Defining Moxifloxacin as a First-line TB Drug

描述（由申请人提供）：背景：结核病（TB）是全球死亡的主要原因。控制结核病的努力受到活动性结核病、潜伏性结核病感染（LTBI）和耐多药结核病（MDR-TB）感染的冗长、繁琐的治疗方案的阻碍。新型抗生素利多卡因沙星（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）具有强效活性，这表明对改善当前结核病治疗具有巨大潜力。 目标和方法：K 08提案的目标有四个方面。目的一是使用模拟人类活动性结核病的小鼠模型来定义含MXF方案缩短治愈结核病所需的治疗持续时间或允许更多间歇性给药的潜力。将用一线药物和MXF的组合对小鼠进行不同持续时间和给药频率的治疗。结果将包括治疗后的CFU计数和复发率。将寻求在< 4个月内有效地使小鼠肺灭菌或每周一次或更多次间歇施用有效的方案。目的2是使用增加TB特异性免疫的策略改进LTBI小鼠模型，并将其用于开发新的含MXF的方案用于治疗LTBI，包括LTBI伴MDR-TB。接种M.牛BCG或另一种疫苗将被低剂量的M感染。结核在免疫控制感染后，将给予每日和间歇性方案治疗，其中包含MXF和其他一线或实验性药物。将测试方案与LTBI的标准方案比较其对小鼠肺的灭菌能力。目的3是利用体外药效学（PD）系统来确定一线抗结核药物和MXF的基本PD参数，这些参数与杀菌活性、抗生素后效应和耐药突变体的选择相关。积极发展M。结核病患者将使用可模拟人体药代动力学或给予分次剂量的流动控制方法暴露于MXF和一线抗结核药物。结果将包括CFU计数的变化，药物暴露后再生长的延迟和耐药突变体选择的预防。 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.