Cavanaugh Joseph S, Jou Ruwen, Wu Mei-Hua, Dalton Tracy, Kurbatova Ekaterina, Ershova Julia, Cegielski J Peter
United States Centers for Disease Control and Prevention, Atlanta, GA, USA.
Taiwan Centers for Disease Control, Taipei, Taiwan, Republic of China.
J Antimicrob Chemother. 2017 Jun 1;72(6):1678-1687. doi: 10.1093/jac/dkx022.
The second-line drugs recommended to treat drug-resistant TB are toxic, expensive and difficult to procure. Given increasing resistance, the need for additional anti-TB drugs has become more urgent. But new drugs take time to develop and are expensive. Some commercially available drugs have reported anti-mycobacterial activity but are not routinely used because supporting laboratory and clinical evidence is sparse.
We analysed 217 MDR M. tuberculosis isolates including 153 initial isolates from unique patients and 64 isolates from follow-up specimens during the course of treatment. The resazurin microdilution assay was performed to determine MICs of trimethoprim/sulfamethoxazole, mefloquine, thioridazine, clofazimine, amoxicillin/clavulanate, meropenem/clavulanate, nitazoxanide, linezolid and oxyphenbutazone. Isoniazid was used for validation. We calculated the MIC 50 and MIC 90 as the MICs at which growth of 50% and 90% of isolates was inhibited, respectively.
The MIC 50 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.2/4; mefloquine, 8; thioridazine, 4; clofazimine, 0.25; amoxicillin/clavulanate, 16/8; meropenem/clavulanate, 1/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 40. The MIC 90 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.4/8; mefloquine, 8; thioridazine, 8; clofazimine, 0.5; amoxicillin/clavulanate, 32/16; meropenem/clavulanate, 8/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 60. By comparison, the MIC 90 of isoniazid was >4 mg/L, as expected. There was no evidence that previous treatment affected susceptibility to any drug.
Most drugs demonstrated efficacy against M. tuberculosis . When these MICs are compared with the published pharmacokinetic/pharmacodynamic profiles of the respective drugs in humans, trimethoprim/sulfamethoxazole, meropenem/clavulanate, linezolid, clofazimine and nitazoxanide appear promising and warrant further clinical investigation.
推荐用于治疗耐药结核病的二线药物有毒、昂贵且难以获取。鉴于耐药性不断增加，对更多抗结核药物的需求变得更加迫切。但新药研发耗时且成本高昂。一些市售药物已报道具有抗分枝杆菌活性，但由于支持性的实验室和临床证据稀少，未被常规使用。
我们分析了217株耐多药结核分枝杆菌分离株，其中包括来自独特患者的153株初始分离株以及治疗过程中随访标本的64株分离株。采用刃天青微量稀释法测定甲氧苄啶/磺胺甲恶唑、甲氟喹、硫利达嗪、氯法齐明、阿莫西林/克拉维酸、美罗培南/克拉维酸、硝唑尼特、利奈唑胺和羟苯丁酮的最低抑菌浓度（MIC）。使用异烟肼进行验证。我们计算MIC50和MIC90，分别为抑制50%和90%分离株生长的MIC。
初始分离株的MIC50（mg/L）如下：甲氧苄啶/磺胺甲恶唑，0.2/4；甲氟喹，8；硫利达嗪，4；氯法齐明，0.25；阿莫西林/克拉维酸，16/8；美罗培南/克拉维酸，1/2.5；硝唑尼特，16；利奈唑胺，0.25；羟苯丁酮，40。初始分离株的MIC90（mg/L）如下：甲氧苄啶/磺胺甲恶唑，0.4/8；甲氟喹，8；硫利达嗪，8；氯法齐明，0.5；阿莫西林/克拉维酸，32/16；美罗培南/克拉维酸，8/2.5；硝唑尼特，16；利奈唑胺，0.25；羟苯丁酮，60。相比之下，异烟肼的MIC90如预期的那样>4mg/L。没有证据表明先前的治疗会影响对任何药物的敏感性。
大多数药物对结核分枝杆菌显示出疗效。当将这些MIC与已发表的各药物在人体中的药代动力学/药效学特征进行比较时，甲氧苄啶/磺胺甲恶唑、美罗培南/克拉维酸、利奈唑胺、氯法齐明和硝唑尼特似乎很有前景，值得进一步进行临床研究。
