Inducible azole resistance associated with a heterogeneous phenotype in Candida albicans

The development of azole resistance in Candida albicans is most problematic in patients with AIDS who receive long courses of drug for therapy or prev ention of oral candidiasis. Recently, the rapid development of resistance w as noted in other immunosuppressed patients who developed disseminated cand idiasis despite fluconazole prophylaxis. One of these series of C. albicans isolates became resistant, with an associated increase in mRNA specific fo r a CDR ATP-binding cassette transporter efflux pump (K. A. Marr, C. N. Lyo ns, T. R. Rustad, R. A. Bowden, and T. C. White, Antimicrob. Agents Chemoth er. 42:2584-2589, 1998). Here we study this series of C. albicans isolates further and examine the mechanism of azole resistance in a second series of C. albicans isolates that caused disseminated infection in a recipient of bone marrow transplantation. The susceptible isolates in both series become resistant to fluconazole after serial growth in the presence of drug, whil e the resistant isolates in both series become susceptible after serial tra nsfer in the absence of drug. Population analysis of the inducible, transie ntly resistant isolates reveals a heterogeneous population of fluconazole-s usceptible and -resistant cells. We conclude that the rapid development of azole resistance occurs by a mechanism that involves selection of a resista nt clone from a heterogeneous population of cells.