Therapeutic Drug Monitoring in the Treatment of Tuberculosis: An Update
Therapeutic Drug Monitoring in the Treatment of Tuberculosis: An Update
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DOI：
10.1007/s40265-014-0222-8
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发表时间：
2014-06-01
期刊：
影响因子：
11.5
通讯作者：
Peloquin, Charles A.
中科院分区：
文献类型：
--
作者：
Alsultan, Abdullah;Peloquin, Charles A.
结核病（TB）是世界上第二大传染性杀手。耐多药结核和极端耐药结核病例在全球范围内有所增加。治疗药物监测（TDM）仍然是使用血浆药物浓度确定剂量的标准临床技术。对于TB患者，TDM为临床医生提供客观信息，以做出明智的给药决定。一些患者对治疗反应缓慢，TDM可以缩短反应和治疗完成的时间。结核病药物的正常血浆浓度范围已经确定。出于实际原因，仅在给药后采集一份或两份样本。给药后2小时的样本接近大多数TB药物的峰值血清药物浓度（C-max）。添加6小时样本使临床医生能够区分延迟吸收和吸收不良。TDM要求迅速离心样本，并迅速收集和冷冻血清。特别是异烟肼和乙硫异烟胺，在室温下在人血清中不稳定。利福平在这些条件下稳定6 h以上。自从我们2002年的综述以来，已经发表了几篇关于结核药物药代动力学、药效学和TDM的论文。因此，我们有更好的信息，有效的结核病治疗所需的浓度。体外和动物模型数据清楚地显示了大多数结核药物的浓度反应。最近的研究强调利福霉素和吡嗪酰胺作为灭菌剂的重要性。可以提出一个强有力的论点，即在没有毒性的情况下最大限度地增加患者对这些药物的接触。此外，“最小抑菌浓度”（MIC）背后的概念意味着应该达到高于最小值的浓度，以最大限度地提高反应。一些但不是所有的临床数据与该方法的实用性一致。结核病药物正常范围的低端设定了合理的“下限”，在此基础上应维持血药浓度。糖尿病患者和艾滋病毒感染者尤其有药物吸收不良和药物相互作用的风险。已发表的指南通常描述两种药物之间的相互作用，而临床情况往往要复杂得多。在“现实生活”的情况下，TDM往往是最好的工具，整理出这些多药物相互作用，并为患者提供安全和足够的剂量。血浆浓度不能解释患者对TB治疗反应的所有变异性，也不能保证患者的结果。然而，结合临床和细菌学数据，TDM可以成为一种决定性的工具，使临床医生能够成功治疗即使是最复杂的结核病患者。
Tuberculosis (TB) is the world's second leading infectious killer. Cases of multidrug-resistant (MDR-TB) and extremely drug-resistant (XDR-TB) have increased globally. Therapeutic drug monitoring (TDM) remains a standard clinical technique for using plasma drug concentrations to determine dose. For TB patients, TDM provides objective information for the clinician to make informed dosing decisions. Some patients are slow to respond to treatment, and TDM can shorten the time to response and to treatment completion. Normal plasma concentration ranges for the TB drugs have been defined. For practical reasons, only one or two samples are collected post-dose. A 2-h post-dose sample approximates the peak serum drug concentration (C-max) for most TB drugs. Adding a 6-h sample allows the clinician to distinguish between delayed absorption and malabsorption. TDM requires that samples are promptly centrifuged, and that the serum is promptly harvested and frozen. Isoniazid and ethionamide, in particular, are not stable in human serum at room temperature. Rifampicin is stable for more than 6 h under these conditions. Since our 2002 review, several papers regarding TB drug pharmacokinetics, pharmacodynamics, and TDM have been published. Thus, we have better information regarding the concentrations required for effective TB therapy. In vitro and animal model data clearly show concentration responses for most TB drugs. Recent studies emphasize the importance of rifamycins and pyrazinamide as sterilizing agents. A strong argument can be made for maximizing patient exposure to these drugs, short of toxicity. Further, the very concept behind 'minimal inhibitory concentration' (MIC) implies that one should achieve concentrations above the minimum in order to maximize response. Some, but not all clinical data are consistent with the utility of this approach. The low ends of the TB drug normal ranges set reasonable 'floors' above which plasma concentrations should be maintained. Patients with diabetes and those infected with HIV have a particular risk for poor drug absorption, and for drug-drug interactions. Published guidelines typically describe interactions between two drugs, whereas the clinical situation often is considerably more complex. Under 'real-life' circumstances, TDM often is the best available tool for sorting out these multi-drug interactions, and for providing the patient safe and adequate doses. Plasma concentrations cannot explain all of the variability in patient responses to TB treatment, and cannot guarantee patient outcomes. However, combined with clinical and bacteriological data, TDM can be a decisive tool, allowing clinicians to successfully treat even the most complicated TB patients.