Brinker Allen D, Wassel Ronald T, Lyndly Jenna, Serrano Jose, Avigan Mark, Lee William M, Seeff Leonard B
Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
Hepatology. 2009 Jan;49(1):250-7. doi: 10.1002/hep.22620.
Telithromycin is the first of a new class of ketolide antibiotics with increased activity against penicillin-resistant and erythromycin-resistant pneumococci. This agent received approval by the United States Food and Drug Administration (FDA) in 2004 for treatment of upper and lower respiratory infections. Following market introduction, spontaneous reports of telithromycin-associated hepatotoxicity, including frank liver failure, were received. To address these reports, an ad hoc group with expertise in spontaneous adverse events reporting and experience in evaluating drug-induced liver injury was formed, including members of the FDA, other federal agencies, and academia. The primary objective of this group was to adjudicate case reports of hepatic toxicity for causal attribution to telithromycin. After an initial screening of all cases of liver injury associated with telithromycin reported to FDA as of April 2006 by one of the authors, 42 cases were comprehensively reviewed and adjudicated. Five cases included a severe outcome of either death (n = 4) or liver transplantation (n = 1); more than half were considered highly likely or probable in their causal association with telithromycin. Typical clinical features were: short latency (median, 10 days) and abrupt onset of fever, abdominal pain, and jaundice, sometimes with the presence of ascites even in cases that resolved. Concurrence in assignment of causality increased after agreement on definitions of categories and interactive discussions.
Telithromycin is a rare cause of drug-induced liver injury that may have a distinctive clinical signature and associated high mortality rate. Consensus for attribution of liver injury to a selected drug exposure by individual experts can be aided by careful definition of terminology and discussion.
泰利霉素是新型酮内酯类抗生素中的首个药物，对耐青霉素和耐红霉素的肺炎球菌活性增强。该药物于2004年获得美国食品药品监督管理局（FDA）批准，用于治疗上、下呼吸道感染。上市后，收到了关于泰利霉素相关肝毒性的自发报告，包括严重肝衰竭。为处理这些报告，成立了一个临时小组，成员包括FDA、其他联邦机构和学术界的专家，他们在自发不良事件报告方面具有专业知识，且有评估药物性肝损伤的经验。该小组的主要目标是判定肝毒性病例报告中泰利霉素的因果关系。在其中一位作者对截至2006年4月向FDA报告的所有与泰利霉素相关的肝损伤病例进行初步筛选后，对42例病例进行了全面审查和判定。5例出现了严重后果，包括死亡（4例）或肝移植（1例）；超过半数病例被认为与泰利霉素的因果关系很可能或极有可能。典型的临床特征为：潜伏期短（中位数为10天），发热、腹痛和黄疸突然发作，即使在病情缓解的病例中有时也会出现腹水。在就类别定义达成一致并进行互动讨论后，因果关系判定的一致性有所提高。
泰利霉素是药物性肝损伤的罕见病因，可能具有独特的临床特征且死亡率较高。通过仔细定义术语和进行讨论，有助于个别专家对肝损伤归因于特定药物暴露达成共识。
