Rodríguez-Tudela and J. V. Martínez-Suárez, Antimicrob. Agents Chemother. 38:45-48, 1994). Preparation of drugs, basal medium, and inocula was done by the recommendations of the National Committee for Clinical Laboratory Standards. The MIC endpoint was calculated objectively from the turbidimetric data read at 24 h as the lowest drug concentration at which growth was just equal to or less than 20% of that in the positive control well (MIC 80%). In vitro susceptibility testing separated azole-susceptible strains from the strains with decreased susceptibilities to azoles if wide ranges of concentrations (20 doubling dilutions) were used for ketoconazole, miconazole, and clotrimazole. By comparison with isolates for which fluconazole MICs were <0.5 g/ml, those isolates for which fluconazole MICs were >4.0 g/ml were in general less susceptible to other azole drugs, but different patterns of decreased susceptibility were found, including uniform increases in the MICs of all azole derivatives, higher MICs of several azoles but not others, and elevated MICs of fluconazole only. On the other hand, decreased susceptibility to any other azole drug was never found among strains for which MICs of fluconazole were lower. Secondary resistance to azole antifungal agents in Candida albicans first appeared in the 1980s in patients with chronic mucocutaneous candidiasis treated with KZ for very long periods of time (25,33,36). The isolates involved had markedly reduced susceptibilities to KZ and cross-resistance to other azole drugs. More recently, resistance to the triazole FZ has been described in C. albicans strains isolated from the oral cavities of AIDS patients in different parts of the world (2, 5-8, 15, 18, 22, 24, 25, 28, 29, 32, 34, 36). The absence in most cases of comparative susceptibility data for alternative azole antifungal agents in these isolates still leaves open the question of whether cross-resistance to azole drugs in C. albicans is a general phenomenon.All of the azole antifungal agents share certain properties that makes in vitro susceptibility testing difficult, mainly partial inhibition of fungal growth that makes MIC endpoint determinations both very difficult and subjective (12,29,35). In the proposed standard of the National Committee for Clinical Laboratory Standards (NCCLS) (23), endpoints for azoles are determined visually at 48 h and the MIC is defined as the lowest drug concentration that reduces growth by 80% relative to the growth of the control (MIC 80%). We have previously shown that increased growth of C. albicans in RP...

Wild-Type MIC Distributions and Epidemiological Cutoff Values for Amphotericin B, Flucytosine, and Itraconazole and Candida spp. as Determined by CLSI Broth Microdilution

“…are well known (16,19,27,36). Although itraconazole has often been used as a comparator in surveys of the in vitro antifungal susceptibilities of opportunistic fungal pathogens, it has rarely been the primary focus of such studies (27); thus, its activity against opportunistic fungi is generally underappreciated (16,21). In part, this may also be due to a perception of rather poor activity of itraconazole against Candida spp., given the very conservative CBPs (susceptible, MIC Յ 0.12 g/ml; susceptible dose-dependent, MIC ϭ 0.25 to 0.5 g/ml; resistant, MIC Ն 1 g/ml) assigned by the CLSI (36).…”

“…These patterns of in vitro susceptibility of the different Candida spp. are well known (16,19,27,36). Although itraconazole has often been used as a comparator in surveys of the in vitro antifungal susceptibilities of opportunistic fungal pathogens, it has rarely been the primary focus of such studies (27); thus, its activity against opportunistic fungi is generally underappreciated (16,21).…”

In Vitro Comparison of Activities of Terbinafine and Itraconazole against Paracoccidioides brasiliensis

“…Martinez-Suarez and Rodriguez-Tudela (13) have reported that addition of as much as 2% glucose to culture media helps in the reading of MICs of azole compounds. According to Espinel-Ingroff et al (3), addition of 2% glucose to RPMI 1640 medium helped in the examination of MIC end points.…”

Antifungal Susceptibility Testing: Practical Aspects and Current Challenges

“…Cartledge et al reported that AIDS patients with oropharyngeal candidiasis treated with 200-mg itraconazole capsules (the least well absorbed formulation of the drug) had a greater rate of failure when the MIC was Ͼ2 g/ml (27). In a supportive laboratory study, isolates with elevated fluconazole MICs were found to have elevated itraconazole MICs that were usually Ն0.5 g/ml, in contrast to Յ0.125 g/ml for isolates with lower fluconazole MICs (123).…”