EDLIND TD, KATIYAR SK; Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2003 Sep 14-17; 43: abstract no. M-403.

Drexel Univ. Coll. of Med., Philadelphia, PA.

Caspofungin (CF) was recently approved for use in Aspergillus infection, but clinical and animal studies suggest that CF and other cell wall synthesis-inhibiting echinocandins will be useful in Candida infection as well. In particular, echinocandins could be valuable against C. albicans or C. glabrata in which acquired resistance to azoles is a significant problem. However, the potential for similar acquired resistance to echinocandins is not clear. To study this, about 10 million cells of 4 C. albicans strains were plated on YPD agar containing CF at 0.15-1 microg/ml (5-30 fold above the MIC). Following 4 days incubation, mutant colonies were observed at relatively high frequency (10[-5)]. Mutants were isolated on drug-free medium and their CF susceptibilities tested: at 24 h there was little or no change in MIC. However, with most mutants trailing growth was apparent after prolonged incubation, suggesting tolerance to the fungicidal activity of CF. This was confirmed by determining viable cell counts after 20 h: for most mutants there was no loss of viability up to the highest concentration tested (0.5-1 microg/ml), while viability of the parent strains was reduced 30-500 fold. With C. glabrata, mutant colonies arose at similar frequency (10[-5)] on 0.25 microg/ml CF. However, 24 h MICs for these mutants averaged 4-fold above the parent strain MIC. Fungicidal activity was greatly reduced at 0.125 microg/ml CF (from 1000 fold to an average of 3 fold), but at 0.25 microg/ml there was equal killing of parent and mutants. The echinocandin target is beta-1,3-glucan synthase, and so expression of genes encoding this enzyme was examined. In 2 of 5 C. albicans mutants, there was upregulated basal expression of GSL2, and following CF treatment (0.1 microg/ml for 2 h) upregulation of both GSL2 (>10-fold) and GSC1 (3-fold) was observed. In 2 C. glabrata mutants tested, 2-4 fold upregulation was observed for a GSL2/GSC1 homolog. These studies indicate that CF treatment of these Candida species readily selects for tolerant mutants, mechanisms for which include upregulated expression of beta-1,3-glucan synthase.

Publication Types:

• Meeting Abstracts

Keywords:

• Antifungal Agents
• Antigens, Fungal
• Azoles
• Candida
• Candida albicans
• Candida glabrata
• Candidiasis
• Fluconazole
• Glucosyltransferases
• Itraconazole
• Microbial Sensitivity Tests
• Peptides, Cyclic
• caspofungin
• glucan synthase
• immunology

Other ID:

• GWAIDS0025902

UI: 102265526

From Meeting Abstracts