Hammerschlag Margaret R, Sharma Roopali
State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203-2098, USA.
Expert Opin Investig Drugs. 2008 Mar;17(3):387-400. doi: 10.1517/13543784.17.3.387.
The ketolides are a subclass of macrolides, which were designed specifically to overcome macrolide-resistant respiratory pathogens. Ketolides lack the cladinose sugar, which is replaced with a 3-ketone group. Ketolides bind to a secondary region on domain II of the 23S rRNA subunit. Telithromycin was the first ketolide to be approved by the FDA in 2004 for treatment of community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB) and sinusitis. However, in 2006, after reports of serious hepatotoxicity, the FDA issued a public health advisory followed by a warning. In 2007 the indications for treatment of AECB and sinusitis were removed from the labeling. Cethromycin (ABT-773) is the only other ketolide currently under clinical development.
To review currently available data on cethromycin, including chemistry, in vitro activity, pharmacokinetics, pharmacodynamics, in vivo activity and results of treatment studies in humans.
A search was made in PubMed, pharmaceutical databases and meeting abstracts using the terms ketolides, ABT-773 and cethromycin.
RESULTS/CONCLUSIONS: Cethromycin has comparable tissue penetration, pharmacokinetics and in vitro activity compared with telithromycin to Streptococcus pneumoniae, including multidrug-resistant isolates, Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila. There is only one published CAP treatment study that compared cethromycin 150 mg q.d. with 150 mg b.i.d. One Phase II and a Phase II/III study have been presented in abstract form, both were non-comparative, dose-ranging studies, which suggested that 150 mg q.d. or 300 mg q.d. were comparable in terms of clinical response and bacterial eradication, although data on the latter are limited. Data on side effects are limited and appear to be mainly gastrointestinal. There have been no reports of serious hepatotoxicity at the time of this writing. Cethromycin may have other uses in addition to treatment of CAP respiratory infections, including treatment of infections due to Neisseria gonorrhoeae and Chlamydia trachomatis and bioterrorism agents including Bacillus anthracis, Yersinia pestis and Francisella tularensis.
酮内酯类是大环内酯类的一个亚类，其设计目的是专门克服对大环内酯类耐药的呼吸道病原体。酮内酯类缺乏克拉定糖，取而代之的是一个3-酮基。酮内酯类与23S rRNA亚基结构域II的一个二级区域结合。泰利霉素是2004年首个获美国食品药品监督管理局（FDA）批准用于治疗社区获得性肺炎（CAP）、慢性支气管炎急性加重（AECB）和鼻窦炎的酮内酯类药物。然而，2006年，在有严重肝毒性的报告后，FDA发布了一份公共卫生咨询报告，随后发出了警告。2007年，AECB和鼻窦炎的治疗适应症从药品标签中删除。塞托霉素（ABT-773）是目前正在进行临床开发的唯一一种其他酮内酯类药物。
综述目前可获得的关于塞托霉素的数据，包括化学性质、体外活性、药代动力学、药效学、体内活性以及人体治疗研究结果。
在PubMed、药学数据库和会议摘要中使用酮内酯类、ABT-773和塞托霉素等术语进行检索。
结果/结论：与泰利霉素相比，塞托霉素对肺炎链球菌（包括多重耐药菌株）、流感嗜血杆菌、卡他莫拉菌、肺炎衣原体、肺炎支原体和嗜肺军团菌具有相当的组织穿透力、药代动力学和体外活性。仅有一项已发表的CAP治疗研究比较了每日150 mg的塞托霉素与每日两次、每次150 mg的塞托霉素。一项II期研究和一项II/III期研究已以摘要形式发表，两者均为非对照、剂量范围研究，结果表明每日150 mg或每日300 mg在临床反应和细菌清除方面相当，不过关于后者的数据有限。副作用数据有限，似乎主要是胃肠道方面的。在撰写本文时，尚无严重肝毒性的报告。除治疗CAP呼吸道感染外，塞托霉素可能还有其他用途，包括治疗淋病奈瑟菌和沙眼衣原体感染以及生物恐怖主义病原体感染，如炭疽芽孢杆菌、鼠疫耶尔森菌和土拉弗朗西斯菌。
