Ketolides — The Modern Relatives of Macrolides
Ketolides — The Modern Relatives of Macrolides
复制标题
酮内酯类 — 大环内酯类的现代亲戚
DOI：
--
复制
发表时间：
2009
影响因子：
4.5
通讯作者：
B. Heinisch
中科院分区：
文献类型：
--
作者：
M. Zeitlinger;C. Wagner;B. Heinisch
与其他广泛使用的抗菌药物一样，大环内酯类药物在治疗流动感染中的大量使用促进了对它们的耐药性的出现。酮内酯类在结构上与大环内酯类相关，旨在克服大环内酯类耐药性，同时具有相同的药效和药代动力学特征。然而，迄今为止，尚未对大环内酯类和酮内酯类的药代动力学比较进行全面综述。本文综述了唯一获批的酮内酯类泰利霉素和目前处于临床Ⅲ期开发的赛红霉素在血浆和相关组织中的药代动力学参数。为了进行比较，选择 14 元大环内酯类克拉霉素和罗红霉素以及 15 元氮杂内酯阿奇霉素作为同类药物的代表。虽然泰利霉素的血浆浓度高于西红霉素，但两种抗菌药物的消除半衰期和清除率相当。重复给药很少影响酮内酯的药代动力学参数。尽管泰利霉素的最大血浆浓度和血浆浓度-时间曲线下面积 (AUC) 值显着较高，但庆霉素较高的抗菌活性导致 0 至 24 小时 AUC (AUC24) 与相关病原体的最低抑菌浓度 (MIC) 之间的比率相似，表明两种抗菌药物在血浆中的抗菌活性相当。尽管泰利霉素和塞红霉素的血浆蛋白结合率为 90%，但它们具有出色的组织渗透性，如约 500 L 的分布体积和高细胞内浓度所示。除了增强对细胞内病原体的杀灭作用外，白细胞中高浓度的大环内酯类、氮杂内酯类和酮内酯类还与抗菌剂向感染部位的递送增加有关。尽管泰利霉素在肺泡巨噬细胞和上皮衬里液中的积累量分别是血浆浓度的 380 倍和 15 倍，但其在软组织间质中的浓度与血浆中的游离部分相当。因此，酮内酯的药代动力学可能有助于解释其对多种呼吸道感染的良好活性，尽管基于血浆药代动力学的药代动力学/药效学计算表明对链球菌以外的病原体仅具有较小的活性。相反，软组织中达到的 AUC24/MIC 比率可能被认为不足以杀死导致软组织感染的细胞外病原体（化脓性链球菌除外）。尽管酮内酯类和大环内酯类具有相关的药代动力学特性，但两种抗菌药物类别的药代动力学不被认为是可以互换的。由于酮内酯类的分布体积与阿奇霉素相似，但血浆浓度和消除半衰期与克拉霉素相似，因此酮内酯类的药代动力学可能被认为介于大环内酯类和氮杂内酯类之间。因此，酮内酯类药物的药代动力学可以被认为与大环内酯类药物相似但不相同。
As with other widely used antibacterials, the abundant use of macrolides for management of ambulant infections has promoted emergence of resistance against them. Ketolides are structurally related to macrolides and were developed to overcome macrolide resistance, while sharing pharmacodynamic and pharmacokinetic characteristics. However, until now, there have been no comprehensive reviews of the comparative pharmacokinetics of macrolides and ketolides.This article reviews the pharmacokinetic parameters in plasma and relevant tissues of telithromycin, the only approved ketolide, and cethromycin, which is currently in phase III of clinical development. For comparison, the 14-membered macrolides clarithromycin and roxithromycin and the 15-membered azalide azithromycin were chosen as representatives of their class.While telithromycin achieves higher plasma concentrations than cethromycin, both antimicrobials display comparable elimination half-lives and clearance. Repeated dosing rarely influences the pharmacokinetic parameters of ketolides. Despite substantially higher maximum plasma concentrations and area under the plasma concentration-time curve (AUC) values of telithromycin, the higher antimicrobial activity of cethromycin leads to similar ratios between the AUC from 0 to 24 hours (AUC24) and the minimum inhibitory concentration (MIC) for relevant pathogens, suggesting comparable antimicrobial activity of both antimicrobials in plasma. Although telithromycin and cethromycin show plasma-protein binding of 90%, they have excellent tissue penetration, as indicated by volumes of distribution of about 500 L and high intracellular concentrations. Besides enhancing killing of intracellular pathogens, the high concentrations of macrolides, azalides and ketolides in leukocytes have been associated with increased delivery of the antimicrobial agent to the site of infection.Although telithromycin has been shown to accumulate in alveolar macrophages and epithelial lining fluid by 380- and 15-fold, respectively (relative to plasma concentrations), its concentration in the interstitium of soft tissues is comparable to the free fraction in plasma. Thus the pharmacokinetics of ketolides may help to explain their good activity against a wide range of respiratory tract infections, although pharmacokinetic/pharmacodynamic calculations based on plasma pharmacokinetics would indicate only minor activity against pathogens except streptococci. In contrast, AUC24/MIC ratios achieved in soft tissue may be considered insufficient to kill extracellular pathogens causing soft tissue infections, except for Streptococcus pyogenes.Although ketolides and macrolides share relevant pharmacokinetic properties, the pharmacokinetics of both antimicrobial classes are not considered interchangeable. With a volume of distribution similar to that of azithromycin but plasma concentrations and an elimination half-life reflecting those of clarithromycin, the pharmacokinetics of ketolides may be considered ‘intermediate’ between those of macrolides and azalides. Thus the pharmacokinetics of ketolides can be considered similar but not identical to those of macrolides.
影响因子：
56.9
作者：
Ban, N;Nissen, P;Steitz, TA
通讯作者：
Steitz, TA