t-2307 and Candidiasis

Topics: Amidines; Animals; Antifungal Agents; Biofilms; Candida tropicalis; Candidiasis; Humans; Male; Microbial Sensitivity Tests

T-2307, a novel arylamidine, shows broad-spectrum activity against pathogenic fungi, including Candida albicans. Ocular candidiasis is one of the serious complications associated with Candida bloodstream infection and is known to be refractory to conventional antifungal agents. The aim of the present study was to clarify the effectiveness of T-2307 against ocular candidiasis using a mouse model.. We evaluated ocular fungal burden in mice infected with C. albicans that received treatment with antifungal agents [T-2307, liposomal amphotericin B (LAMB) or fluconazole] for 3 consecutive days. We also assessed survival rates of mice after C. albicans infection followed by treatment for 7 consecutive days. In addition, ocular T-2307 concentrations and in vitro effectiveness against C. albicans biofilm formation were evaluated.. The ocular fungal burdens were significantly reduced after T-2307 treatment compared with the control group (no treatment received) and were comparable with those observed following treatment with LAMB or fluconazole in both early- and late-phase treatment experiments. In addition, all of the mice treated with antifungal agents survived for 3 weeks after infection, whereas mice in the control group died within 3 days. The ocular T-2307 trough concentration was maintained above the MIC in the infected mice. An in vitro biofilm inhibition experiment showed that T-2307 suppressed C. albicans biofilm formation at the sub-MIC level, which was comparable with amphotericin B.. Given these results in experimental disseminated candidiasis, T-2307 may be an effective treatment against the complication of ocular candidiasis.

Topics: Amidines; Animals; Antifungal Agents; Biofilms; Candida albicans; Candidiasis; Colony Count, Microbial; Drug Resistance, Fungal; Eye; Eye Infections; Female; Kidney; Mice, Inbred C57BL; Microbial Sensitivity Tests; Specific Pathogen-Free Organisms

Candida species are major causes of invasive mycoses in immunocompetent and immunocompromised hosts. Treatment options are limited in the setting of antifungal resistance and increased rates of echinocandin-resistant Candida glabrata have been reported. The novel arylamidine T-2307 demonstrates potent in vitro antifungal activity against Candida species. Our objective was to evaluate the in vitro and in vivo activity of T-2307 against resistant C. glabrata.. In vitro activity was determined against 42 clinical C. glabrata isolates, including 17 echinocandin-resistant strains. Neutropenic ICR mice were inoculated intravenously with an echinocandin-resistant C. glabrata isolate (T-2307; caspofungin MICs ≤0.008 and 0.5 mg/L, respectively). Therapy with vehicle control, T-2307 (0.75, 1.5, 3 or 6 mg/kg subcutaneously once daily) or caspofungin (1 or 10 mg/kg intraperitoneally once daily) began 1 day post-challenge. Kidneys were collected on day 8 and fungal burden was assessed by counting cfu.. T-2307 demonstrated potent in vitro activity against C. glabrata (geometric mean MIC 0.0135 mg/L), which was maintained against echinocandin-resistant isolates (geometric mean MIC 0.0083 mg/L). T-2307 also demonstrated in vivo efficacy in mice infected with echinocandin-resistant C. glabrata. Significant reductions in fungal burden were observed at each dosage level of T-2307 compared with control. Reductions in fungal burden were also observed with high-dose caspofungin.. T-2307 demonstrated potent in vitro activity against C. glabrata, including echinocandin-resistant isolates, which translated into in vivo efficacy against invasive candidiasis caused by an echinocandin-resistant C. glabrata strain. These results demonstrate the potential for T-2307 as therapy against echinocandin-resistant Candida.

Topics: Amidines; Animals; Antifungal Agents; Candida glabrata; Candidiasis; Colony Count, Microbial; Disease Models, Animal; Humans; Kidney; Male; Mice, Inbred ICR; Microbial Sensitivity Tests; Treatment Outcome

We evaluated the in vitro and in vivo activities of the investigational arylamidine T-2307 against echinocandin-resistant Candida albicans. T-2307 demonstrated potent in vitro activity, and daily subcutaneous doses between 0.75 and 6 mg/kg of body weight significantly improved survival and reduced fungal burden compared to placebo control and caspofungin (10 mg/kg/day) in mice with invasive candidiasis caused by an echinocandin-resistant strain. Thus, T-2307 may have potential use in the treatment of echinocandin-resistant C. albicans infections.

Topics: Amidines; Animals; Antifungal Agents; Candida albicans; Candidiasis; Drug Resistance, Fungal; Echinocandins; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests