Activity of a Long-Acting Injectable Bedaquiline Formulation in a Paucibacillary Mouse Model of Latent Tuberculosis Infection
Activity of a Long-Acting Injectable Bedaquiline Formulation in a Paucibacillary Mouse Model of Latent Tuberculosis Infection
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DOI：
10.1128/aac.00007-19
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发表时间：
2019-04-01
影响因子：
4.9
通讯作者：
Andries, Koen
中科院分区：
文献类型：
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作者：
Kaushik, Amit;Ammerman, Nicole C.;Andries, Koen
贝达喹啉的强效抗结核活性和长半衰期使其成为用于治疗潜伏性结核感染（LTBI）的长效/缓释制剂的有吸引力的候选物。我们的目的是在经验证的少杆菌小鼠LTBI模型中评价长效注射（LAI）贝达喹啉制剂。用牛分枝杆菌rBCG 30免疫BALB/c小鼠，然后用M.结核病H37 Rv.在攻毒感染后13周开始治疗，采用以下方案之一：未经治疗的阴性对照方案;每日利福平阳性对照方案（10 mg/kg体重），每周一次利福喷丁（15毫克/公斤）和异烟肼（50 mg/kg）或每日贝达喹啉（25 mg/kg）; LAI贝达喹啉160 mg/剂每月一次、两次或三次给药的试验方案（BLAI-160）;以及每天2.67 mg/kg（B-2.67）、5.33 mg/kg（B-5.33）或8 mg/kg（B-8）的贝达喹啉的测试方案，以分别递送与一个、两个或三个剂量的BLAI-160相同总量的贝达喹啉。除BLAI-160（肌内注射）外，所有药物均经口给药。主要结果是M.在12周治疗期间，肺结核CFU计数。阴性和阳性对照方案的表现符合预期。到第12周，1、2和3剂BLAI-160分别导致2.9、3.2和3.5 log（10）CFU/肺降低。每日口服B-2.67、B-5.33和B-8分别使肺CFU计数降低1.6、2.8和4.1 log（10）。一个剂量的BLAI-160表现出至少12周的活性。BLAI-160的持续活性表明，它显示出作为短期LTBI治疗的前景，需要很少的患者接触以确保治疗完成。
The potent antituberculosis activity and long half-life of bedaquiline make it an attractive candidate for use in long-acting/extended-release formulations for the treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with Mycobacterium bovis rBCG30, BALB/c mice were challenged by aerosol infection with M. tuberculosis H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: an untreated negative-control regimen; positive-control regimens of daily rifampin (10 mg/kg of body weight), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI bedaquiline at 160 mg/dose (BLAI-160); and test regimens of daily bedaquiline at 2.67 mg/kg (B-2.67), 5.33 mg/kg (B-5.33), or 8 mg/kg (B-8) to deliver the same total amount of bedaquiline as one, two, or three doses of BLAI-160, respectively. All drugs were administered orally, except for BLAI-160 (intramuscular injection). The primary outcome was the decline in M. tuberculosis lung CFU counts during 12 weeks of treatment. The negative-and positive-control regimens performed as expected. One, two, and three doses of BLAI-160 resulted in decreases of 2.9, 3.2, and 3.5 log(10) CFU/lung, respectively, by week 12. Daily oral dosing with B-2.67, B-5.33, and B-8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log(10), respectively. One dose of BLAI-160 exhibited activity for at least 12 weeks. The sustained activity of BLAI-160 indicates that it shows promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.