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

背景和背景结核病（TB）是一种细菌感染，每年在全世界造成100多万人死亡。结核病的治疗包括连续数月服用复杂的抗生素混合物。虽然结核病感染通常发生在肺部，但身体的其他部位也可能受到影响，例如大脑和脊柱。脑部结核感染通常发生在儿童和免疫系统受到抑制的人群中。在现有的治疗条件下，五分之一的结核病脑感染患者会死亡，而存活下来的患者中有一半以上会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无法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与血液相比，脑脊液和脊髓液中不同抗生素的浓度。这一信息将与以前从人类患者身上获得的样本用于建立数学模型的研究中的测量结果一起使用。这些模型将描述药物浓度随时间在大脑不同区域的变化。这可以用来进行计算机模拟，以找到最能治疗大脑结核感染的药物剂量和组合。这些剂量和药物组合可以在临床试验中进行测试。另一个问题是，来自血液和脊髓液样本的结核病在实验室中生长非常缓慢（或者根本不生长）。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才能最好地诊断和监测结核病，使用已经开发和测试的用于结核病肺部感染的新检测方法。方法结核分枝杆菌感染涉及结核细菌、免疫系统和抗生素药物之间复杂的相互作用。由于这个原因，研究结核病治疗的实验必须使用受感染的动物。体内模型的使用将允许收集无法从人类患者那里定期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用于显示每种药物到达大脑的量，并突出显示“热点”（含有高浓度药物）和“冷点”（含有低浓度药物）。这些扫描结果将与那些显示结核细菌在大脑中生存和生长的地方的扫描结果进行比较。总之，这些信息将被用来建立数学模型，描述药物在大脑不同区域和脊髓液中的剂量随时间的变化。开发的模型将使我们能够利用计算机模拟来预测治疗是否会在新的条件下起作用（例如，如果使用更高的剂量或新的组合），并确定最有可能有效治疗感染的药物组合和剂量。潜在的应用和益处这项工作的发现有可能通过确定更有效的治疗方法，直接改善结核病脑感染患者的生活。该项目的发现将为规划新的和现有的治疗方法的临床试验提供证据，并协助国家和国际组织发布关于医生应该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如何到达它们的作用部位。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关于如何最好地治疗影响大脑的许多其他疾病和身体其他部位的感染的信息，例如癫痫、中风或癌症。

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.