Spatially-resolved PKPD modelling for optimised treatment of central nervous system infection due to Mycobacterium tuberculosis

背景与背景结核病(TB)是一种细菌感染，每年在全球范围内导致100多万人死亡。结核病的治疗需要服用几个月的复杂的抗生素鸡尾酒。虽然结核病感染通常发生在肺部，但身体的其他部位也会受到影响，如大脑和脊柱。大脑中的结核病感染通常发生在儿童和免疫系统受抑制的人中。在目前可用的治疗下，五分之一的结核病脑部感染患者死亡，超过一半的幸存者患有严重的永久性残疾。其中一个原因可能是用于治疗结核病的抗生素没有到达细菌生存和生长的大脑区域。目的和目的本研究的目的是了解和描述不同抗生素在大脑和脊髓液中相对于血液的浓度。这些信息将与先前研究中的测量一起使用，在先前的研究中，样本是从人类患者那里获得的，以建立数学模型。这些模型将描述药物在大脑不同区域的浓度如何随时间变化。这可以用来进行计算机模拟，以找到治疗大脑中结核病感染的最佳药物剂量和组合。这些剂量和药物组合然后可以在临床试验中进行测试。另一个问题是，血液和脊髓液样本中的结核病在实验室中生长非常缓慢(或者可能根本不生长)。这使得结核病成为一种难以诊断的疾病。因此，该项目还将研究如何通过已经开发和测试的结核病肺部感染的新测试来最好地诊断和监测结核病。方法结核病感染涉及结核病细菌、免疫系统和抗生素药物之间的复杂相互作用。因此，研究结核病治疗的实验必然会使用受感染的动物。活体模型的使用将允许收集无法从人类患者那里常规获得或在实验室中合成的组织样本(例如脑组织)。动物将感染结核病，并接受不同剂量的药物。一种新的扫描技术将被用来显示每种药物到达大脑的量，并突出显示“热点”(包含高浓度药物)和“冷点”(包含低浓度药物)。这些扫描将与那些显示结核病细菌在大脑中生活和生长的地方的扫描进行比较。总而言之，这些信息将被用来建立数学模型，描述随着时间的推移，大脑不同区域和脊髓液中的药物数量。开发的模型将允许我们使用计算机模拟来预测治疗在新的条件下是否有效(例如，如果使用更高剂量或新的组合)，并确定最有可能有效治疗感染的药物的组合和剂量。潜在的应用和好处这项工作的发现有可能通过确定更有效的治疗方法来直接改善患有结核病脑感染的人的生活。该项目的发现将为规划新的和现有治疗方法的临床试验提供证据，并帮助国家和国际组织发布关于医生应使用哪些药物和剂量治疗结核病的指南和建议。这项工作还将开发新的方法，利用最先进的扫描和数学模型来研究药物到达作用部位的程度。除了提供有关结核病最佳治疗方法的信息外，这些方法还可用于提供如何最好地治疗许多其他影响大脑的疾病和身体其他部位的感染，如癫痫、中风或癌症的信息。

Background and ContextTuberculosis (TB) is a bacterial infection that causes over a million deaths per year worldwide. TB treatment involves taking a complex cocktail of antibiotics for many months. Although TB infection usually occurs in the lung, other sites of the body can also be affected, such as the brain and spine. TB infection in the brain usually occurs in children and those who have a suppressed immune system. With currently available treatment, one in five patients with TB brain infections die, and over half of those who survive have significant permanent disabilities. One reason for this may be that antibiotics used to treat TB do not get to the areas of the brain where the bacteria are living and growing.Aims and ObjectivesThe aim of this research is to understand and describe the concentration of different antibiotics in the brain and spinal fluid compared to the blood. This information will be used along with measurements from previous studies where samples were obtained from human patients to build mathematical models. These models will describe how the concentrations of drugs change in different areas of the brain over time. This can be used to make computer simulations to find drug doses and combinations that will best treat TB infection in the brain. These doses and drug combinations can then be tested in clinical trials. Another problem is that TB from blood and spinal fluid samples grow very slowly (or may not grow at all) in the laboratory. This makes TB a difficult condition to diagnose. This project will also, therefore, investigate how TB can best be diagnosed and monitoring with new tests that have been developed and tested in TB lung infection.MethodsTB infection involves a complex interaction between the TB bacteria, the immune system, and antibiotic medicines. For this reason, the experiments to study TB treatments will necessarily use infected animals. The use of an in vivo model will allow for tissue samples to be collected that cannot be obtained regularly from human patients or synthesised in the lab (for example brain tissue). Animals will be infected with TB and receive drugs at different doses. A new scanning techniques will be used to show how much of each drug reaches the brain and highlight 'hot spots' (containing high concentrations of drug) and 'cold spots' (containing low drug concentrations). These scans will be compared to those showing where in the brain the TB bacteria are living and growing. Together, this information will be used to build mathematical models that describe the amount of drugs in different areas of the brain and in the spinal fluid over time. The models developed will allow us to make predictions about whether treatment would work under new conditions using computer simulations (for example if a higher dose or new combination is used) and identify the combination and doses of drugs that have the highest chance of effectively treatment the infection. Potential Applications and BenefitsThe findings of this work have the potential to directly improve the lives of people who suffer from TB brain infection by identifying treatments which are more effective. The findings from the project will provide evidence to plan clinical trials of new and existing treatments, and assist national and international organisations that publish guidelines and recommendations on which drugs and doses doctors should use to treat TB. The work will also develop new methods to study how well drugs reach their site of action using of state-of-the-art scans and mathematical models. As well as giving information about the best treatments for TB these methods may be used to provide information on how to best treat many other diseases affecting the brain and infections elsewhere in the body, such as epilepsy, stroke or cancer.