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The novel arylamidine T-2307 demonstrates in vitro and in vivo activity against echinocandin-resistant Candida glabrata
- Publication Year :
- 2015
- Publisher :
- Oxford University Press, 2015.
-
Abstract
- OBJECTIVES 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
- Subjects :
- 0301 basic medicine
Microbiology (medical)
Male
Antifungal Agents
Echinocandin
030106 microbiology
Amidines
Colony Count, Microbial
Candida glabrata
Microbial Sensitivity Tests
Biology
Neutropenia
Kidney
Microbiology
03 medical and health sciences
chemistry.chemical_compound
In vivo
polycyclic compounds
medicine
Animals
Humans
Pharmacology (medical)
Original Research
Pharmacology
Mice, Inbred ICR
Candidiasis
bacterial infections and mycoses
medicine.disease
Caspofungin Acetate
biology.organism_classification
In vitro
Disease Models, Animal
Infectious Diseases
Treatment Outcome
chemistry
Immunocompetence
Caspofungin
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....264d0ba7a9bb6f2e7d5f8c648648acce