治疗药物监测（TDM），是指通过测定患者体内的药物暴露、药理标志物或药效指标，利用定量药理模型，以药物治疗窗为基准，制订适合患者的个体化给药方案。其核心是个体化药物治疗。在近日举行的2023年美国感染病周（IDWeek 2023）大会上，美国费城儿童医院的Kevin J.Downes教授带来了《治疗药物监测和抗生素剂量优化的实用新方法》的主题报告，并在接受《感染医线》的采访中分享其精彩观点。
专家简介
Kevin J.Downes，医学博士
美国宾夕法尼亚州费城儿童医院儿科助理教授
Kevin Downes是宾夕法尼亚大学佩雷尔曼医学院的儿科助理教授，也是费城儿童医院传染病科的主治医师。他是临床药理学CHOP T32项目的负责人，这是一个由NICHD和NIGMS赞助的与托马斯·杰斐逊大学的决斗项目。他的研究兴趣包括抗微生物PK/PD、药效学、微量采样和TDM，以及探索新型生物标志物在危重症和免疫功能低下儿童管理中的作用。
01
《感染医线》：早上好，您的演讲非常精彩，感谢您接受我们的采访。首先，请您详细介绍下儿科患者目前在TDM方面面临的挑战？您在临床实践中如何解决这些问题，以确保有效和安全的抗生素剂量？
Dr. Downes：目前在儿童TDM方面存在许多挑战。我认为首先是监测步骤本身，在测量中，我们需要更新的工具来获取提供有用信息的药物水平。一些新技术使用较小的样本，允许我们在更精确的时间采集样本，从而为给药提供信息。此外，我们需要更多可以解释结果的人员。当涉及剂量时，在治疗范围内测量单个水平并解释它只能提供这么多信息。我们需要更多可操作的数据，使我们能够使用个体药物水平，然后向临床医生提供药物剂量指导。现在临床上有些可用的软件程序，使我们能够做到这一点，并为患者提供更精确的剂量。
Good morning Dr. Dao, first of all I just want to say it's a great presentation and thank you for having this interview with us. Thank you. And for the first question, could you elaborate on the current challenges in the theoretical drugs monitoring in pediatric patients? How do your practical approaches address those issues to ensure effective and safe antibiotic dosage?
Well there are a number of challenges currently to therapeutic drug monitoring in children. I think first off the monitoring step itself, the measurement, we need newer tools to be able to obtain informative drug levels. And there are some newer technologies that are available to us to use smaller samples that allow us to collect samples at a more precise time that will be informative for dosing. Additionally we need more people available to interpret the results.Measuring a single level and interpreting it within a therapeutic range only provides so much information when it comes to dosing.We need some more actionable data that can allow us to use that individual drug level and then provide drug dosing guidance back to the clinicians. And now there are software programs available to us clinically that allow us to do that and provide more precise dosing for patients.
02
《感染医线》：您在儿童抗生素管理尤其是个体化剂量优化方面，做了大量工作。您是否可以分享一些您在抗生素剂量优化新方法上成功的具体案例或案例研究？
Dr. Downes：是的，我认为有很多案例研究，大多数TDM都集中在最大限度地减少药物毒性上，而这有很多案例。在这个领域成功的有班克霉素和肾毒性、氨基糖苷类抗生素和肾毒性等。我发现，最成功的是我们利用这些信息来提供更为有效的目标。因此，当我们在处理药代动力学改变，比如正在接受体外膜肺氧合（ECMO）或连续性肾脏替代治疗（CRRT）的儿童时，这些儿童可能明显超重或体重不足，基于标准体重的给药剂量确实不是最佳方法。我认为，这就是我们可以利用TDM来真正改善儿童药物暴露的地方。
And you've worked extensively on antibiotic stewardship in children focusing on individualizing dose optimization. Could you provide specific examples or case studies where your novel approaches to antibiotic dose optimization have proven to be successful?
Yeah so in terms of case studies I think there's a lot of, most of therapeutic drug monitoring has focused on minimizing toxicity and there's a lot of examples. of successes in this area when it comes to bankamycin and kidney toxicity, aminoglycosides and kidney toxicity, etc. Where I find that the most successes come is when we use that information to provide more effective targets. So when we deal with children who have altered pharmacokinetics such as those who are on ECMO or CRRT, children who may be significantly over or under weight where standard weight -based dosing is really not the optimal approach. I think that's where we can utilize TDM to really improve the exposures that those children are receiving.
03
《感染医线》：您最近关于儿童尿路感染和急性肾损伤的研究成果，如何转化成治疗TDM和抗生素剂量优化的可行见解？是否有些可以在临床实践中立即实施的关键要点？
Dr. Downes：从实施的临床角度来看，我认为主要的收获是我们需要能够设定一个目标——针对患者的个性化目标。当我们这样做的时候，我们可以充分利用一些可用的工具来提供更有效和安全的治疗。我不认为每个患者都有同一个治疗范围，这意味着我们应用的就像来自实验室的治疗范围需要进行个体化定制。因此，每个患者都有自己的目标范围，一些更可能成功，另一些更可能有毒。我们只需要真正做出这些临床决策，就可以告诉患者最佳目标。而这需要时间和精力，因此也是定期这样做的另一个障碍。
And considering your recent articles on UTIs and acute kidney injuries in children, how does your research translate into actionable insights for theoretical drug monitoring and antibiotic dose optimization? Are there any key takeaways that clinicians can immediately implement in their practice?
Well, from a clinical side in terms of implementation, I think that the main take home is that we need to be able to set a target and that target needs to be individualized for the patient that's in front of us. And when we do that, we can leverage some of the tools available to us to provide more effective and safe therapy. I don't think that there is a therapeutic range for an individual patient, meaning the therapeutic range that we apply like from the lab needs to be tailored to that individual. So each patient has their own sort of range of targets and some being more likely to be successful and others being more likely to be toxic. And we just need to really make those clinical decisions to say what is the best target for this patient in front of me. And it takes time and effort to do that, which I think is another barrier to doing this regularly.
04
《感染医线》：最后一个问题是，你预计未来在周期性传染病领域，特别是在TDM和抗生素方面，会取得哪些进展和革新？以及专业人士如何准备适应这些变化？
Dr. Downes：我认为随着技术的进步，我们正处于一个非常激动人心的时期。当用于TDM的样本收集时，设备领域的进步可改善我们如何根据体积、时间和患者体验来收集样本。我还认为，从数学角度来看，随着人工智能的进步，我们正处于一个非常激动人心的时刻。我认为，随着即将到来的技术进步，我们将能够更有效地为患者提供量身定制的个性化给药剂量，而持续药物监测等技术是该领域的又一进步，也将真正帮助我们在个人层面定制治疗方案。持续药物监测是一个特别令我兴奋的领域。
And for the last question, looking forward, what advancements and innovations do you anticipate in the field of periodic infectious disease, particularly in therapeutic drug monitoring and antibiotic, those organizations, how can professions prepare to adapt those changes?
Yeah, I think we're in a really exciting time for this with advancements in technology, so that advancements in the device field where we can have improvements in how we collect samples with the volume and the timing and the patient experience when it comes to collection of samples for therapeutic drug monitoring. I also think we're in a really exciting time when it comes to advancements from a mathematical standpoint with advancements in AI. We have, I think the future is such that we're going to be able to really provide tailored personalized dosing much more effectively with advancements in the technologies that are coming and something like continuous drug monitoring, which is an additional advancement in the field and not too far off, will really help us tailor therapy at the individual level. And I think that's an area I'm particularly excited for is continuous drug monitoring.