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）在全球范围内感染超过20亿人，每年造成140万人死亡。因药物敏感的MTB而引起的结核病（TB）的标准治疗方法包括2个月的利福平（RIF），异烟肼（INH），吡嗪酰胺（PZA）和Ethambutol（Emb），然后进行4个月的RIF和INH。在临床结核病患者中，MTB存在于3种代谢状态：对数期生长，半休眠酸性相和非复制耐力（NRP）状态。 NRP MTB需要长时间的治疗才能杀死并负责疾病复发。 RIF，INH和EMB杀死对数相生长MTB，而PZA杀死了酸性期MTB。 RIF还杀死了NRP MTB。因此，标准方案中只有一种药物在酸性相和NRP MTB上具有活性。由于使用经验性抗生素组合的TB，由Microbes引起的TB的经验性抗生素组合的患病率正在上升，这些抗生素是由先验药物中一种或多种药物耐药的，即使在直接观察治疗以及患者与长期治疗过程中的患者中，在药物的给药中都有错误。在研究中，具有新型抗生素具有新型作用机制的新抗生素被添加到药物敏感的MTB和MDR-TB的标准方案中，在动物模型中进行细菌灭菌的时间，以及在临床试验中痰液转化为阴性的时间缩短了，表明由标准的第一和第二行TB药物组成的标准第一和第二行药物的治疗方法没有优化以杀死MTB。我们的长期目标是开发改进的结核病方案。总体假设是，在所有3种代谢状态下杀死杀死MTB的药效（PD）的结核病方案，并防止放大较不敏感的细菌亚群，将提供有效的较短疗程结核病治疗方案，可改善治疗结果并降低抗药性。我们将通过完成以下特定目标来检验这一假设，并开发高效的短期课程：特定目标＃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.确定这些单一药物方案是否可以防止耐药性。特定目标＃2。使用HFIM，比较了3种代谢状态下DS-MTB杀死DS-MTB的速率和范围，以及这些抗生素对特定AIM＃1中PD优化方案的易感性MTB种群的影响，用作2和3个药物组合。采用创新的数学模型来确定每种抗生素的剂量和频率在3种药物方案中，预计通过优化每个代谢状态中MTB杀死MTB并防止耐药性，预计将提供较短的课程，高效治疗人类结核病。特定目标＃3。使用HFIM，表征了PD优化3种药物方案对3个代谢状态MTB杀死的速率和程度的疗效，该菌株对1种药物成分具有抗性。 特定目标＃4。前瞻性地验证了创新的PD优化3种药物的性能在新型的肺结核模型中，其中MTB在日志阶段，酸性期和NRP状态共存，以及在TB的另一个创新的TB中，使用最先进的TB模型，使用最先进的剂量给出了“人类化的pk profiles”，该动物profiles生成了PK profiles。使用新型的鼠模型来表征该方案对DS-和MDR-TB杀死的相对功效。