In Vivo Activity of Oritavancin in Animal Infection Models and Rationale for a New Dosing Regimen in Humans
In Vivo Activity of Oritavancin in Animal Infection Models and Rationale for a New Dosing Regimen in Humans
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DOI：
10.1093/cid/cis001
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发表时间：
2012-04-15
影响因子：
11.8
通讯作者：
Craig, William A.
中科院分区：
文献类型：
--
作者：
Ambrose, Paul G.;Drusano, George L.;Craig, William A.
奥利万星是一种新型糖肽类抗生素，对革兰氏阳性球菌具有浓度依赖性杀伤作用，药代动力学特征为广泛的组织分布和较长的终末半衰期。由于奥利万星粘附在小瓶和试管上，其对葡萄球菌和肠球菌的活性被低估了16至32倍，这阻碍了它的发展。动物模型的剂量分割研究表明，峰浓度是疗效的主要指标。奥利万星每日一次静脉给药对耐甲氧西林金黄色葡萄球菌（MRSA）心内膜炎、兔青霉素敏感和头孢菌素耐药肺炎球菌脑膜炎、大鼠葡萄球菌和肠球菌中心静脉导管感染以及小鼠吸入性炭疽24小时预防后有效。口服奥利万星比万古霉素对仓鼠艰难梭菌感染更有效。药效学表明，1200 mg的奥利万星单次给药对人体有效。在血小板减少小鼠中模拟该剂量对甲氧西林敏感的S。金黄色葡萄球菌和MRSA大腿和菌血症感染和肺炎球菌肺部感染。
Oritavancin is a novel glycopeptide antibiotic with concentration-dependent killing of Gram-positive cocci and pharmacokinetics characterized by extensive tissue distribution and a long terminal half-life. Its development was hindered by a 16- to 32-fold underestimation of activity against staphylococci and enterococci because of oritavancin's sticking to vials and tubes. Dose-fractionation studies in animal models suggested the peak concentration was the major index for efficacy. Once-daily intravenous administration of oritavancin was effective in methicillin-resistant Staphylococcus aureus (MRSA) endocarditis, penicillin-susceptible and cephalosporin-resistant pneumococcal meningitis in rabbits, staphylococcal and enterococcal central venous catheter infections in rats, and 24-hour postprophylaxis of inhaled anthrax in mice. Orally administered oritavancin was more effective than vancomycin in Clostridium difficile infection in hamsters. Pharmacodynamics suggested that a single dose of oritavancin at 1200 mg would be efficacious in humans. Simulation of this dose in neutropenic mice was highly effective in methicillin-sensitive S. aureus and MRSA thigh and bacteremia infections and pneumococcal lung infections.