Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA
Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, USA.
Antimicrob Agents Chemother. 2018 Jul 27;62(8). doi: 10.1128/AAC.00248-18. Print 2018 Aug.
pulmonary infection is a global problem. Standard combination therapy consists of isoniazid at 300 mg/day, rifampin at 600 mg/day, and ethambutol at 15 mg/kg of body weight/day for 18 months. Coincubation of with different clofazimine concentrations over 7 days in test tubes resulted in a maximal kill (maximum effect []) of 2.03 log CFU/ml below the day 0 bacterial burden. The concentration associated with was 110 times the MIC. Next, the effects of human-like concentration-time profiles of clofazimine human-equivalent doses ranging from 0 to 200 mg daily for 21 days were examined in the hollow-fiber model of intracellular (HFS-). On day 14, when the clofazimine microbial effect was maximal, the was 2.57 log CFU/ml, while the dose associated with was 100 mg/day. However, no dose killed to levels below the day 0 bacterial burden. Thus, the antimicrobial effect of clofazimine monotherapy in the HFS- was modest. Human-equivalent concentration-time profiles of standard combination therapy and doses were used as comparators in the HFS- On day 14, standard therapy killed to a level 2.32 log CFU/ml below the day 0 bacterial burden. The effect of standard therapy was consistent with a biexponential decline, with kill rate constants of 1.85 per day (half-life = 0.37 days) and 0.06 per day (half-life = 12.76 days) ( > 0.99). This means that standard therapy would take 9.3 to 12 months to completely eliminate in the model, which is consistent with clinical observations. This observation for standard therapy means that the modest to poor effect of clofazimine on identified here is likely to be the same in the clinic.
肺部感染是一个全球性问题。标准联合疗法包括每天 300 毫克异烟肼、600 毫克利福平、15 毫克/公斤体重乙胺丁醇，疗程 18 个月。在试管中，将与不同浓度氯法齐明共同孵育 7 天，结果显示细菌负荷量较第 0 天减少 2.03 对数 CFU/ml，达到最大杀伤（最大效应[效]）。氯法齐明的浓度与 MIC 相关，为 MIC 的 110 倍。接着，在中空纤维细胞内结核分枝杆菌模型（HFS-）中，检测了人类等效剂量为 0 至 200 毫克/天，为期 21 天的氯法齐明人体相似时-量曲线的效果。第 14 天，当氯法齐明的微生物效应达到最大时，结核分枝杆菌减少 2.57 对数 CFU/ml，而与 相关的剂量为 100 毫克/天。然而，没有剂量能将细菌负荷量降低到第 0 天以下。因此，氯法齐明单药治疗在 HFS-中的抗菌效果有限。标准联合治疗的人体等效时-量曲线和剂量被用作 HFS-的对照。第 14 天，标准治疗使细菌负荷量较第 0 天减少 2.32 对数 CFU/ml。标准治疗的效果与双指数下降一致，每日杀灭率常数为 1.85（半衰期=0.37 天）和 0.06（半衰期=12.76 天）（>0.99）。这意味着标准治疗需要 9.3 至 12 个月才能完全消除模型中的结核分枝杆菌，这与临床观察一致。对于标准治疗的这种观察结果意味着，在这里确定的氯法齐明对结核分枝杆菌的适度至较差的效果很可能在临床上也是如此。
