ABSTRACTEchinocandins are a preferred therapy for invasive candidiasis due to their potency and broad spectrum. Resistance, especially inCandida glabrata, is an emerging threat to their use. Pharmacodynamic (PD) studies examining reduced susceptibility secondary tofksmutations inC. glabrataare lacking. The current study explored PD targets for anidulafungin, caspofungin, and micafungin in anin vivoinvasive candidiasis model against 11C. glabrataisolates with known or putativefksmutations. The PD targets were compared to those of 8 wild-type (WT) isolates. The MIC ranges in the WT group were 0.03 to 0.25 mg/liter for anidulafungin, 0.03 to 0.25 mg/liter for caspofungin, and 0.01 to 0.06 mg/liter for micafungin. The MIC ranges for mutants were 0.06 to 4, 0.25 to 16, and 0.13 to 8 mg/liter for the same compounds, respectively. The mean free drug 24-h area under the concentration-time curve (AUCf)/MIC ratio associated with a stasis endpoint for the WT group was 13.2 for anidulafungin, 2.04 for caspofungin, and 6.78 for micafungin. Comparative values for mutants were 3.43, 2.67, and 0.90, respectively. Pharmacokinetic data from patients suggest that theC. glabrataPD targets needed for success in this model could be achieved based on MIC values of 0.25 mg/liter for anidulafungin, 2 mg/liter for caspofungin, and 0.5 mg/liter for micafungin. These values are higher than recently identified epidemiology cutoff values (ECVs). The results suggest that drug-specific MIC breakpoints could be increased for caspofungin and micafungin againstC. glabrataand could include organisms with mutations infks-1andfks-2. While identification of genetic mutants is epidemiologically important, the phenotype (MIC) provides a better predictor of therapeutic efficacy.
De novo centromere formation on chromosome fragments with an inactive centromere in maize (Zea mays)
