Van Bambeke Françoise, Harms Joerg M, Van Laethem Yves, Tulkens Paul M
Université Catholique de Louvain, Faculté de Médecine, Unité de Pharmacologie Cellulaire et Moléculaire, UCL7370 Avenue Mounier 73, 1200 Brussels, Belgium.
Expert Opin Pharmacother. 2008 Feb;9(2):267-83. doi: 10.1517/14656566.9.2.267.
Ketolides differ from macrolides by removal of the 3-O-cladinose (replaced by a keto group), a 11,12- or 6,11-cyclic moiety and a heteroaryl-alkyl side chain attached to the macrocyclic ring through a suitable linker. These modifications allow for anchoring at two distinct binding sites in the 23S rRNA (increasing activity against erythromycin-susceptible strains and maintaining activity towards Streptococcus pneumoniae resistant to erythromycin A by ribosomal methylation), and make ketolides less prone to induce methylase expression and less susceptible to efflux in S. pneumoniae. Combined with an advantageous pharmacokinetic profile (good oral bioavailability and penetration in the respiratory tract tissues and fluids; prolonged half-life allowing for once-a-day administration), these antimicrobial properties make ketolides an attractive alternative for the treatment of severe respiratory tract infections such as pneumonia in areas with significant resistance to conventional macrolides. For telithromycin (the only registered ketolide so far), pharmacodynamic considerations suggest optimal efficacy for isolates with minimum inhibitory concentration values < or = 0.25 mg/l (pharmacodynamic/pharmacokinetic breakpoint), calling for continuous and careful surveys of bacterial susceptibility. Postmarketing surveillance studies have evidenced rare, but severe, side effects (hepatotoxicity, respiratory failure in patients with myasthenia gravis, visual disturbance and QTc prolongation in combination with other drugs). On these bases, telithromycin indications have been recently restricted by the US FDA to community-acquired pneumonia, and caution in patients at risk has been advocated by the European authorities. Should these side effects be class related, they may hinder the development of other ketolides such as cethromycin (in Phase III, but on hold in the US) or EDP-420 (Phase II).
酮内酯类药物与大环内酯类药物的不同之处在于，其去除了3-O-克拉定糖（被酮基取代）、11,12-或6,11-环状部分以及通过合适连接基连接到大环上的杂芳基-烷基侧链。这些修饰使得酮内酯类药物能够锚定在23S rRNA的两个不同结合位点（增强对红霉素敏感菌株的活性，并通过核糖体甲基化维持对耐红霉素A的肺炎链球菌的活性），并使酮内酯类药物不易诱导甲基化酶表达，且在肺炎链球菌中不易被外排。结合有利的药代动力学特征（良好的口服生物利用度以及在呼吸道组织和体液中的渗透；半衰期延长，允许每日一次给药），这些抗菌特性使酮内酯类药物成为治疗严重呼吸道感染（如在对传统大环内酯类药物有显著耐药性的地区的肺炎）的有吸引力的替代药物。对于泰利霉素（目前唯一已注册的酮内酯类药物），药效学考虑表明，对于最低抑菌浓度值≤0.25 mg/l的分离株具有最佳疗效（药效学/药代动力学断点），这就需要持续且仔细地监测细菌敏感性。上市后监测研究已证实存在罕见但严重的副作用（肝毒性、重症肌无力患者的呼吸衰竭、视觉障碍以及与其他药物联合使用时的QTc延长）。基于这些原因，美国食品药品监督管理局（FDA）最近已将泰利霉素的适应症限制为社区获得性肺炎，欧洲当局也提倡对有风险的患者谨慎使用。如果这些副作用与类别相关，它们可能会阻碍其他酮内酯类药物（如赛托霉素，处于III期，但在美国被搁置）或EDP-420（II期）的开发。
