High-dose rifampicin kills persisters, shortens treatment duration, and reduces relapse rate in vitro and in vivo.
High-dose rifampicin kills persisters, shortens treatment duration, and reduces relapse rate in vitro and in vivo.
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DOI：
10.3389/fmicb.2015.00641
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发表时间：
2015
影响因子：
5.2
通讯作者：
Coates A
中科院分区：
文献类型：
--
作者：
Hu Y;Liu A;Ortega-Muro F;Alameda-Martin L;Mitchison D;Coates A
尽管大剂量利福平有望通过缩短治疗时间来改善结核病控制，但这些归因于根除持久性细菌的效果尚不清楚。采用复苏促进因子（RPFs）检测体外缺氧和体内小鼠结核病模型在增加剂量利福平治疗前后是否存在持续性结核分枝杆菌。测定利福平在小鼠体内的药动学参数和剂量依赖性。采用康奈尔小鼠模型，检测大剂量利福平联合异烟肼、吡嗪酰胺的疗效及复发率。体外和体内均存在大量rpf依赖性持续物。固定相培养物对利福平耐受，而高浓度利福平可以根除平板计数阳性但不依赖rpf的持久性细菌。在小鼠感染模型中，增加剂量的利福平对rpf依赖性持续存在者的根除表现出剂量依赖性。增加利福平剂量可显著降低出现抗生素耐药性的风险。在Cornell模型中，给予大剂量利福平治疗的小鼠内脏清除率更快；与标准剂量利福平方案14周相比，治疗后8周器官无结核分枝杆菌。器官不育，板计数和rpf依赖性持续性阴性。与标准剂量方案相比，无疾病复发（87.5%）。大剂量利福平治疗可根除rpf依赖性持续者，缩短治疗时间而无疾病复发。优化利福平，使其在副作用可接受的情况下发挥最大功效，将为人体研究提供有价值的信息，并有可能改善目前的结核病化疗。
Although high-dose rifampicin holds promise for improving tuberculosis control by potentially shortening treatment duration, these effects attributed to eradication of persistent bacteria are unclear. The presence of persistent Mycobacterium tuberculosis was examined using resuscitation promoting factors (RPFs) in both in vitro hypoxia and in vivo murine tuberculosis models before and after treatment with incremental doses of rifampicin. Pharmacokinetic parameters and dose-dependent profile of rifampicin in the murine model were determined. The Cornell mouse model was used to test efficacy of high-dose rifampicin in combination with isoniazid and pyrazinamide and to measure relapse rate. There were large numbers of RPF-dependent persisters in vitro and in vivo. Stationary phase cultures were tolerant to rifampicin while higher concentrations of rifampicin eradicated plate count positive but not RPF-dependent persistent bacteria. In murine infection model, incremental doses of rifampicin exhibited a dose-dependent eradication of RPF-dependent persisters. Increasing the dose of rifampicin significantly reduced the risk of antibiotic resistance emergence. In Cornell model, mice treated with high-dose rifampicin regimen resulted in faster visceral clearance; organs were M. tuberculosis free 8 weeks post-treatment compared to 14 weeks with standard-dose rifampicin regimen. Organ sterility, plate count and RPF-dependent persister negative, was achieved. There was no disease relapse compared to the standard dose regimen (87.5%). High-dose rifampicin therapy results in eradication of RPF-dependent persisters, allowing shorter treatment duration without disease relapse. Optimizing rifampicin to its maximal efficacy with acceptable side-effect profiles will provide valuable information in human studies and can potentially improve current tuberculosis chemotherapy.