Innate inflammatory response and immunopharmacologic activity of micafungin, caspofungin, and voriconazole against wild-type and FKS mutant Candida glabrata.

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Innate inflammatory response and immunopharmacologic activity of micafungin, caspofungin, and voriconazole against wild-type and FKS mutant Candida glabrata.

Antimicrob Agents Chemother. 2015 Jun 22;

Authors: Beyda ND, Liao G, Endres BT, Lewis RE, Garey KW

Abstract
OBJECTIVES: Direct or indirect interactions antifungals have with the host immune response may play a significant role in defining their activity in-vivo. However, the impact acquired antifungal resistance has on the immunopharmacologic activity of antifungals is not well described. We assessed the immunopharmacologic activity of caspofungin, micafungin, and voriconazole among isolates of C. glabrata with or without FKS-mediated echinocandin resistance.
METHODS: Clinical bloodstream isolates of C. glabrata from patients that did (n=5) or did not (n=3) develop persistent candidemia and which did (n=2) or did not (n=11) harbor FKS gene mutations were included. A cell-based assay was used to compare differences in macrophage activation among isolates when grown in the presence or absence of sub-inhibitory concentrations of caspofungin, micafungin, or voriconazole.
RESULTS: In the absence of antifungals, macrophage activation was significantly lower for index C. glabrata isolates obtained from persistent candidemia patients vs. non-persistent patients (33% vs. 79% increase over negative controls respectively; p<0.01). Growth of isolates possessing wild-type FKS genes in sub-inhibitory concentrations of micafungin or caspofungin, but not voriconazole, significantly increased macrophage inflammatory responses compared to untreated controls (1.25 - 2.75 fold increase, p<0.01). For isolates harboring the FKS2 HS1 S663P mutation however, a significant increase was only observed with micafungin treatment (1.75 fold increase vs. negative control, p<0.01). Macrophage activation correlated with the level of unmasking of β-glucan in the cell wall.
CONCLUSIONS: The diminished macrophage inflammatory response to isolates which caused persistent candidemia and differential immunopharmacologic activity of echinocandins among FKS mutants suggest that certain strains of C. glabrata may have a higher propensity for immunoevasion and development of antifungal resistance during treatment.

PMID: 26100700 [PubMed - as supplied by publisher]