title: Efficacy of SCH-56592 in a temporarily neutropenic murine model of invasive aspergillosis with an itraconazole-susceptible and an itraconazole-resistant isolate of Aspergillus fumigatus.
abstract: SCH-56592 (SCH) is a novel triazole antifungal agent with excellent in vitro activity against Aspergillus. We compared three doses (5, 10, and 25 mg/kg of body weight) of SCH with itraconazole (ITZ; 25 mg/kg) and amphotericin B (AB; 5 mg/kg) in a temporarily neutropenic murine model of disseminated aspergillosis (lungs and kidneys) against one ITZ-susceptible (AF71) and one ITZ-resistant (AF90) isolate of Aspergillus fumigatus. Treatment started 24 h after infection and lasted for 10 days. Dosing regimens for SCH were once daily for 10 days, those for ITZ were three times daily for 2 days and then twice daily for 3 to 10 days, and those for AB were once daily on days 1, 2, 4, and 7. Both isolates killed 90% of control mice. Kidneys and lungs from survivors were cultured on day 11. Against AF71, all three doses of SCH and ITZ yielded a 90 to 100% survival rate and AB yielded 40% survival (P < or = 0.01 to 0.0001 for all treatment groups compared with the controls). All three doses of SCH were superior to AB in cultures of lung and kidney tissue samples (P < or = 0.01 to 0.0002) and SCH at 25 mg/kg was superior to ITZ in cultures of kidneys (P = 0.01). Against AF90, the highest dose of SCH (25 mg/kg) resulted in a 100% survival rate, compared with 60 and 20% survival rates for the groups treated with SCH at 10 and 5 mg/kg, respectively. Treatment with ITZ yielded no survivors. AB therapy achieved a 50% survival rate. SCH at 25 mg/kg (P < 0.001), SCH at 10 mg/kg (P < or = 0.005), and AB (P < 0.05) were superior to ITZ in cultures of lungs and kidneys. There was a correlation between the MICs of SCH and quantitative organ culture results and between the minimum fungicidal concentration of AB with quantitative organ culture results. SCH appears to be a highly effective anti-Aspergillus compound in this model. There appears to be a degree of cross-resistance between itraconazole and SCH.
authors.affiliation: Department of Medicine, Hope Hospital, Salford, and University of Manchester, United Kingdom.
authors.forename: K L
authors.initials: KL
authors.lastname: Oakley
authors.forename: G
authors.initials: G
authors.lastname: Morrissey
authors.forename: D W
authors.initials: DW
authors.lastname: Denning
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001228:Aspergillosis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000302:isolation & purification; D004352:Drug Resistance, Microbial; D017964:Itraconazole / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000150:complications* / Q000378:metabolism; D015996:Survival Rate; D013997:Time Factors; D014230:Triazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; D017964:Itraconazole; C101425:posaconazole