Activity of ketoconazole against Mycobacterium tuberculosis in vitro and in the mouse model
Activity of ketoconazole against Mycobacterium tuberculosis in vitro and in the mouse model
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DOI：
10.1099/jmm.0.47058-0
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发表时间：
2007-08-01
影响因子：
3
通讯作者：
Zhang, Ying
中科院分区：
文献类型：
--
作者：
Byrne, Sean T.;Denkin, Steven M.;Zhang, Ying
迫切需要开发能够有效对抗耐药结核分枝杆菌菌株并能缩短结核病 (TB) 治疗时间的新药。此前已有报道，唑类抗真菌药在体外具有抗结核活性。本研究评估了酮康唑 (KTC) 的抗结核分枝杆菌活性。 KTC在酸性和中性条件下对不同结核分枝杆菌菌株的MIC范围为8～16μg ml(-1)，最低杀菌浓度比MIC高约2倍。当与吡嗪酰胺 (PZA) 和利福平 (RIF) 联合使用时，KTC 在体外增强了对抗老的、不生长的杆菌的活性。单次口服75 mg kg(-1)剂量的KTC在给药后导致抑制血清浓度为2 In。在已建立的肺结核小鼠模型中评估了 KTC 的体内活性，并单独比较以及与异烟肼 (INH)、PZA 和 RIF 联合使用。短期治疗后，单独使用 KTC 效果甚微，对脾菌落计数具有临界抑菌作用，但对肺计数无抑制作用。 KTC 与 INH、PZA 和 RIF 联合添加时，显着改善了肺部的治疗结果（与 INH、PZA 和 RIF 治疗相比）。用 KTC、PZA 和 RIF 治疗的小鼠肺部杆菌数量最低。需要进一步研究以确定 KTC 在结核病治疗中的作用。
There is an urgent need for the development of new drugs that are active against drug-resistant Mycobacterium tuberculosis strains and can shorten tuberculosis (TB) therapy. It has previously been reported that the azole class of antifungals has anti-TB activity in vitro. This study evaluated ketoconazole (KTC) for activity against M. tuberculosis. The MIC of KTC for different M. tuberculosis strains ranged from 8 to 16 mu g ml(-1) under both acidic and neutral conditions, with the minimum bactericidal concentration being about twofold higher than the MIC. KTC had enhanced activity against old, non-growing bacilli in vitro when combined with pyrazinamide (PZA) and rifampicin (RIF). A single oral dose of KTC at 75 mg kg(-1) led to an inhibitory serum concentration 2 In after administration. The in vivo activity of KTC was evaluated in established pulmonary TB in the murine model, compared alone and in combination with isoniazid (INH), PZA and RIF. KTC alone exhibited little effect after short-term treatment, with a borderline bacteriostatic effect on spleen colony counts but not on lung counts. KTC, when added in combination with INH, PZA and RIF, significantly improved the treatment outcome in the lungs (compared with treatment with INH, PZA and RIF). The lowest numbers of bacilli in lungs were found in mice treated with KTC, PZA and RIF. Further investigation is necessary to determine the role of KTC in the treatment of TB.