Background: Treatment options against resistant C. albicans are limited. The inositol acyltransferase inhibitor E1210 has in vitro and in vivo activity against different pathogenic fungi, including Candida, Aspergillus, Fusarium, and Scedosporium spp. Our objective was to evaluate the in vitro potency and in vivo activity of E1210 against echinocandin-resistant C. albicans. Methods: Antifungal susceptibility testing was performed against 29 C. albicans clinical isolates, including 16 echinocandin-resistant strains by CLSI methods. Immunocompetent ICR mice (N = 20/treatment group) were inoculated intravenously with C. albicans 43001 (E1210, fluconazole [FLU], and caspofungin [CAS] MICs < 0.03, >64, and 1 μg/ml, respectively). Therapy with placebo control, E1210 (2.5, 10, or 40 mg/kg PO BID), FLU (20 mg/kg PO BID) or CAS (10 mg/kg IP QD) began 1 day post-challenge and continued for 7 days. Mice were followed off therapy until day 21 to assess survival. Kidneys were collected on day 8, and fungal burden was assessed by colony-forming units (CFU). Results: E1210 demonstrated potent in vitro activity against C. albicans, as the MICs ranged between < 0.03 – 0.25 μg/ml against all isolates, including echinocandin-resistant isolates. In vivo, survival was significantly longer in mice treated with E1210 10 and 40 mg/kg (>21 days) compared to placebo and CAS (8 and 13.5 days, respectively; p < 0.01). Percent survival was also significantly longer in mice treated with E1210 10 and 40 mg/kg (55% and 60%, respectively) compared to placebo (20%; p < 0.05). Fungal burden was also significantly lower with each dose of E1210 (mean range log10 CFU/g 4.19 - 4.79 log10 CFU/g) compared to placebo (5.60 log10 CFU/g; p < 0.05) and CAS (5.88 log10 CFU/g; p < 0.01). FLU also resulted in significant improvements in survival (>21 days and 70% survival) and reductions in fungal burden (3.52 log10 CFU/g) compared to placebo and CAS (p < 0.05). Conclusions: E1210 demonstrated potent in vitro and in vivo activity against echinocandin-resistant C. albicans in this study. These results demonstrate the potential for E1210 for the treatment of invasive candidiasis caused by resistant C. albicans.
Full conference title:
- ICAAC 54th (2014)