Linezolid in vitro:: mechanism and antibacterial spectrum
Linezolid in vitro:: mechanism and antibacterial spectrum
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DOI：
10.1093/jac/dkg249
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发表时间：
2003-05-01
影响因子：
5.2
通讯作者：
Livermore, DM
中科院分区：
文献类型：
--
作者：
Livermore, DM
恶唑烷酮类药物是目前可获得的新型革兰氏阳性抗菌药物中的重要药物。它们在20世纪80年代末由杜邦制药公司发现，但利奈唑胺是第一个适合开发的类似物，只有在20世纪90年代由Pharmacia重新检查该家族时才被发现。恶唑烷酮与原核核糖体的50 S亚基结合，阻止蛋白质合成起始复合物的形成。这是一种新的作用模式;其他蛋白质合成抑制剂要么阻断多肽延伸，要么导致mRNA的误读。利奈唑胺的MIC随检测方法、实验室和细菌存活的薄雾而略有不同，但所有工作人员均发现敏感性分布较窄且呈单峰，链球菌、肠球菌和葡萄球菌的MIC值在0.5 - 4 mg/L之间。对耐其他抗生素的革兰氏阳性球菌，包括耐甲氧西林葡萄球菌和耐万古霉素肠球菌，保留了全部活性。莫拉氏菌属、巴氏杆菌属和拟杆菌属的MIC为4-8 mg/L。但其它革兰氏阴性细菌由于内源性外排活性而具有抗性。耐药性很难在体外选择，但迄今为止，在少数肠球菌感染和2例MRSA病例的治疗期间报告了耐药性;该机制需要形成利奈唑胺结合位点的23 S rRNA突变。选择耐药的风险因素包括留置器械、未引流病灶、治疗时间延长和剂量不足。
Oxazolidinones are prominent among the new Gram-positive antimicrobial agents now becoming available. They were discovered by DuPont Pharmaceuticals in the late 1980s but linezolid, the first analogue suitable for development, was found only when the family was re-examined by Pharmacia in the 1990s. Oxazolidinones bind to the 50S subunit of the prokaryotic ribosome, preventing formation of the initiation complex for protein synthesis. This is a novel mode of action; other protein synthesis inhibitors either block polypeptide extension or cause misreading of mRNA. Linezolid MICs vary slightly with the test method, laboratory, and significance attributed to thin hazes of bacterial survival, but all workers find that the susceptibility distributions are narrow and unimodal, with MIC values between 0.5 and 4 mg/L for streptococci, enterococci and staphylococci. Full activity is retained against Gram-positive cocci resistant to other antibiotics, including methicillin-resistant staphylococci and vancomycin-resistant enterococci. MICs are 4-8 mg/L for Moraxella, Pasteurella and Bacteroides spp. but other Gram-negative bacteria are resistant as a result of endogenous efflux activity. Resistance is difficult to select in vitro but has been reported during therapy in a few enterococcal infections and in two MRSA cases to date; the mechanism entails mutation of the 23S rRNA that forms the binding site for linezolid. Risk factors for selection of resistance include indwelling devices, undrained foci, protracted therapy and underdosage.