title: The novel arylamidine T-2307 demonstrates in vitro and in vivo activity against echinocandin-resistant Candida glabrata.
abstract: OBJECTIVE
  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.
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX, USA wiederholdn@uthscsa.edu.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Wiederhold
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX, USA South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Najvar
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Annette W
authors.initials: AW
authors.lastname: Fothergill
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX, USA South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: Rosie
authors.initials: R
authors.lastname: Bocanegra
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX, USA South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: Marcos
authors.initials: M
authors.lastname: Olivo
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Dora I
authors.initials: DI
authors.lastname: McCarthy
authors.affiliation: Toyama Chemical Co., Ltd, Toyama, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Fukuda
authors.affiliation: Toyama Chemical Co., Ltd, Toyama, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Mitsuyama
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX, USA South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Patterson
mesh_terms: D000578:Amidines / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D041221:Candida glabrata / Q000187:drug effects* / Q000302:isolation & purification; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology*; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D006801:Humans; D007668:Kidney / Q000382:microbiology; D008297:Male; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D016896:Treatment Outcome
chemical_list: D000578:Amidines; D000935:Antifungal Agents; C573060:T-2307