Posaconazole with Caspofungin against Candida Glabrata in a mouse model

Objective: Last year we reported on synergistic testing of caspofungin and posaconazole against Candida glabrata in a mouse model. A trend toward synergy was seen with lower doses of caspofungin. In this current study we wanted to determine if increased levels of caspofungin would result in significant synergy with posaconazole. Methods: The isolate had an MIC of 1µg/ml to caspofungin and 2µg/ml to posaconazole. Mice were immunosuppressed one day before infection with 5-flourouracil at 150 mg/kg. Mice were infected at 1 X 108 colony forming units (cfu)/mouse and randomly distributed among the following groups (N=10): control (saline), caspofungin 0.06 mg/kg, caspofungin 0.125 mg/kg, posaconazole 40mg/kg, caspofungin 0.06 mg/kg + posaconazole 40mg/kg, and caspofungin 0.125 mg/kg + posaconazole 40mg/kg. Treatment occurred days 1-7 post infection. Mice were terminated on day 8 post challenge. The kidneys were weighed, and homogenized in saline with antibiotics. Serial dilutions were plated on Sabouraud plates. Colony counts were used to determine organ fungal burden measured as CFU per gram of organ. The Mann-Whitney test (non-parametric) was used for statistical analysis. P<0.05 determined statistical significance. Results: Caspofungin 0.06mg/kg + posaconazole 40mg/kg and caspofungin 0.125mg/kg + posaconazole 40mg/kg yielded an improved response over controls. All combination groups failed to show an improved response over their respective posaconazole and caspofungin monotherpy groups. Posaconazole 40mg/kg and caspofungin 0.125mg/kg were the only monotherapy gropus that significantly lowered fungal burden. Conclusion: Using these two antifungal therapies at the tested concentrations no true synergistic relationship was found in this model. There appears to exist no antagonism between these two drugs. This study was supported by grant number NIDCR T-32 DE14318 and NIH contract N01-AI-225475