Efficacy Versus Hepatotoxicity of High-dose Rifampin, Pyrazinamide, and Moxifloxacin to Shorten Tuberculosis Therapy Duration: There Is Still Fight in the Old Warriors Yet!
Efficacy Versus Hepatotoxicity of High-dose Rifampin, Pyrazinamide, and Moxifloxacin to Shorten Tuberculosis Therapy Duration: There Is Still Fight in the Old Warriors Yet!
复制标题
大剂量利福平、吡嗪酰胺和莫西沙星缩短结核病治疗时间的功效与肝毒性：老战士们仍在战斗！
DOI：
10.1093/cid/ciy627
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Gumbo,Tawanda
中科院分区：
文献类型：
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作者：
Srivastava,Shashikant;Deshpande,Devyani;Magombedze,Gesham;Gumbo,Tawanda
背景一种可以提高疗效并缩短抗结核治疗持续时间的方法是基于药代动力学/药效动力学的剂量优化。然而，这可能会增加毒性。方法我们模拟了人体等效剂量的莫西沙星 800 毫克/天、利福平 1800 毫克/天和吡嗪酰胺 4000 毫克/天（高剂量方案）与异烟肼 300 毫克/天、利福平 600 毫克/天和吡嗪酰胺 2000 毫克/天（标准疗法）在杀菌中达到的浓度-时间曲线。结核病中空纤维系统模型（HFS-TB）的灭菌效果研究。在细胞内结核分枝杆菌 (Mtb) HFS-TB 实验中，我们添加了 3 维人体器官型肝脏，以确定基于乳酸脱氢酶 (LDH) 的高剂量方案的潜在肝毒性。治疗持续 28 天，结核菌负荷基于菌落计数。我们计算了HFS-TB中Mtb群体的灭绝时间（TTE），并使用基于态射的变换和拉丁超立方抽样来确定患者的最短治疗持续时间。结果标准治疗在杀菌效果和灭菌效果实验中的杀灭率为0.97（95％置信区间[CI]，.91-.99）log10菌落形成单位（CFU）/mL/天，并且分别为 0.56 (95% CI, .49–.59) log10CFU/mL/天。高剂量方案的杀菌和灭菌效果杀灭率分别为 0.99 (95% CI, .96–.99) log10CFU/mL/天和 0.72 (95% CI, .56–.79) log10CFU/mL/天。标准治疗患者 TTE 的置信上限为 4.5-5 个月，而高剂量治疗方案为 3.7 个月。任何时间点两种方案之间的LDH浓度均无差异(P>0.05)。结论与标准治疗相比，高剂量方案可适度缩短治疗时间而不增加肝毒性。
BackgroundOne 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.MethodsWe 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 intracellularMycobacterium 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 andMtbbacterial burden was based on colony counts. We calculated the time to extinction (TTE) of theMtbpopulation in the HFS-TB and used morphism-based transformation and Latin hypercube sampling to identify the minimum therapy duration in patients.ResultsThe kill rate of standard therapy in the bactericidal effect and sterilizing effect experiments were 0.97 (95% confidence interval [CI], .91–.99) log10colony-forming units (CFU)/mL/day, and 0.56 (95% CI, .49–.59) log10CFU/mL/day, respectively. The high-dose regimen’s bactericidal and sterilizing effect kill rates were 0.99 (95% CI, .96–.99) log10CFU/mL/day and 0.72 (95% CI, .56–.79) log10CFU/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).ConclusionsThe high-dose regimen may moderately shorten therapy without increased hepatotoxicity compared to standard therapy.