Combination Therapy Modeling for M tuberculosis Resistance Suppression and Kill

描述（由申请人提供）：结核分枝杆菌（Mtb）感染全球超过20亿人，每年造成140万人死亡。药敏结核所致结核病的标准治疗包括2个月的利福平（RIF）、异烟肼（INH）、吡嗪酰胺（PZA）和乙胺丁醇（EMB），随后4个月的RIF和INH。在临床结核患者中，结核分枝杆菌以3种代谢状态存在：对数生长期、半休眠酸性期和非复制持久性（NRP）状态。NRP Mtb需要长期治疗才能杀死，并导致疾病复发。RIF、INH和EMB杀灭对数相生长Mtb，而PZA杀灭酸性相Mtb。RIF也杀死NRP Mtb。因此，标准方案中只有一种药物对酸性期和NRP Mtb有效。耐多药结核（MDR-TB）的流行率正在上升，原因是使用经验性抗生素组合治疗由预先方案中对一种或多种药物具有耐药性的微生物引起的结核病，即使在直接观察疗法下也存在给药错误，以及患者不遵守长期疗程。在药物敏感结核和耐多药结核的标准治疗方案中加入具有新机制的新抗生素的研究中，动物模型的细菌灭菌时间和临床试验的痰转阴时间缩短，表明由标准一线和二线结核药物组成的方案并不能优化杀死结核分枝杆菌。我们的长期目标是开发改进的结核病治疗方案。总体假设是，药效学（PD）优化的结核病治疗方案可以杀死所有三种代谢状态下的结核分枝杆菌，并防止不太敏感的细菌亚群扩增，这将提供一种有效的短期结核病治疗方案，从而改善治疗结果并减少耐药性。我们将通过完成以下具体目标来检验这一假设并制定一个高效的短期方案：在体外中空纤维感染模型（HFIM）中模拟具有所有代谢状态活性的3种新型结核抗生素临床相关剂量的游离肺PK谱，确定每种药物的p指数、药物暴露和剂量间隔，pd优化了3种代谢状态下DS-Mtb的杀伤速度和程度。确定这些单药方案是否可以预防耐药性。具体目标2。通过HFIM，比较在3种代谢状态下DS-Mtb的杀伤率和程度，以及这些抗生素在将Specific Aim #1中开发的pd优化方案作为2和3种药物组合使用时对较不敏感的Mtb人群的影响。采用创新的数学模型，确定3种药物方案中每种抗生素的剂量和给药频率，该方案通过优化在每种代谢状态下杀死结核分枝杆菌和预防耐药性，预计将为治疗人类结核病提供更短的疗程和高效的方案。具体目标#3。利用HFIM，表征pd优化的3种药物方案对对1种药物成分耐药的菌株在3种代谢状态下的Mtb杀灭率和程度的功效。

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) infects over 2 billion people worldwide and causes 1.4 million deaths annually. The standard treatment for tuberculosis (TB) due to drug-susceptible Mtb consists of 2 months of rifampin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB) followed by 4 months of RIF and INH. In patients with clinical TB, Mtb exists in 3 metabolic states: log phase growth, semi-dormant acidic phase, and a non-replicating persister (NRP) state. NRP Mtb requires prolonged therapy to kill and is responsible for disease relapse. RIF, INH and EMB kill log phase growth Mtb, while PZA kills acidic phase Mtb. RIF also kills NRP Mtb. Thus, only one drug in the standard regimen is active against acidic phase and NRP Mtb. The prevalence of multidrug resistant Mtb (MDR-TB) is rising due to the use of empiric antibiotic combinations for TB caused by microbes that are resistant to one or more drugs in the regimen a priori, errors in the administration of the medications even under Direct Observed Therapy, and patient non-compliance with the long treatment course. In studies in which new antibiotics with novel mechanisms of action are added to the standard regimen for drug-susceptible Mtb and MDR-TB the time to bacterial sterilization in animal models and the time for sputum conversion to negative in clinical trials are shortened, showing that regimens consisting of the standard first and second line TB drugs are not optimized to kill Mtb. Our long term objective is to develop improved TB regimens. The overarching hypothesis is that TB regimens that are pharmacodynamically (PD) optimized to kill Mtb in all 3 metabolic states and to prevent amplification of less-susceptible bacterial subpopulations will provide a potent shorter course TB regimen that will improve treatment outcomes and reduce resistance. We will test this hypothesis and develop a highly effective short course regimen by completing the following Specific Aims: Specific Aim #1. Simulating in an in vitro hollow fiber infection model (HFIM) the free pulmonary PK profiles for clinically relevant doses of 3 novel TB antibiotics that have activity in all metabolic states, identify the P-indices, drug exposures, and dosing intervals of each drug that PD-optimizes the rapidity and extent of killing of DS-Mtb in each of the 3 metabolic states. Determine if these single drug regimens can prevent resistance. Specific Aim #2. With the HFIM, compare the rates and extents of killing of DS-Mtb in the 3 metabolic states and the effect of these antibiotics on the less susceptible Mtb population when the PD-optimized regimens developed in Specific Aim #1 are used as 2 and 3 drug combinations. Employ innovative mathematical models to identify the dose and frequency of administration of each antibiotic in a 3 drug regimen that is predicted to provide a shorter course, highly effective regimen for the treatment of human TB by optimizing the killing of Mtb in each metabolic state and by preventing resistance. Specific Aim #3. Using the HFIM, characterize the efficacy of the PD-optimized 3 drug regimen on the rate and extent of killing of Mtb in 3 metabolic states for strains that are resistant to 1 of the drug components. Specific Aim #4. Prospectively validate the performance of the innovative PD-optimized 3 drug regimen in a novel murine model of pulmonary TB in which Mtb in log phase, acidic phase, and NRP state co-exist and in another innovative in vivo model of TB using state-of-the-art dosing algorithms that "humanize" the PK profiles generated in the animals. Use the novel murine model to characterize the relative efficacy of this regimen for the killing of DS- and MDR-TB.