氟喹诺酮类药物抗菌作用的量效关系研究

FLUOROQUINOLONES: STUDIES ON THE MECHANISM OF THEIR BACTERICIDAL PARADOX

诺氟沙星、依诺沙星和培氟沙星对大肠杆菌2280和阴沟杆菌1029的杀菌作用随剂量增加而呈双相变化,其最强杀菌浓度(MBC)均为1～2μg/ml。三种药物在1/4MIC～MBC范围内抑制细菌DNA合成作用迅速增强,以后逐渐趋于坪值;而RNA合成需在较高浓度(≥0.5μg/ml)时才逐渐受到抑制。此DNA与RNA合成之量-效抑制曲线的交点均在1～2μg/ml之间。利福定(100μg/ml)和氯霉素(25μg/ml)几乎能完全拮抗三种药物的杀菌作用。以上结果提示:氟喹诺酮药物的杀菌作用与其抑制细菌DNA合成有关,且须以RNA和蛋白质不断合成为前提条件;其在较高浓度(>MBC)时杀菌作用逐渐减弱,与它能进行性抑制细菌RNA合成,继之蛋白质合成受阻有关。

Three fluoroquinolones(FQs), including Norfloxacin (NFX), Enoxacin(ENX) and Pefloxacin(PFX), were found to be most strongest bactericidal against E. coli 2280 and E. cloacae 1029 at 1 to 2μg/ml. Increases in the concentrations of these agents above this range reduced, rather than increased, their bactericidal effects. Therefore, the mode of actions of FQ_s was investigated. It was found that these agents in the range of l/4MIC^MBC(the most bactericidal concentration) could rapidly and increasingly inhibit the bacterial DNA synthesis by increasing the concentrations of FQ_s. At 1μg/ml, DNA synthesis could be inhibited by 75% or more. Above the concentration this action gradually lead to a'plateau'. However, the inhibittion of RNA synthesis could occur only at higher concentrations (0.5μg/ml) . These two inhibition curves of each of FQ_s crossed between] and 2μg/ml, which exactly equal MBCs of these FQ_s. In addition, Rifadin (100μg/ ml) and Chloramphenicol (25μ/ml) were able to abolish the bactericidal actions of FQ_s. These results suggested that the bactericidal actions of NFX, ENX, and PFX are all interrelated with their inhibitory effects on bacterial DNA synthesis, and continuous RNA and protein synthesis are prequisites for the bactericidal action. The reduction of bactericidal actions of FQ_s at higher concentrations may be due to their inhibiting bacterial RNA and protein synthesis.