Fukuoka T, Domon H, Kakuta M, Ishii C, Hirasawa A, Utsui Y, Ohya S, Yasuda H
Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Jpn J Antibiot. 1997 Apr;50(4):411-9.
We investigated the in vitro and in vivo combination effects between panipenem (PAPM) and vancomycin (VCM) on highly methicillin-resistant strains of Staphylococcus aureus (MRSA) isolated from various clinical specimens. Examination of combination between panipenem and vancomycin using checkerboard titration showed a good effect with mean fractional inhibitory index of 0.32 +/- 0.12 on 40 MRSA strains, and the effects were judged as synergistic against 33 strains (83%) and additive against 7 strains (17%). In the combination of PAPM and VCM at 1/4 MIC each against exponentially growing MRSA, bactericidal activity was found when PAPM was added at 1 hour or 2 hours prior to VCM-addition, and PAPM with VCM was added simultaneously, although bactericidal activity was scarcely demonstrated when VCM was added at 1 hour or 2 hours prior to PAPM-addition. Bactericidal activity was enhanced against MRSA in the combination of PAPM and VCM at 1/4 MIC each for MRSA than the bactericidal activity of VCM at 1 MIC alone, and the combination showed a strong bactericidal activity against P. aeruginosa. VCM alone, however, had no bactericidal activity in the in vitro mixed cultures of the two bacteria. Furthermore, the combination of PAPM and VCM induced a marked damage to cell surface and bacteriolysis against MRSA and P. aeruginosa in the mixed cultures, although VCM alone induced only slight morphological alterations. Penicillin-binding proteins (PBPs) including MRSA-specific PBP 2' were decreased greatly in the amounts in MRSA-cells with the increase of VCM-treated concentration. The combination therapy of PAPM and VCM showed a greater efficacy than the therapeutic efficacy of each antibiotic alone against mixed infection in burned mice caused by MRSA and P. aeruginosa, and the activity was judged as synergistic based on the FED index smaller than 0.34.
我们研究了帕尼培南（PAPM）与万古霉素（VCM）对从各种临床标本中分离出的耐甲氧西林金黄色葡萄球菌（MRSA）的体外和体内联合作用。采用棋盘滴定法检测帕尼培南与万古霉素的联合作用，结果显示对40株MRSA菌株效果良好，平均抑菌指数为0.32±0.12，其中33株（83%）为协同作用，7株（17%）为相加作用。在对指数生长期的MRSA分别使用1/4 MIC的PAPM和VCM联合时，当在添加VCM前1小时或2小时添加PAPM以及同时添加PAPM和VCM时，均发现有杀菌活性，而当在添加PAPM前1小时或2小时添加VCM时几乎未显示杀菌活性。对于MRSA，PAPM和VCM各1/4 MIC联合的杀菌活性比单独使用1 MIC的VCM的杀菌活性增强，且该联合对铜绿假单胞菌显示出较强的杀菌活性。然而，单独的VCM在两种细菌的体外混合培养中没有杀菌活性。此外，在混合培养中，PAPM和VCM的联合对MRSA和铜绿假单胞菌的细胞表面造成明显损伤并导致细菌溶解，而单独的VCM仅引起轻微的形态改变。随着VCM处理浓度的增加，包括MRSA特异性PBP 2'在内的青霉素结合蛋白（PBPs）在MRSA细胞中的含量大幅下降。在由MRSA和铜绿假单胞菌引起的烧伤小鼠混合感染中，PAPM和VCM联合治疗的疗效比单独使用每种抗生素的疗效更佳，基于FED指数小于0.34判断该联合作用为协同作用。
