title: In vitro and in vivo antifungal activities of T-2307, a novel arylamidine, against Cryptococcus gattii: an emerging fungal pathogen.
abstract: T-2307, a novel arylamidine, exhibits potent broad-spectrum activities against the majority of fungal pathogens. In this study, the antifungal activity of T-2307 against Cryptococcus gattii was evaluated in comparison with those of amphotericin B, fluconazole and voriconazole in vitro and in vivo .
  
  
  
  The MICs for 15 clinical isolates were determined according to CLSI guidelines and time-kill studies were performed using C. gattii YF2784. In a murine model for intranasal pulmonary infection caused by C. gattii YF2784, the test compounds were administered once daily for 7 days from 2 h or 14 days post-infection. The viable counts in the lungs and brain were determined at 21 days post-infection.
  
  
  
  The MIC range, MIC 50 , MIC 90 and geometric mean MIC of T-2307 were 0.0078-0.0625, 0.0313, 0.0625 and 0.0394 mg/L, respectively. The MIC of T-2307 was significantly lower than those of fluconazole, voriconazole and amphotericin B. T-2307 showed concentration-dependent fungicidal activity at 4 times the MIC or higher. Administration of T-2307 at 2 mg/kg/day, amphotericin B at 1 mg/kg/day and fluconazole at 160 mg/kg/day from 2 h post-infection significantly reduced viable counts in the lungs and brain. However, when the administration was started 14 days post-infection, only T-2307 significantly reduced the viable counts in both the lungs and the brain at 1 mg/kg/day.
  
  
  
  T-2307 shows excellent in vitro and in vivo antifungal activities against C. gattii and would be a promising new candidate for the treatment of cryptococcosis.
authors.affiliation: Research Laboratories, Toyama Chemical Co., Ltd, 2-4-1 Shimookui, Toyama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishikawa
authors.affiliation: Research Laboratories, Toyama Chemical Co., Ltd, 2-4-1 Shimookui, Toyama, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Fukuda
authors.affiliation: Research Laboratories, Toyama Chemical Co., Ltd, 2-4-1 Shimookui, Toyama, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Mitsuyama
authors.affiliation: Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Tashiro
authors.affiliation: Infection Control and Education Center, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Akitaka
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Takazono
authors.affiliation: Second Department of Internal Medicine, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Saijo
authors.affiliation: Infection Control and Education Center, Nagasaki University Hospital, Nagasaki, Japan.|Second Department of Internal Medicine, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Second Department of Internal Medicine, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Imamura
authors.affiliation: Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.|Second Department of Internal Medicine, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Taiga
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kakeya
authors.affiliation: Department of Clinical Infectious Diseases, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.affiliation: Second Department of Internal Medicine, Nagasaki University Hospital, Nagasaki, Japan.|Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mukae
authors.affiliation: Second Department of Internal Medicine, Nagasaki University Hospital, Nagasaki, Japan.|Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
authors.affiliation: Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Izumikawa
mesh_terms: D000578:Amidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000666:Amphotericin B / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D001921:Brain / Q000382:microbiology; D003453:Cryptococcosis / Q000188:drug therapy* / Q000382:microbiology; D056285:Cryptococcus gattii / Q000187:drug effects* / Q000472:pathogenicity; D003455:Cryptococcus neoformans / Q000187:drug effects; D004195:Disease Models, Animal; D055808:Drug Discovery; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008168:Lung / Q000382:microbiology; D008172:Lung Diseases, Fungal / Q000188:drug therapy / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D065819:Voriconazole / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000578:Amidines; D000935:Antifungal Agents; C573060:T-2307; D000666:Amphotericin B; D015725:Fluconazole; D065819:Voriconazole