Influence of serum and albumin on echinocandin pharmacodynamics
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Background: The use of human serum (HS) or bovine serum albumin (BSA) during susceptibility testing may help discriminate between echinocandin susceptible and resistant C. albicans and C. glabrata strains. However, the influence of these protein components and that of specific FKS mutations on the in vitro potency of the echinocandins remains unclear. Our objective was to evaluate the in vitro pharmacodynamics of the echinocandins in the presence and absence of these biological matrices against resistant C. albicans and C. glabrata isolates. Methods: Thirteen C. albicans clinical isolates (2 wild-type and 11 FKS mutants (F641S and S645P) and twenty C. glabrata clinical isolates (16 FKS mutants and 4 with unknown resistance mechanisms) were used. MICs were measured in duplicate according to the CLSI M27-A3 guideline for caspofungin, micafungin, and anidulafungin in RPMI, or RPMI supplemented with either 5% HS or 5% BSA. Pharmacodynamic analysis was also performed with the XTT viability assay, and non-linear regression analysis was usedto determine the IC50 values. Differences in geometric mean (GM) MICs and mean IC50 values were assessed by ANOVA and the Student’s t-test. Results: The addition of BSA significantly increased the GM MIC (6-24 fold) and IC50 (9-25 fold) of each echinocandin compared to RPMI (p < 0.0001) for isolates with FKS mutations. Increases in MIC (4-12 fold) and IC50 values (3-5 fold) were also observed with the addition of HS. Although increases in MICs and IC50s were also observed against the wild-type isolates, these values remained < 1 μg/mL for each echinocandin. When comparing the results of specific FKS mutations in C. albicans, the MIC and IC50 values were higher in each growth condition for isolates with S645P mutations (HS & BSA GM 8.0 & 12 μg/mL; mean IC50 5.5 & 21 μg/mL, respectively) compared to those with F641S mutations (HS & BSA GM 3.7 & 9.8 μg/mL; IC50 4.0 & 16 μg/mL, respectively). Conclusions: The addition of HS and BSA significantly influenced the pharmacodynamics of the echinocandins, but to different degrees. The specific FKS mutation may influence these in vitro potency changes, but further work is needed to evaluate these matrices and standardize echinocandin testing in their presence.