Defining Moxifloxacin as a First-line TB Drug

描述(申请人提供)：背景：结核病(TB)是世界范围内死亡的主要原因。活动性结核病、潜伏性结核病感染(LTBI)和耐多药结核病(MDR-TB)的治疗方案冗长、繁琐，阻碍了控制结核病的努力。新的抗生素莫西沙星(MXF)在体外和实验性小鼠结核病模型中对结核分枝杆菌(包括MDR-TB)具有很强的活性，表明MXF在改善目前的结核病治疗方面具有巨大的潜力。 目标和方法：K08提案的目标有四个方面。目的I是利用模拟人类活动性结核病的小鼠模型来确定含有MXF的方案的潜力，以缩短治愈结核病所需的治疗时间或允许更多的间歇性给药。一线药物和MXF的组合将对小鼠进行不同的持续时间和剂量频率的治疗。结果将包括治疗后的CFU计数和复发率。将寻求在4个月内有效消毒小鼠肺的方案，或者每周一次或更多间歇给药有效。目标2是利用提高结核特异性免疫的策略改进LTBI的小鼠模型，并利用该模型开发含有MXF的新的LTBI治疗方案，包括LTBI合并MDR-TB。接种牛分枝杆菌卡介苗或其他疫苗的小鼠将感染低剂量的结核分枝杆菌。在对感染进行免疫控制后，将使用含有MXF和其他一线或试验性药物的每日和间歇方案进行治疗。测试方案将与LTBI的标准方案进行比较，以了解它们对小鼠肺部的消毒能力。目的3利用体外药效学(PD)系统测定一线抗结核药物和MXF的基本药效参数，这些参数与杀菌活性、抗生素后效应和耐药突变株的选择有关。活跃生长的结核分枝杆菌将接触到MXF和一线抗结核药物，使用一种可以模拟人体药代动力学或给予分次剂量的流动控制方法。结果将包括CFU计数的变化，药物暴露后重新生长的延迟，以及防止耐药突变株的选择。 相关性：这些研究的结果将有助于确定结核病的最佳治疗方案，可用于设计新的临床试验，或在某些情况下直接应用于临床实践。

DESCRIPTION (provided by applicant): Background: Tuberculosis (TB) is a leading cause of mortality worldwide. Efforts to control TB are hampered by the lengthy, cumbersome treatment regimens for active TB, latent TB infection (LTBI), and infection with multidrug-resistant TB (MDR-TB). The new antibiotic moxifloxacin (MXF) has potent activity against Mycobacterium tuberculosis (including MDR-TB) in vitro and in experimental murine models of TB, suggesting great potential to improve current therapy of TB. Objectives and Methods: The objectives of this K08 proposal are four-fold. Objective I is to use a murine model simulating active TB in humans to define the potential of MXF-containing regimens to shorten the duration of therapy needed to cure TB or to permit more intermittent drug administration. Mice will be treated for varying durations and dosing frequencies with combinations of first-line agents and MXF. Outcomes will include CFU counts and relapse rates after therapy. Regimens that effectively sterilize mouse lungs in < 4 months or are effective with once-weekly or more intermittent administration will be sought. Objective 2 is to improve upon a murine model of LTBI using strategies to increase TB-specific immunity and to employ it to develop new MXF-containing regimens for the treatment of LTBI, including LTBI with MDR-TB. Mice vaccinated with M. bovis BCG or another vaccine will be infected with a low dose of M. tuberculosis. After immune control of infection, treatment with daily and intermittent regimens containing MXF and other first-line or experimental agents will be given. Test regimens will be compared to standard regimens for LTBI for their ability to sterilize mouse lungs. Objective 3 is to utilize an in vitro pharmacodynamic (PD) system to determine basic PD parameters for first-line anti-TB agents and MXF that correlate with bactericidal activity, post-antibiotic effects and selection of drug-resistant mutants. Actively growing M. tuberculosis will be exposed to MXF and first-line anti-TB drugs using a flow-controlled methodology that can simulate human pharmacokinetics or give fractionated doses. Outcomes will include change in CFU counts, delay in re-growth after drug exposure and prevention of resistant mutant selection. Relevance: Results of these studies will help to define optimal treatment regimens for TB that can be used to design new clinical trials or, in some cases, directly applied to clinical practice.