PK/PD Optimized Cephalosporins Based Treatment Regimens for Children With MDR-TB

项目概要/摘要 暴露于结核病（TB）细菌的儿童进展为活动性结核病的风险更大。年轻 儿童（<2岁）由于免疫系统的无效， 安全壳根据世界卫生组织2017年的报告，每年约有100万儿童患结核病 占结核病病例总数的近10%。2016年，约3%的儿童报告病例被诊断为患有 耐多药（MDR）结核病（定义为对两种最有效的一线抗结核药物异烟肼耐药 和利福平）。儿科结核病管理的障碍之一是安全有效的治疗方法的可用性 考虑到年龄特异性药代动力学变异性，专门为儿童设计的MDR-TB治疗方案。 我们的广泛目标是使用我们的结核病中空纤维系统模型来简化结核病药物开发。给定 由于新型结核病药物的供应渠道仍然很窄，人们对重新利用旧药物用于新用途重新产生了兴趣。 β-内酰胺类抗生素是许多抗菌治疗方案的支柱;然而，它们对 结核分枝杆菌（Mtb）尚未得到充分研究。我们从β-内酰胺类药物中筛选了13种药物 的抗生素，包括头孢菌素亚类，对耐药的结核分枝杆菌临床菌株。在这 我们将把6种头孢菌素推进到下一阶段的研究。头孢菌素具有 因为儿童的药代动力学和安全性特征已经明确。我们将联合收割机 头孢菌素与其他两种口服药物-耐多药结核病治疗方案不可或缺的支柱-氟喹诺酮类 在所有年龄段的人群中，以及替地唑胺，一种有效对抗革兰氏阳性病原体的新恶唑烷酮， 结核分枝杆菌，以创造一个有效的治疗儿童耐多药结核病的方案。我们的药物和联合方案 开发方法使用我们经过验证的中空纤维，应用药代动力学/药效学科学 细胞内结核分枝杆菌系统模型（HFS-TB）。我们有关于每种药物的最佳暴露目标的信息， 来自为收集初步数据而进行的HFS-TB研究的作为单一疗法的最大Mtb杀灭。工作流 （1）使用棋盘研究来评估加和性、协同作用或拮抗作用 每种头孢菌素与氟喹诺酮类药物，（2）加入浓度为达到最佳暴露目标的替地唑胺， 在HFS-TB中测试的头孢菌素-阿托沙星药物对，比较Mtb杀灭率与二线 使用MDR-TB的5种药物（阿米卡星-左氧氟沙星-乙硫异烟胺-环丝氨酸-吡嗪酰胺）的MDR-TB方案 临床菌株，（3）HFS-TB结果的数学建模，以预测Mtb的灭绝时间， 拟定的新型药物联合方案的最佳治疗持续时间，（4）计算机模拟临床试验 结合儿科特异性药代动力学变异性以及结核分枝杆菌菌株最小抑制 浓度变异性，以确定每种药物的最佳剂量，以实现儿科患者的暴露目标 人口。结果将是专门为儿童耐多药结核病设计的新治疗方案， 相对较短的时间跨度，解决了全球消除结核病时代未满足的主要临床需求。

Project summary/Abstract Children exposed to tuberculosis (TB) bacterium have a greater risk of progressing to active TB disease. Younger children (<2 years) are especially susceptible to developing disseminated disease due to ineffective immunologic containment. As per World Health Organization 2017 report, ~1 million children become ill with TB each year representing nearly 10% of the total TB cases. In 2016, ~3% of the reported cases in children diagnosed to have multi-drug resistant (MDR) TB (defined as being resistant to the two most potent first-line anti-TB drugs, isoniazid and rifampin). One of the hurdles in pediatric TB management is the availability of a safe and effective treatment regimen for MDR-TB designed specifically for children considering the age specific pharmacokinetic variability. Our broad objective is to use our hollow fiber system model for TB to streamline TB drug development. Given that the pipeline for novel TB drugs is still slim, there is renewed interest in repurposing old drugs for new use. β-lactam antibiotics are the backbone of many antibacterial treatment regimens; however, their efficacy against Mycobacterium tuberculosis (Mtb) have not been fully explored. We screened 13 drugs from the β-lactams class of the antibiotics including the cephalosporins sub-class, against drug resistant clinical strains of Mtb. In this grant application we will advance 6 cephalosporins to the next phase of investigations. Cephalosporins have an advantage because the pharmacokinetic and safety profile in children is well defined. We will combine the leading cephalosporins with two other oral drugs—moxifloxacin, an integral backbone of MDR-TB treatment regimens in people of all ages, and tedizolid, a new oxazolidinone effective against gram-positive pathogens as well as Mtb to create a potent regimen effective against MDR-TB in children. Our drug and combination regimen development approach apply pharmacokinetic/pharmacodynamic science using our validated hollow fiber system model for intracellular Mtb (HFS-TB). We have information on each drug’s optimal exposure target for maximal Mtb kill as monotherapy from the HFS-TB studies performed to collect preliminary data. The workflow of the current application will be - (1) use of checkerboard studies to evaluate additivity, synergy or antagonism of each cephalosporin with moxifloxacin, (2) add tedizolid at concentration to achieve optimal exposure target to the cephalosporins-moxifloxacin drug pair(s) to test in the HFS-TB comparing Mtb kill rates with a second-line MDR-TB regimen of five drugs (amikacin-levofloxacin-ethionamide-cycloserine-pyrazinamide) using MDR-TB clinical strains, (3) mathematical modeling of the HFS-TB results to predict Mtb time-to-extinction that will inform optimal duration of therapy with the proposed novel drug combination regimens, (4) in silico clinical trial simulations incorporating pediatric-specific pharmacokinetic variability as well as Mtb-strain minimum inhibitory concentration variability to establish optimal dose of each drug to achieve exposure targets among pediatric populations. The outcome will be novel treatment regimen(s) specially designed for MDR-TB in children in relatively short time span, addressing a major unmet clinical need in the global era of TB elimination.