Once-a-week tigecycline for the treatment of drug-resistant TB
Once-a-week tigecycline for the treatment of drug-resistant TB
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DOI：
10.1093/jac/dkz061
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发表时间：
2019-06-01
影响因子：
5.2
通讯作者：
Gumbo, Tawanda
中科院分区：
文献类型：
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作者：
Deshpande, Devyani;Magombedze, Gesham;Gumbo, Tawanda
背景：耐多药结核病和广泛耐药结核病预后较差。目的：观察替加环素单药治疗结核中空纤维系统模型的疗效。方法：我们利用替加环素在结核中空纤维系统模型中的类人浓度-时间谱进行了药代动力学/药效学研究，在5个单独的实验中，使用处于对数期生长或半休眠或细胞内杆菌作为单药治疗的结核分枝杆菌。我们还比较了异烟肼/利福平/吡嗪酰胺联合治疗（标准治疗）的疗效。然后，我们应用消光数学、态射和拉丁超立方体抽样来确定替加环素单药治疗的持续时间。结果：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MIC中位数为2 mg/L。替加环素单药治疗对慢性生长、半休眠和细胞内结核分枝杆菌均有较好的杀伤效果。在相同的累积剂量下，每周一次的剂量与每日治疗的效果相同；因此，替加环素的疗效与AUC(0-24)/MIC比值有关。替加环素在治疗4周后改为每日二甲胺四环素对杆菌的灭菌有效。与最佳杀伤相关的AUC(0-24)/MIC比值为42.3。替加环素单药治疗的最大杀菌效果（第0天-第28天）为3.06 +/- 0.20 log(10) cfu/mL (r(2)=0.92)，而优化标准治疗的最大杀菌效果为3.92+0.45 log(10) cfu/mL （r(2)=0.80）。在我们的模型中，在替加环素单药治疗持续12个月的情况下，达到细菌种群灭绝的XDR-TB患者比例为64.51%。结论：替加环素可以治愈推荐治疗无效的XDR-TB或MDR-TB患者。在耐多药结核病治疗方案中，每周一次的替加环素也可以取代二线注射剂。
Background: MDR-TB and XDR-TB have poor outcomes.Objectives: To examine the efficacy of tigecycline monotherapy in the hollow fibre system model of TB.Methods: 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 Mycobacteriumtuberculosis 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.Results: 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 AUC(0-24)/MIC ratio. Tigecycline replacement by daily minocycline after 4 weeks of therapy was effective in sterilizing bacilli. The AUC(0-24)/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 log(10) cfu/mL (r(2)=0.92) compared with 3.92+0.45 log(10) cfu/mL (r(2)=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%.Conclusions: 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.