Comparative efficacy of fluconazole and liposomal amphotericin B in diabetic mice infected with azole resistant or sensitive Candida albicans

Abstract

Objective: Diabetes compromises blood circulation and immune responses, as well as major metabolic pathways, which can lead to increased susceptibility to infection. In the present study, we examined this possibility using diabetic versus non-diabetic mice with systemic candidiasis caused by a Candida albicans azole sensitive(C.alb-S) or azole resistant(C.alb-R) strain. Infected mice were treated with fluconazole (Flu) or liposomal amphotericin B (AmBisome®, AmBi). Methods: ICR male mice (3-4 weeks old) were maintained on a high (60%) fat diet for 4 weeks. Diabetes was then chemically induced by one intraperitoneal nicotinamide (60 mg/kg) and streptozotocin (100 mg/kg) treatment; by day 7-14 mean blood glucose levels were ≥200 mg/dL Diabetic mice (n=9-14/gp) and nondiabetic mice (n=14-16/gp) were challenged intravenously (IV) with C.alb-R (ATCC 62342) (diabetic: 3.5x10ex6 cells/mouse; non-diabetic: 1.4x10ex6 cells/mouse) or C.alb-S (CP620) (diabetic: 1.5x10ex6 cells/mouse; non-diabetic: 6.9 x10ex6 cells/mouse) and 24h later, given 5 mg/kg AmBi or 5% dextrose in water (D5W) intravenously for 6 days or Flu 40 mg/kg PO 2X/day for 6 days. Tissues (kidneys, liver, spleen) were collected (n=3-6/group) on d4 (diabetic) and d7 (nondiabetic) post-challenge, homogenized and plated on Sabouraud's agar to determine fungal burden (CFU/g). Other mice (n=6-10/gp) were monitored for morbidity to d28. Results: With a C.alb-R infection, AmBi treated, non-diabetic and diabetic mice, had significantly better survival than Flu or D5W treated mice (AmBi 83-100% survival, Flu 0-30% survival, D5W (0-20% survival) (p≤0.01). Significant decreases in CFU/g kidneys were observed with AmBi treatment versus D5W or Flu in diabetic and non-diabetic mice (p≤ 0.04); no fungi were recovered in livers or spleens of AmBi treated mice (p≤ 0.04). In comparison, with C.alb-S infection, AmBi or Flu treated, non-diabetic mice had 100% and 80% survival, respectively, but in diabetic mice, survival was 100% for AmBi and only 16% for Flu even though this was a Flu sensitive strain (p=0.0021). D5W yielded 0% (non-diabetic) and 14% (diabetic) survival. The fungal burden in the livers and spleens was significantly lower with AmBi treatment versus Flu or D5W, with AmBi treatment reducing the liver and spleen fungal burdens to undetectable levels. In the kidneys, the fungal burden in non-diabetic mice was significantly lower for AmBi versus Flu or D5W, but there was no significant difference in kidney fungal burden in diabetic mice given AmBi or Flu. Conclusions: In non-diabetic mice, AmBi and Flu were effective in systemic candidiasis caused a C. albicans azole sensitive strain, while AmBi was effective in treating non-diabetic diabetic mice infected with a C. albicans azole sensitive or resistant strain. Notably, in diabetic mice challenged with a C. albicans azole sensitive strain, Flu was associated with poor survival and elevated tissue fungal burden, indicating that the diabetic condition enhanced susceptibility to systemic candidiasis whether it was cause...