高剂量利福平、吡嗪酰胺和莫西沙星在缩短结核病治疗疗程中的疗效与肝毒性：老战士仍有战斗力！
Efficacy Versus Hepatotoxicity of High-dose Rifampin, Pyrazinamide, and Moxifloxacin to Shorten Tuberculosis Therapy Duration: There Is Still Fight in the Old Warriors Yet!
机构信息
Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
出版信息
Clin Infect Dis. 2018 Nov 28;67(suppl_3):S359-S364. doi: 10.1093/cid/ciy627.
BACKGROUND
One approach that could increase the efficacy and reduce the duration of antituberculosis therapy is pharmacokinetics/pharmacodynamics-based optimization of doses. However, this could increase toxicity.
METHODS
We mimicked the concentration-time profiles achieved by human equivalent doses of moxifloxacin 800 mg/day, rifampin 1800 mg/day, and pyrazinamide 4000 mg/day (high-dose regimen) vs isoniazid 300 mg/day, rifampin 600 mg/day, and pyrazinamide 2000 mg/day (standard therapy) in bactericidal and sterilizing effect studies in the hollow fiber system model of tuberculosis (HFS-TB). In an intracellular Mycobacterium tuberculosis (Mtb) HFS-TB experiment, we added a 3-dimensional human organotypic liver to determine potential hepatotoxicity of the high-dose regimen, based on lactate dehydrogenase (LDH). Treatment lasted 28 days and Mtb bacterial burden was based on colony counts. We calculated the time to extinction (TTE) of the Mtb population in the HFS-TB and used morphism-based transformation and Latin hypercube sampling to identify the minimum therapy duration in patients.
RESULTS
The kill rate of standard therapy in the bactericidal effect and sterilizing effect experiments were 0.97 (95% confidence interval [CI], .91-.99) log10 colony-forming units (CFU)/mL/day, and 0.56 (95% CI, .49-.59) log10 CFU/mL/day, respectively. The high-dose regimen's bactericidal and sterilizing effect kill rates were 0.99 (95% CI, .96-.99) log10 CFU/mL/day and 0.72 (95% CI, .56-.79) log10 CFU/mL/day, respectively. The upper confidence bound for TTE in patients was 4.5-5 months for standard therapy vs 3.7 months on the high-dose regimen. There were no differences in LDH concentrations between the 2 regimens at any time point (P > .05).
CONCLUSIONS
The high-dose regimen may moderately shorten therapy without increased hepatotoxicity compared to standard therapy.
背景
一种可以提高疗效和缩短抗结核治疗时间的方法是基于药代动力学/药效学优化剂量。然而，这可能会增加毒性。
方法
我们模拟了人体等效剂量莫西沙星 800mg/天、利福平 1800mg/天和吡嗪酰胺 4000mg/天（高剂量方案）与异烟肼 300mg/天、利福平 600mg/天和吡嗪酰胺 2000mg/天（标准治疗）在中空纤维系统结核模型（HFS-TB）中的杀菌和杀菌效果研究中的浓度-时间曲线。在细胞内结核分枝杆菌（Mtb）HFS-TB 实验中，我们添加了一个 3 维人体器官样肝脏，以根据乳酸脱氢酶（LDH）确定高剂量方案的潜在肝毒性。治疗持续 28 天，根据菌落计数确定 Mtb 细菌负荷。我们计算了 HFS-TB 中 Mtb 种群的灭绝时间（TTE），并使用基于形态的变换和拉丁超立方抽样来确定患者的最短治疗时间。
结果
标准治疗在杀菌效果和杀菌效果实验中的杀菌率分别为 0.97（95%置信区间[CI]，0.91-0.99）log10 菌落形成单位（CFU）/mL/天和 0.56（95%CI，0.49-0.59）log10 CFU/mL/天。高剂量方案的杀菌和杀菌效果的杀菌率分别为 0.99（95%CI，0.96-0.99）log10 CFU/mL/天和 0.72（95%CI，0.56-0.79）log10 CFU/mL/天。标准治疗的患者 TTE 上限置信区间为 4.5-5 个月，高剂量方案为 3.7 个月。两种方案在任何时间点的 LDH 浓度均无差异（P>.05）。
结论
与标准治疗相比，高剂量方案可能会适度缩短治疗时间，而不会增加肝毒性。
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