Telavancin: a novel semisynthetic lipoglycopeptide agent to counter the challenge of resistant Gram-positive pathogens
Telavancin: a novel semisynthetic lipoglycopeptide agent to counter the challenge of resistant Gram-positive pathogens
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DOI：
10.1177/2049936117690501
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发表时间：
2017-03-01
影响因子：
5.7
通讯作者：
Sahni, Shubham
中科院分区：
文献类型：
--
作者：
Das, Biswadeep;Sarkar, Chayna;Sahni, Shubham
Telavancin (TD-6424) 是一种半合成脂糖肽万古霉素衍生物，是 Theravance 开发的一种新型抗菌剂，用于克服耐药革兰氏阳性细菌感染，特别是耐甲氧西林金黄色葡萄球菌 (MRSA)。美国食品和药物管理局 (USFDA) 于 2009 年批准特拉万星用于治疗由革兰氏阳性菌引起的复杂皮肤和皮肤结构感染 (cSSSI)，包括 MRSA（金黄色葡萄球菌、无乳链球菌、化脓性链球菌、咽峡炎链球菌或粪肠球菌）。特拉万星有两种拟议的作用机制。在体外，特拉万星由于破坏细胞膜完整性而具有快速、浓度依赖性的杀菌作用。特拉万星对需氧和厌氧革兰氏阳性菌具有明显的体外活性。特拉万星和万古霉素具有相似的活性谱。革兰氏阴性细菌通常对特拉万星不敏感。特拉万星已在多种菌血症、心内膜炎、脑膜炎和肺炎动物模型中成功进行了测试。已经进行了特拉万星与治疗革兰氏阳性菌引起的复杂性皮肤和软组织感染的标准疗法（FAST 1和FAST 2）和III期[特拉万星在复杂性皮肤和皮肤结构感染中的评估1（ATLAS 1和ATLAS 2）]临床试验，以评估特拉万星在cSSSI中的疗效和安全性。已开展评估特拉万星治疗医院肺炎安全性和有效性的Ⅲ期临床试验[特拉万星治疗医院获得性肺炎1型和2型（ATTAIN 1和ATTAIN 2）的评估]。已开展一项 II 期随机、双盲临床试验，以评估特拉万星治疗无并发症金黄色葡萄球菌菌血症的安全性和有效性[特拉万星用于治疗无并发症金黄色葡萄球菌菌血症 (ASSURE)]。由万古霉素中间金黄色葡萄球菌 (VISA) 菌株（对达托霉素不敏感）引起的起搏器导线相关感染性心内膜炎已成功用肠外特拉万星治疗 8 周。特拉万星与血清白蛋白广泛结合（接近 93%），并且分布体积相对较小。特拉万星不被任何细胞色素 P450 微粒体酶生物转化，主要通过尿液排泄。尽管耐受性良好，但令人担忧的不良反应（包括肾功能障碍和 QTc 延长）仍值得关注。鉴于其与血浆蛋白的广泛结合、半衰期长和抗生素后作用长，它是对抗耐药革兰氏阳性病原体（即 MRSA）引起的感染的一种很有前景的治疗手段。
Telavancin (TD-6424), a semisynthetic lipoglycopeptide vancomycin-derivative, is a novel antimicrobial agent developed by Theravance for overcoming resistant Gram-positive bacterial infections, specifically methicillin-resistant Staphylococcus aureus (MRSA). The US Food and Drug Administration (USFDA) had approved telavancin in 2009 for the treatment of complicated skin and skin structure infections (cSSSIs) caused by Gram-positive bacteria, including MRSA (S. aureus, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus anginosus group, or Enterococcus faecalis). Telavancin has two proposed mechanisms of action. In vitro, telavancin has a rapid, concentration-dependent bactericidal effect, due to disruption of cell membrane integrity. Telavancin has demonstrable in vitro activity against aerobic and anaerobic Gram-positive bacteria. Telavancin and vancomycin have similar spectra of activity. Gram-negative bacteria are usually non-susceptible to telavancin. Telavancin has been successfully tested in various animal models of bacteremia, endocarditis, meningitis, and pneumonia. Phase II Telavancin versus Standard Therapy for Treatment of Complicated Skin and Soft-Tissue Infections due to Gram-Positive Bacteria (FAST 1 and FAST 2) and phase III [Assessment of Telavancin in Complicated Skin and Skin Structure Infections 1 (ATLAS 1 and ATLAS 2)] clinical trials have been conducted for evaluating telavancin's efficacy and safety in cSSSIs. Phase III clinical trials have been carried out for evaluating telavancin's safety and efficacy in nosocomial pneumonia [Assessment of Telavancin for Treatment of Hospital acquired Pneumonia 1 and 2 (ATTAIN 1 and ATTAIN 2)]. A phase II randomized, double-blind, clinical trial has been carried out for evaluating telavancin's safety and efficacy in uncomplicated S. aureus bacteremia [Telavancin for Treatment of Uncomplicated S. aureus Bacteremia (ASSURE)]. Pacemaker lead-related infective endocarditis due to a vancomycin intermediate S. aureus (VISA) strain (non-daptomycin susceptible) was successfully treated with parenteral telavancin for 8 weeks. Telavancin extensively binds to serum albumin (similar to 93%) and has a relatively small volume of distribution. Telavancin is not biotransformed by any cytochrome P450 microsomal enzymes and excreted mainly in the urine. Though well-tolerated, worrisome adverse effects, including renal dysfunction and QTc prolongation are of potential concern. Given its extensive binding to plasma proteins, long half-life, and a long post-antibiotic effect, it represents a promising addition to the therapeutic armamentarium in combating infections caused by resistant Gram-positive pathogens, namely, MRSA.