Candida glabrata Mutants Demonstrating Paradoxical Reduced Caspofungin Susceptibility but Increased Micafungin Susceptibility

Echinocandins, including caspofungin (CSP) and micafungin (MCF), are highly active versus Candida glabrata (MIC of <= 0.06 mu g/ml). True resistance (MIC of >= 1 mu g/ml) is a rare event and strictly associated with mutations in beta-1,3-glucan synthase gene FKS1 or FKS2. In contrast, we show here that mutants exhibiting reduced susceptibility to CSP (CRS; MICs of 0.12 to 0.5 mu g/ml) are readily selected in vitro and, paradoxically, demonstrate increased susceptibility to MCF (MIS) ranging from 4- to 32-fold. CRS-MIS mutants were generated from all 10 C. glabrata strains tested and were tentatively identified within a collection of clinical isolates. Intriguingly, sequencing and gene disruption demonstrated that CRS-MIS is Fks independent.