Dartois Véronique, Barry Clifton E
The Novartis Institute for Tropical Diseases, Biopolis, Singapore, Singapore.
Curr Clin Pharmacol. 2010 May;5(2):96-114. doi: 10.2174/157488410791110797.
Failure of first-line chemotherapy to cure tuberculosis (TB) patients occurs, in part, because of the development of resistance to isoniazid (INH) and rifampicin (RIF) the two most sterilizing agents in the four-drug regimen used to treat primary infections. Strains resistant to both INH and RIF are termed multidrug-resistant (MDR). Treatment options for MDR patients involve a complex array of twenty different drugs only two classes of which are considered to be highly effective (fluoroquinolones and aminoglycosides). Resistance to these two classes results in strains known as extensively drug-resistant (XDR) and these types of infections are becoming increasingly common. Many of the remaining agents have poorly defined pharmacology but nonetheless are widely used in the treatment of this disease. Several of these agents are known to have highly variable exposures in healthy volunteers and little is known in the patients in which they must be used. Therapeutic drug monitoring (TDM) is infrequently used in the management of MDR or XDR disease yet the clinical pharmacokinetic studies that have been done suggest this might have a large impact on disease outcome. We review what is known about the pharmacologic properties of each of the major classes of second- and third-line antituberculosis agents and suggest where judicious use of TDM would have the maximum possible impact. We summarize the state of knowledge of drug-drug interactions (DDI) in these classes of agents and those that are currently in clinical trials. Finally we consider what little is known about the ability of TB drugs to reach their ultimate site of action--the interior of a granuloma by penetrating the diseased lung area. Careful consideration of the pharmacology of these agents is essential if we are to avoid further fueling the growing epidemic of highly drug-resistant TB and critical in the development of new antituberculosis drugs.
一线化疗未能治愈结核病患者，部分原因是对异烟肼（INH）和利福平（RIF）产生了耐药性，这两种药物是用于治疗原发性感染的四联疗法中最具杀菌作用的药物。对INH和RIF均耐药的菌株被称为耐多药（MDR）。耐多药患者的治疗选择涉及二十种不同药物的复杂组合，其中只有两类被认为是高效的（氟喹诺酮类和氨基糖苷类）。对这两类药物产生耐药性会导致出现广泛耐药（XDR）菌株，这类感染正变得越来越普遍。其余许多药物的药理学特性尚不明确，但仍被广泛用于治疗这种疾病。已知其中几种药物在健康志愿者中的血药浓度差异很大，而对于必须使用这些药物的患者却知之甚少。治疗药物监测（TDM）在耐多药或广泛耐药疾病的管理中很少使用，但已开展的临床药代动力学研究表明，这可能对疾病转归有很大影响。我们综述了关于二线和三线抗结核药物各主要类别药理学特性的已知信息，并指出合理使用TDM可能产生最大影响的方面。我们总结了这些药物类别以及目前正在进行临床试验的药物中药物相互作用（DDI）的知识现状。最后，我们考虑对于抗结核药物通过穿透患病肺区到达其最终作用部位——肉芽肿内部的能力了解甚少的情况。如果我们要避免进一步助长高度耐药结核病的不断蔓延，仔细考虑这些药物的药理学至关重要，这对于开发新的抗结核药物也至关重要。
