Yoshimatsu Tetsuyuki, Nuermberger Eric, Tyagi Sandeep, Chaisson Richard, Bishai William, Grosset Jacques
Division of Infectious Diseases, Department of Medicine, Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231-1001, USA.
Antimicrob Agents Chemother. 2002 Jun;46(6):1875-9. doi: 10.1128/AAC.46.6.1875-1879.2002.
Moxifloxacin (MXF) is a new 8-methoxyquinolone with potent activity against Mycobacterium tuberculosis and a half-life of 9 to 12 h in humans. Previous in vivo studies using daily doses of 100 mg/kg of body weight have demonstrated bactericidal activity comparable to that of isoniazid (INH) in a murine model of tuberculosis (TB). Recent pharmacokinetic data suggest that MXF may have been underadministered in these studies and that a 400-mg/kg dose in mice better approximates the area under the concentration-time curve obtained in humans after a 400-mg oral dose. Therefore, the bactericidal activity of MXF in doses up to 400 mg/kg given daily or weekly for 28 days was assessed in mice infected intravenously with 5 x 10(6) CFU of M. tuberculosis. INH was used as a positive control. After 3 days of daily therapy, the CFU counts from splenic homogenates for mice treated with MXF in doses of 100 to 400 mg/kg/day were lower than those from pretreatment controls. No significant differences in CFU counts were seen when mice receiving INH or MXF at 50 mg/kg/day were compared to pretreatment controls. After 28 days of therapy, dose-dependent reductions in CFU counts in splenic homogenates were seen for daily MXF therapy. The maximum bactericidal effect was seen with daily doses of 400 mg/kg, which resulted in a reduction in CFU counts of 1 log(10) greater than that with INH treatment, although the difference was not statistically significant. CFU counts from lung homogenates after 28 days of therapy were significantly lower in all treatment groups than in untreated controls. The weekly administration of MXF in doses ranging from 50 to 400 mg/kg resulted in no significant bactericidal activity. Mice receiving daily MXF doses of 200 and 400 mg/kg/day failed to gain weight and appeared ill after 28 days of therapy, findings suggestive of drug toxicity. In conclusion, MXF has dose-dependent bactericidal activity against M. tuberculosis in the mouse when given in doses up to 400 mg/kg, where its pharmacokinetic profile better approximates that of standard human dosages. Combination regimens which take advantage of the enhanced pharmacodynamic profile of MXF at these doses have the potential to shorten the course of antituberculous therapy or allow more intermittent (i.e., once-weekly) therapy and should be evaluated in the mouse model of TB.
莫西沙星（MXF）是一种新型8 - 甲氧基喹诺酮类药物，对结核分枝杆菌具有强大活性，在人体内半衰期为9至12小时。以往使用每日100mg/kg体重剂量的体内研究表明，在小鼠结核病模型中，其杀菌活性与异烟肼（INH）相当。近期的药代动力学数据表明，在这些研究中莫西沙星的给药剂量可能不足，在小鼠中400mg/kg的剂量能更好地模拟人类口服400mg后浓度 - 时间曲线下的面积。因此，在静脉注射感染5×10⁶CFU结核分枝杆菌的小鼠中，评估了每日或每周给予高达400mg/kg剂量的莫西沙星连续28天的杀菌活性。异烟肼用作阳性对照。每日治疗3天后，给予100至400mg/kg/天莫西沙星治疗的小鼠脾匀浆中的CFU计数低于治疗前对照组。将接受50mg/kg/天异烟肼或莫西沙星治疗的小鼠与治疗前对照组比较时，CFU计数未见显著差异。治疗28天后，每日莫西沙星治疗的小鼠脾匀浆中CFU计数呈剂量依赖性降低。每日400mg/kg剂量时杀菌效果最佳，导致CFU计数降低比异烟肼治疗多1个对数（10），尽管差异无统计学意义。治疗28天后，所有治疗组肺匀浆中的CFU计数均显著低于未治疗对照组。每周给予50至400mg/kg剂量的莫西沙星未产生显著杀菌活性。接受每日200和400mg/kg/天莫西沙星治疗的小鼠在治疗28天后体重未增加且出现病态，提示药物毒性。总之，当给予高达400mg/kg剂量时，莫西沙星在小鼠中对结核分枝杆菌具有剂量依赖性杀菌活性，此时其药代动力学特征更接近标准人类剂量。利用这些剂量下莫西沙星增强的药效学特征的联合治疗方案有可能缩短抗结核治疗疗程或允许更间歇（即每周一次）的治疗，应在小鼠结核病模型中进行评估。
