title: Efficacy of the investigational echinocandin ASP9726 in a guinea pig model of invasive pulmonary aspergillosis.
abstract: ASP9726 is an investigational echinocandin with in vitro activity against Aspergillus species. We evaluated the pharmacokinetics and efficacy of this agent in an established guinea pig model of invasive pulmonary aspergillosis. ASP9726 plasma concentrations were measured in guinea pigs administered either a single dose or multiple doses of this agent at 2.5, 5, and 10 mg/kg of body weight/day by subcutaneous injection. Immunosuppressed guinea pigs were inoculated with A. fumigatus AF293, and ASP9726 (2.5, 5, and 10 mg/kg/day), voriconazole (10 mg/kg by oral gavage twice daily), or caspofungin (3 mg/kg/day by intraperitoneal injection) was administered for 8 days. Changes in fungal burden were measured by enumerating CFU and by quantitative PCR of specimens from within the lungs, as well as by analysis of serum (1 → 3)-β-D-glucan and galactomannan. Lung histopathology was also evaluated. ASP9726 plasma concentrations increased in a dose-proportional manner, and the drug was well tolerated at each dose. Each dose of ASP9726, voriconazole, and caspofungin significantly reduced pulmonary fungal burden as measured by quantitative PCR and by determining (1 → 3)-β-D-glucan and galactomannan levels, but only voriconazole significantly reduced numbers of CFU. ASP9726 at 5 mg/kg also significantly improved survival. Histopathology demonstrated morphological changes in hyphae in animals exposed to ASP9726 and caspofungin, consistent with the activities of the echinocandins. These results suggest that ASP9726 may be efficacious for the treatment of invasive pulmonary aspergillosis.
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas, 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, Texas, USA South Texas Veterans Health Care System, San Antonio, Texas, USA.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Najvar
authors.affiliation: Astellas Pharmaceuticals, Inc., Tsubuka, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA South Texas Veterans Health Care System, San Antonio, Texas, USA.
authors.forename: Rosie A
authors.initials: RA
authors.lastname: Bocanegra
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Monica L
authors.initials: ML
authors.lastname: Herrera
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Wickes
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA South Texas Veterans Health Care System, San Antonio, Texas, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Kirkpatrick
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA South Texas Veterans Health Care System, San Antonio, Texas, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Patterson
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D054714:Echinocandins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006168:Guinea Pigs; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy*; D008168:Lung / Q000382:microbiology; D008297:Male
chemical_list: C000592174:ASP9726; D054714:Echinocandins