Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis
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DOI：
10.1128/aac.00451-06
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发表时间：
2006-08-01
影响因子：
4.9
通讯作者：
Grosset, Jacques H.
中科院分区：
文献类型：
--
作者：
Nuermberger, Eric;Rosenthal, Ian;Grosset, Jacques H.
创建新的化疗方案，允许缩短治疗时间是抗结核药物开发的一个主要优先事项。在本研究中，我们使用实验性结核病治疗的小鼠模型来确定将研究性新硝基咪唑并吡喃PA-824并入标准一线方案中是否有可能缩短6个月的治疗持续时间。如前所述，PA-824单独给药在治疗的前2个月内具有显著的杀菌活性。此外，与利福平、异烟肼和吡嗪酰胺的标准方案相比，PA-824替代异烟肼导致治疗2个月后肺CFU计数显著降低，培养物阴性转化更快。尽管如此，完成6个月治疗后复发的小鼠比例没有差异（用PA-824代替异烟肼治疗的19只小鼠中有2只复发，用标准方案治疗的46只小鼠中有0只复发）。同时，在任何评估中，没有其他含PA-824的试验方案上级标准方案。因此，我们无法确定PA-824在包括两种或多种当前一线药物的缩短治疗方案中的明确作用。未来的临床前研究应包括评估PA-824与新候选药物以及现有抗结核药物的新型组合，以评估其实质性改善药物敏感性和耐多药结核病治疗的潜力。
The creation of new chemotherapeutic regimens that permit shortening the duration of treatment is a major priority for antituberculosis drug development. In this study, we used the murine model of experimental tuberculosis therapy to determine whether incorporation of the investigational new nitroimidazopyran PA-824 into the standard first-line regimen has the potential to shorten the 6-month duration of treatment. As demonstrated previously, PA-824 alone had significant bactericidal activity over the first 2 months of treatment. Moreover, the substitution of PA-824 for isoniazid led to significantly lower lung CFU counts after 2 months of treatment and to more rapid culture-negative conversion compared to the standard regimen of rifampin, isoniazid, and pyrazinamide. Despite this, there was no difference in the proportion of mice relapsing after completing 6 months of therapy (2 of 19 mice treated with PA-824 in place of isoniazid relapsed versus 0 of 46 mice treated with the standard regimen). Meanwhile, no other PA-824-containing regimen tested was superior to the standard regimen on any assessment. Thus, we were unable to establish a clear role for PA-824 in a treatment-shortening regimen that includes two or more of the current first-line drugs. Future preclinical studies should include the evaluation of novel combinations of PA-824 with new drug candidates in addition to existing antituberculosis drugs for their potential to substantially improve the treatment of both drug-susceptible and multidrug-resistant tuberculosis.