Combination Therapy Modeling for M tuberculosis Resistance Suppression and Kill

结核分枝杆菌耐药性抑制和杀灭的联合治疗建模

• 批准号: 8878433
• 负责人: George Louis Drusano
• 金额: $ 107.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878433
• 关键词: Algorithms; Animal Model; Animals; Antibiotics; Bacteria; Cessation of life; Clinical; Clinical Trials; Combined Antibiotics; Combined Modality Therapy; Disease; Dose; Drug Combinations; Drug Exposure; Drug Prescriptions; Drug resistance in tuberculosis; Drug usage; Employee Strikes; Ethambutol; Exhibits; Extreme drug resistant tuberculosis; FDA approved; Fiber; Fluoroquinolones; Frequencies; Goals; Growth; Human; Human body; In Vitro; Infection; Injectable; Lung; Metabolic; Microbe; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Patient Noncompliance; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Population; Prevalence; Pulmonary Tuberculosis; Pyrazinamide; Recurrent disease; Regimen; Relative (related person); Resistance; Rifampin; Simulate; Speed; Sputum; Sterilization; Testing; Time; Treatment Protocols; Treatment outcome; Tuberculosis; clinically relevant; dosage; improved; in vivo Model; indexing; innovation; isoniazid; killings; mathematical model; mortality; nonhuman primate; novel; prevent; public health relevance; resistant strain; standard care; tuberculosis drugs; tuberculosis treatment

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.

描述（由申请人提供）：结核分枝杆菌 (Mtb) 感染全世界超过 20 亿人，每年导致 140 万人死亡。药物敏感 Mtb 引起的结核病 (TB) 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)，然后是 4 个月的 RIF 和 INH。在临床结核病患者中，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续状态 (NRP)。 NRP Mtb 需要长期治疗才能杀死，并导致疾病复发。 RIF、INH 和 EMB 杀死对数生长期 Mtb，而 PZA 杀死酸性期 Mtb。 RIF 也杀死了 NRP Mtb。因此，标准方案中只有一种药物对酸性相和 NRP Mtb 有活性。耐多药结核分枝杆菌（MDR-TB）的患病率正在上升，原因是使用经验性抗生素组合治疗由对治疗方案中的一种或多种药物耐药的微生物引起的结核病，即使在直接观察治疗下也存在药物给药错误，以及患者不遵守长疗程。在将具有新颖作用机制的新型抗生素添加到药物敏感结核分枝杆菌和耐多药结核病的标准治疗方案中的研究中，动物模型中细菌灭菌的时间和临床试验中痰液转阴的时间都缩短了，这表明由标准一线和二线结核病药物组成的治疗方案并未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，经过药效学 (PD) 优化以杀死所有 3 种代谢状态下的 Mtb 并防止不易感染的细菌亚群扩增的结核病治疗方案将提供一种有效的短程结核病治疗方案，从而改善治疗结果并降低耐药性。我们将测试这一假设，并通过完成以下具体目标来制定高效的短期治疗方案：具体目标#1。在体外中空纤维感染模型 (HFIM) 中模拟临床相关剂量的 3 种新型结核病抗生素（在所有代谢状态下均具有活性）的自由肺部 PK 曲线，确定每种药物的 P 指数、药物暴露量和给药间隔，以 PD 优化在 3 种代谢状态下杀灭 DS-Mtb 的速度和程度。确定这些单一药物治疗方案是否可以预防耐药性。具体目标#2。使用 HFIM，比较在 3 种代谢状态下杀死 DS-Mtb 的速率和程度，以及当将特定目标 #1 中开发的 PD 优化方案用作 2 种和 3 种药物组合时，这些抗生素对不易受影响的 Mtb 人群的影响。采用创新的数学模型来确定 3 种药物治疗方案中每种抗生素的给药剂量和频率，预计通过优化每种代谢状态下的结核分枝杆菌杀灭并防止耐药性，为治疗人类结核病提供疗程更短、高效的治疗方案。具体目标#3。使用 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 种代谢状态下杀死 Mtb 的速率和程度的功效。 具体目标#4。前瞻性验证创新的 PD 优化 3 种药物方案在新型小鼠肺结核模型中的性能，其中对数期、酸性期和 NRP 状态的 Mtb 共存，并在另一个创新的体内结核病模型中使用最先进的剂量算法，将动物中生成的 PK 曲线“人性化”。使用新型小鼠模型来表征该方案杀灭 DS 结核病和耐多药结核病的相对功效。