Fujimura Takaji, Yamano Yoshinori, Yoshida Isamu, Shimada Jingoro, Kuwahara Shogo
Discovery Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan.
Antimicrob Agents Chemother. 2003 Mar;47(3):923-31. doi: 10.1128/AAC.47.3.923-931.2003.
The in vitro antibacterial activity of S-3578, a new parenteral cephalosporin, against clinical isolates was evaluated. The MICs of the drug at which 90% of the isolates were inhibited were 4 micro g/ml for methicillin-resistant Staphylococcus aureus (MRSA) and 2 micro g/ml for methicillin-resistant Staphylococcus epidermidis, which were fourfold higher than and equal to those of vancomycin, respectively. The anti-MRSA activity of S-3578 was considered to be due to its high affinity for penicillin-binding protein 2a (50% inhibitory concentration, 4.5 micro g/ml). In time-kill studies with 10 strains each of MRSA and methicillin-susceptible S. aureus, S-3578 caused more than a 4-log(10) decrease of viable cells on the average at twice the MIC after 24 h of exposure, indicating that it had potent bactericidal activity. Furthermore, in population analysis of MRSA strains with heterogeneous or homogeneous resistance to imipenem, no colonies emerged from about 10(9) cells on agar plates containing twice the MIC of S-3578, suggesting the low frequency of emergence of S-3578-resistant strains from MRSA. S-3578 was also highly active against penicillin-resistant Streptococcus pneumoniae (PRSP), with a MIC(90) of 1 micro g/ml, which was comparable to that of ceftriaxone. S-3578 also had antibacterial activity against a variety of gram-negative bacteria including Pseudomonas aeruginosa, though its activity was not superior to that of cefepime. In conclusion, S-3578 exhibited a broad antibacterial spectrum and, particularly, had excellent activity against gram-positive bacteria including methicillin-resistant staphylococci and PRSP. Thus, S-3578 was considered to be worthy of further evaluation.
对新型肠外头孢菌素S-3578针对临床分离菌株的体外抗菌活性进行了评估。该药物抑制90%分离菌株的最低抑菌浓度(MIC),对耐甲氧西林金黄色葡萄球菌(MRSA)为4μg/ml,对耐甲氧西林表皮葡萄球菌为2μg/ml,分别比万古霉素高四倍和与万古霉素相当。S-3578对MRSA的抗菌活性被认为是由于其对青霉素结合蛋白2a的高亲和力(50%抑制浓度为4.5μg/ml)。在对10株MRSA和10株甲氧西林敏感金黄色葡萄球菌进行的时间杀菌研究中,S-3578在暴露24小时后,在两倍MIC浓度下平均使活菌数量减少超过4个对数(10),表明它具有强大的杀菌活性。此外,在对亚胺培南耐药性为异质性或同质性的MRSA菌株进行群体分析时,在含有两倍S-3578 MIC的琼脂平板上,约10⁹个细胞未出现菌落,提示MRSA产生S-3578耐药菌株的频率较低。S-3578对青霉素耐药肺炎链球菌(PRSP)也具有高活性,MIC₉₀为1μg/ml,与头孢曲松相当。S-3578对包括铜绿假单胞菌在内的多种革兰氏阴性菌也有抗菌活性,但其活性不优于头孢吡肟。总之,S-3578呈现出广泛的抗菌谱,尤其对包括耐甲氧西林葡萄球菌和PRSP在内的革兰氏阳性菌具有优异活性。因此,S-3578被认为值得进一步评估。