Background: FKS mutations alter the sensitivity of glucan synthase for echinocandin drugs in Candidaspp. and have been linked to clinical failures. All fks mutations increase MIC values but not all mutations have the potential for adverse clinical outcome. To better understand the potential clinical significance of these mutations, a neutropenic murine kidney burden model was used as a surrogate to assess the relationship between specific fks mutations. Six well-characterized clinical isolates of Candida glabratadisplaying a broad spectrum of fks mutations displaying low to moderate micafungin (MFG) MIC values (0.06 to 0.5 mg/L) were evaluated in this model. Methods: A neutropenic murine candidiasis model was used to establish the MFG Effective Doses. Mice were rendered neutropenic by cytoxan injection and i.v. infected with C. glabrata. Daily treatments of PBS, 0.05, 0.5, 5.0, or 50 mg/kg of MFG starting at 3 h post infection for up to 4 days. A susceptible strain ATCC 90030 was used as a comparator in all studies. A Non-linear regression analysis was performed using Graphpad Prism 5.0 software to calculate 99% effective doses (ED99). Echinocandin susceptibility testing was performed following CLSI method M27-A3. Results: MFG ED99 values of the C. glabrata fks mutants ranged from 3.1 to 36.2 mg/kg/qd or ~11 to 125 times higher than the susceptible strain ATCC 90030 (0.3 mg/kg/qd). The ED99 values for four out of the six fks mutants were only 11-25 fold greater than ATCC 90030 and all mutants responded well to escalating MFG doses. The fks mutant strains DPL 42 (Fks1p D632) and DPL 236 (Fks2p L664) displayed the highest ED99 values at 125 and 88 times higher than ATCC 90030, respectively. Conclusions: The ED99 data of these FKS mutants suggest that the precise nature of the fks genotype is a better predictor of echinocandin resistance. These mutations have lower frequencies of clinical resistance indicating that C. glabrata fks genotype ranking for clinical resistance may be distinct from other clinically important Candida spp.
Full conference title:
53rd Interscience Conference on Antimicrobial Agents and Chemotherapy
- ICAAC, 53rd (2013)