Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
Lung Infection and Immunity Unit, Department of Medicine, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Observatory, South Africa.
J Antimicrob Chemother. 2019 Jun 1;74(6):1607-1617. doi: 10.1093/jac/dkz061.
MDR-TB and XDR-TB have poor outcomes.
To examine the efficacy of tigecycline monotherapy in the hollow fibre system model of TB.
We performed pharmacokinetic/pharmacodynamic studies using tigecycline human-like concentration-time profiles in the hollow fibre system model of TB in five separate experiments using Mycobacterium tuberculosis in log-phase growth or as semi-dormant or intracellular bacilli, as monotherapy. We also compared efficacy with the isoniazid/rifampicin/pyrazinamide combination (standard therapy). We then applied extinction mathematics, morphisms and Latin hypercube sampling to identify duration of therapy with tigecycline monotherapy.
The median tigecycline MIC for 30 M. tuberculosis clinical and laboratory isolates (67% MDR/XDR) was 2 mg/L. Tigecycline monotherapy was highly effective in killing M. tuberculosis in log-phase-growth and semi-dormant and intracellular M. tuberculosis. Once-a-week dosing had the same efficacy as daily therapy for the same cumulative dose; thus, tigecycline efficacy was linked to the AUC0-24/MIC ratio. Tigecycline replacement by daily minocycline after 4 weeks of therapy was effective in sterilizing bacilli. The AUC0-24/MIC ratio associated with optimal kill was 42.3. Tigecycline monotherapy had a maximum sterilizing effect (day 0 minus day 28) of 3.06 ± 0.20 log10 cfu/mL (r2 = 0.92) compared with 3.92 ± 0.45 log10 cfu/mL (r2 = 0.80) with optimized standard therapy. In our modelling, at a tigecycline monotherapy duration of 12 months, the proportion of patients with XDR-TB who reached bacterial population extinction was 64.51%.
Tigecycline could cure patients with XDR-TB or MDR-TB who have failed recommended therapy. Once-a-week tigecycline could also replace second-line injectables in MDR-TB regimens.
耐多药结核病（MDR-TB）和广泛耐药结核病（XDR-TB）的治疗效果较差。
在分枝杆菌中空纤维系统模型中研究替加环素单药治疗的疗效。
我们在分枝杆菌中空纤维系统模型中进行了 5 项独立实验，使用类似于人体的替加环素浓度-时间曲线，对对数生长期或处于半休眠或细胞内状态的结核分枝杆菌进行替加环素单药治疗的药代动力学/药效学研究。我们还将其疗效与异烟肼/利福平/吡嗪酰胺联合治疗（标准治疗）进行了比较。然后，我们应用消光数学、态射和拉丁超立方抽样来确定替加环素单药治疗的疗程。
30 株结核分枝杆菌临床和实验室分离株（67% MDR/XDR）的替加环素中位 MIC 为 2mg/L。替加环素单药治疗对数生长期生长、半休眠和细胞内结核分枝杆菌非常有效。每周一次给药与每日治疗相同累积剂量的疗效相同；因此，替加环素的疗效与 AUC0-24/MIC 比值相关。治疗 4 周后，替加环素每日用米诺环素替代治疗可有效杀菌。与最佳杀菌效果相关的 AUC0-24/MIC 比值为 42.3。替加环素单药治疗的最大杀菌效果（第 0 天减去第 28 天）为 3.06 ± 0.20log10cfu/mL（r2 = 0.92），而优化后的标准治疗为 3.92 ± 0.45log10cfu/mL（r2 = 0.80）。在我们的模型中，替加环素单药治疗 12 个月后，XDR-TB 患者达到细菌群体灭绝的比例为 64.51%。
替加环素可治愈接受推荐治疗后失败的 XDR-TB 或 MDR-TB 患者。每周一次替加环素也可替代 MDR-TB 方案中的二线注射剂。
