ABSTRACT
We report 4 cases of invasive zygomycosis in hematopoietic stem cell transplant recipients, all occurring after May 2003, when voriconazole began to be used as antifungal prophylaxis. No cases of zygomycosis had been detected in this population in the 3 years prior to May 2003. All 4 patients were receiving immunosuppressive therapy for presumed graft-versus-host disease. Profoundly immunosuppressed patients receiving voriconazole prophylaxis remain at risk for less-common pathogens that are intrinsically resistant to this agent.
Subject(s)
Fungi/drug effects , Fungi/isolation & purification , Hematopoietic Stem Cell Transplantation/adverse effects , Pyrimidines/therapeutic use , Rhizopus/drug effects , Rhizopus/isolation & purification , Triazoles/therapeutic use , Zygomycosis/epidemiology , Zygomycosis/prevention & control , Adult , Antifungal Agents/therapeutic use , Female , Graft vs Host Disease/prevention & control , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , VoriconazoleABSTRACT
Population studies have indicated that natural resistance to flucytosine (5FC) in Candida albicans is limited to one of the five major clades, clade I. In addition, while 73% of clade I isolates are less susceptible to 5FC (MIC >/= 0.5 microg/ml), only 2% of non-clade I isolates are less susceptible. In order to determine the genetic basis for this clade-specific resistance, we sequenced two genes involved in the metabolism of 5FC that had previously been linked to resistance (cytosine deaminase and uracil phosphoribosyltransferase), in 48 isolates representative of all clades. Our results demonstrate that a single nucleotide change from cytosine to thymine at position 301 in the uracil phosphoribosyltransferase gene (FUR1) of C. albicans is responsible for 5FC resistance. The mutant allele was found only in group I isolates. The 5FC MICs for strains without copies of the mutant allele were almost exclusively /=0.5 microg/ml, and those for strains with two copies of the mutant allele were >/=16 microg/ml. Thus, the two alleles were codominant. The presence of this allele is responsible for clade I-specific resistance to 5FC within the C. albicans population and thus by inference is likely to be the major underlying 5FC resistance mechanism in C. albicans. This represents the first description of the genetic mutation responsible for 5FC resistance.
