肺炎克雷伯菌对左氧氟沙星耐药的分子机制  

The molecular mechanism of Kp resistance to levofloxacin

作　　者：何晓静[1] 李晓冰[1] 于莹[1] 菅凌燕[1] HE Xiao-jing;LI Xiao-bing;YU Ying;JIAN Ling-yan(Department of Pharmacy,Shengjing Hospital of China Medical Universit)

机构地区：[1]中国医科大学附属盛京医院药学部,辽宁沈阳110004

出　　处：《中国医院药学杂志》2018年第15期1578-1581,共4页Chinese Journal of Hospital Pharmacy

基　　金：辽宁省自然科学基金项目(编号:2014021090)

摘　　要：目的:研究左氧氟沙星(levofloxacin,LVF)不同给药剂量和给药时间情况下,肺炎克雷伯菌(Klebsiella pneumoniae,Kp)耐药变化的分子机制。方法:建立Kp肺部感染小鼠模型,各组小鼠分别采用30,60,90 mg·kg^(-1)剂量LVF,连续治疗7 d;筛选并培养LVF给药及停药后不同时间的耐药突变Kp菌株,采用限制片段长度多态性-聚合酶式链反应法或PCR后直接测序的方法,检测Kp菌株耐药基因的变化。结果:LVF治疗后,15和90 mg·kg^(-1)剂量组分离的Kp菌株突变率低;30和60mg·kg^(-1)剂量组,Kp菌株突变率升高;LVF给药及停药后不同时间,15和90 mg·kg^(-1)剂量组均未检测到耐药基因gyrA、gyrB、parC和parE的突变和qnrA、qnrS和aac(6’)-Ib-cr;30和60 mg·kg^(-1)剂量组,给药5、7 d及停药后1、3 d,分别检测到qnrA、qnrS和aac(6’)-Ib-cr。结论:LVF 90 mg·kg^(-1)剂量组有效率高而耐药率低。根据以MPC为基础的PK/PD参数指定给药方案,可在获得满意治疗效果的同时,降低Kp对LVF的耐药。OBJECTIVE To study the dynamic resistant mechanisms of Kp using different dosages and different times of administration of levofloxacin（ LVF）. METHODS Kp lung infected mice models were constructed. Mice in different groups were administered different doses for seven days. Then the resistant Kp strains isolated from the different time periods after the drug withdrawal were screened and cultivated to detect the changes of the resistance gene in the Kp strains by polymerase chain reaction-restriction fragment length polymorphism（ RFLP-PCR） method or direct sequencing method after PCR. RESULTS After the oral administration of LVF,the mutation rates of 15 and 90 mg·kg^-1 groups were low,yet those of 30 and 60 mg·kg^-1 groups were high. The Kp pulmonary infected mice of 15 and 90 mg·kg^-1 groups showed no mutation in such resistance genes as gyr A,gyr B,par C or par E. Comparatively,qnr A,qnr S and aac（6＇）-Ib-cr had been detected in 30 and 60 mg·kg^-1 groups in the 5 th and 7 th days of oral administration of LVF,and the 1 st and 3 rd day after LVF withdrawal. CONCLUSION Among all the different LVF groups,the group of 90 mg·kg^-1 has the highest effective rate and the lowest resistance rate. The PK/PD parameters based on MPC can help us obtain a good efficacy of LVF. Meanwhile,the resistance of Kp to LVF is reduced significantly.

关 键 词：左氧氟沙星 肺炎克雷伯菌 防突变浓度 突变选择窗 耐药 

分 类 号：R978.1[医药卫生—药品]