Oakley K L, Morrissey G, Denning D W
Department of Medicine, Hope Hospital, Salford, and University of Manchester, United Kingdom.
Antimicrob Agents Chemother. 1997 Jul;41(7):1504-7. doi: 10.1128/AAC.41.7.1504.
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.
SCH-56592（SCH）是一种新型三唑类抗真菌药物，对曲霉菌具有出色的体外活性。我们在一个暂时中性粒细胞减少的播散性曲霉病（肺部和肾脏）小鼠模型中，将三种剂量（5、10和25mg/kg体重）的SCH与伊曲康唑（ITZ；25mg/kg）和两性霉素B（AB；5mg/kg）进行了比较，受试菌株为一株对ITZ敏感（AF71）和一株对ITZ耐药（AF90）的烟曲霉。感染后24小时开始治疗，持续10天。SCH的给药方案为每日一次，共10天；ITZ的给药方案为每日三次，共2天，然后每日两次，共3至10天；AB的给药方案为在第1、2、4和7天每日一次。两种菌株致使90%的对照小鼠死亡。在第11天对存活小鼠的肾脏和肺部进行培养。对于AF71，所有三种剂量的SCH和ITZ的存活率均为90%至100%，而AB的存活率为40%（与对照组相比，所有治疗组的P≤0.01至0.0001）。在肺和肾组织样本培养中，所有三种剂量的SCH均优于AB（P≤0.01至0.0002），25mg/kg的SCH在肾脏培养中优于ITZ（P = 0.01）。对于AF90，SCH的最高剂量（25mg/kg）导致存活率为100%，而分别接受10mg/kg和5mg/kg SCH治疗的组的存活率为60%和20%。ITZ治疗无存活者。AB治疗的存活率为50%。25mg/kg的SCH（P < 0.001）、10mg/kg的SCH（P≤0.005）和AB（P < 0.05）在肺和肾培养中优于ITZ。SCH的最低抑菌浓度与器官定量培养结果之间以及AB的最低杀菌浓度与器官定量培养结果之间存在相关性。在该模型中，SCH似乎是一种高效的抗曲霉菌化合物。伊曲康唑和SCH之间似乎存在一定程度的交叉耐药性。
