title: Activity of aminocandin (IP960; HMR3270) compared with amphotericin B, itraconazole, caspofungin and micafungin in neutropenic murine models of disseminated infection caused by itraconazole-susceptible and -resistant strains of Aspergillus fumigatus.
abstract: Aminocandin (IP960; HMR3270; NXL201) is a new echinocandin with broad-spectrum in vitro activity against Aspergillus and Candida spp. We compared the activity of aminocandin with that of amphotericin B (AmB), itraconazole (ITC) and caspofungin (CAS) in murine models of disseminated aspergillosis against three strains of A. fumigatus, two of which were fully susceptible (AF293 and A1163) and one was resistant to ITC (AF91). Mice were rendered temporarily neutropenic or persistently neutropenic with cyclophosphamide and were infected intravenously 3 days later. Temporarily neutropenic mice were treated with either intraperitoneal (i.p.) AmB (5mg/kg/dose), oral (p.o.) ITC (25mg/kg/dose), intravenous (i.v.) aminocandin (0.25-10mg/kg/dose), i.p. aminocandin (1mg/kg/dose) or solvent control for 9 days. Mice were euthanised 11 days post infection and the kidneys and liver were removed for quantitative culture. Following infection with AF293, only aminocandin 5mg/kg i.v. yielded 100% survival. Aminocandin 1mg/kg i.v., AmB 5mg/kg i.p. or ITC 25mg/kg p.o. were equivalent (P>0.05). Aminocandin 5mg/kg was superior to aminocandin 0.25mg/kg (P<0.0001) as well as all controls (P<0.0001) in reducing mortality. Following infection with AF91, only aminocandin at 5mg/kg and 1mg/kg i.v. yielded 100% survival, which was superior to ITC, aminocandin 0.25mg/kg and controls (all P<0.0001). In the persistently neutropenic model with A1163, aminocandin, CAS and micafungin (2-10mg/kg) were all effective at prolonging survival, with some impact on reducing culture burdens, even with alternate-day dosing (4mg/kg). The only fungicidal regimen was aminocandin 5mg/kg, which sterilised 40% and 50% of mice following infection with AF293 and AF91, respectively. Aminocandin at doses of > or =1mg/kg is highly effective in reducing mortality and organ burden in disseminated infection caused by ITC-susceptible and -resistant A. fumigatus.
authors.affiliation: School of Translational Medicine, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK. peter.warn@manchester.ac.uk
authors.forename: Peter A
authors.initials: PA
authors.lastname: Warn
authors.forename: Andrew
authors.initials: A
authors.lastname: Sharp
authors.forename: Graham
authors.initials: G
authors.lastname: Morrissey
authors.forename: David W
authors.initials: DW
authors.lastname: Denning
mesh_terms: D000284:Administration, Oral; D000666:Amphotericin B / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000302:isolation & purification; D000077336:Caspofungin; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D054714:Echinocandins / Q000008:administration & dosage / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D017964:Itraconazole / Q000008:administration & dosage / Q000627:therapeutic use; D007668:Kidney / Q000382:microbiology; D055666:Lipopeptides / Q000008:administration & dosage / Q000627:therapeutic use; D008099:Liver / Q000382:microbiology; D008297:Male; D000077551:Micafungin; D051379:Mice; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; C476911:aminocandin; D017964:Itraconazole; D000666:Amphotericin B; D000077336:Caspofungin; D000077551:Micafungin