Sumita Y, Nouda H, Kanazawa K, Fukasawa M
Discovery Research Laboratories III, Sumitomo Pharmaceuticals Research Center, Osaka, Japan.
Antimicrob Agents Chemother. 1995 Apr;39(4):910-6. doi: 10.1128/AAC.39.4.910.
The in vitro and in vivo antibacterial activities of SM-17466, a new 1 beta-methyl carbapenem, were evaluated against a wide range of clinical bacterial isoaltes and compared with the activities of meropenem, imipenem, vancomycin, and arbekacin. SM-17466 had a broad spectrum of action against gram-positive bacteria, showing especially potent activity against methicillin-resistant staphylococci. The MICs of SM-17466, meropenem, imipenem, vancomycin, and arbekacin at which 90% of clinical isolates of methicillin-resistant Staphylococcus aureus were inhibited were 3.13, 50, 100, 1.56, and 3.13 micrograms/ml, respectively. This activity of SM-17466 was almost equivalent to those of the antibiotics used for the treatment of infections caused by this organism. SM-17466 also showed bactericidal activity against methicillin-resistant S. aureus. In contrast, SM-17466 was less active against gram-negative bacteria, especially against Pseudomonas aeruginosa, compared with the other carbapenems; however, of the carbapenems, SM-17466 exhibited the highest activity against Haemophilus influenzae and Bacteriodes fragilis. SM-17466, at a 50% inhibitory concentration of less than 1 microgram/ml, bound to penicillin-binding proteins 1 to 4 in methicillin-susceptible S. aureus and also had good binding to penicillin-binding protein 2' in a methicillin-resistant strain (50% inhibitory concentration, 5.9 micrograms/ml). This high affinity, which was 10 and 20 times greater than those for meropenem and imipenem, respectively, was reflected in the potent activity of SM-17466 against methicillin-resistant S. aureus. SM-17466 demonstrated excellent in vivo efficacy against methicillin-susceptible and -resistant S. aureus strains in a mouse peritoneal infection model: the efficacy of SM-17466 against methicillin-resistant strains was equal to or one-third that of vancomycin. This activity was comparable to the in vitro activity of SM-17466. The subcutaneous injection of SM-17466 in mice revealed that the half-life of SM-17466 in serum was about 18 min, intermediate between those of vancomycin and arbekacin and 1.5-fold that of imipenem-cilastatin. SM-17466 was resistant to hydrolysis by swine renal dehydropeptidase I, to an extent comparable to the resistance shown by meropenem.
新型1β-甲基碳青霉烯类药物SM-17466的体外和体内抗菌活性针对多种临床分离菌株进行了评估，并与美罗培南、亚胺培南、万古霉素和阿贝卡星的活性进行了比较。SM-17466对革兰氏阳性菌具有广谱抗菌作用，对耐甲氧西林葡萄球菌显示出特别强的活性。对90%的耐甲氧西林金黄色葡萄球菌临床分离株产生抑制作用时，SM-17466、美罗培南、亚胺培南、万古霉素和阿贝卡星的最低抑菌浓度（MIC）分别为3.13、50、100、1.56和3.13微克/毫升。SM-17466的这种活性几乎等同于用于治疗该菌所致感染的抗生素的活性。SM-17466对耐甲氧西林金黄色葡萄球菌也显示出杀菌活性。相比之下，与其他碳青霉烯类药物相比，SM-17466对革兰氏阴性菌的活性较低，尤其是对铜绿假单胞菌；然而，在碳青霉烯类药物中，SM-17466对流感嗜血杆菌和脆弱拟杆菌表现出最高活性。SM-17466在低于1微克/毫升的50%抑制浓度下，能与甲氧西林敏感金黄色葡萄球菌中的青霉素结合蛋白1至4结合，并且在耐甲氧西林菌株中也能与青霉素结合蛋白2'良好结合（50%抑制浓度为5.9微克/毫升）。这种高亲和力分别比美罗培南和亚胺培南高10倍和20倍，这反映在SM-17466对耐甲氧西林金黄色葡萄球菌的强效活性上。在小鼠腹腔感染模型中，SM-17466对甲氧西林敏感和耐药的金黄色葡萄球菌菌株均显示出优异的体内疗效：SM-17466对耐甲氧西林菌株的疗效与万古霉素相当或为其三分之一。该活性与SM-17466的体外活性相当。对小鼠皮下注射SM-17466显示，SM-17466在血清中的半衰期约为18分钟，介于万古霉素和阿贝卡星之间，是亚胺培南-西司他丁的1.5倍。SM-17466对猪肾脱氢肽酶I具有耐药性，耐药程度与美罗培南相当。
