TAK-599 is a water-soluble prodrug of a cephalosporin compound, T-91825. In vitro and in vivo antibacterial activities of T-91825 and TAK-599, respectively, were examined. T-91825 was active against both gram-positive and gram-negative bacteria, unlike vancomycin and linezolid, which are inactive against gram-negative bacteria. The 90% minimum inhibitory concentration of T-91825 against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) was 2 micro g/ml. This activity was comparable to those of vancomycin, linezolid, teicoplanin, and arbekacin. T-91825 was similarly active against vancomycin-intermediate S. aureus. In a time-kill study, T-91825 showed more rapid and distinct decrease of viable cells of two MRSA strains than did vancomycin and linezolid in vitro. The effect of TAK-599 against systemic infection caused by clinical isolates of MRSA in mice was comparable or superior to that of vancomycin, linezolid, teicoplanin, and arbekacin. In addition, TAK-599 at a dose of 20 mg/kg significantly decreased bacterial counts in lungs of mice in an experimental pneumonia model caused by MRSA in which vancomycin and linezolid were totally ineffective at the same dose. These results suggest the usefulness of TAK-599 in the treatment of MRSA infections in humans.

中文翻译：

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T-91825（一种新型抗 MRSA 头孢菌素）的体外抗菌活性及其前药 TAK-599 的体内抗 MRSA 活性。


TAK-599 是头孢菌素化合物 T-91825 的水溶性前药。分别检查了 T-91825 和 TAK-599 的体外和体内抗菌活性。 T-91825 对革兰氏阳性菌和革兰氏阴性菌均具有活性，而万古霉素和利奈唑胺对革兰氏阴性菌没有活性。 T-91825对临床分离的耐甲氧西林金黄色葡萄球菌（MRSA）的90%最低抑制浓度为2微克/毫升。该活性与万古霉素、利奈唑胺、替考拉宁和阿贝卡星的活性相当。 T-91825 对万古霉素中间体金黄色葡萄球菌也具有类似的活性。在一项时间杀灭研究中，T-91825 在体外表现出比万古霉素和利奈唑胺更快、更明显地减少两种 MRSA 菌株活细胞的能力。 TAK-599 对小鼠体内 MRSA 临床分离株引起的全身感染的作用与万古霉素、利奈唑胺、替考拉宁和阿贝卡星相当或优于。此外，在 MRSA 引起的实验性肺炎模型中，20 mg/kg 剂量的 TAK-599 显着降低了小鼠肺部细菌计数，而相同剂量的万古霉素和利奈唑胺完全无效。这些结果表明 TAK-599 在治疗人类 MRSA 感染中的有用性。