Liu Ming-tao, Sheng Mei-yan, Zhang Yun, Li Yu
Department of Pulmonary Diseases, Qilu Hospital, Shandong University, Jinan 250012, China.
Zhonghua Yi Xue Za Zhi. 2011 May 31;91(20):1427-31.
To observe whether the mutant selective windows (MSW) of ciprofloxacin would be reduced after its combination against Pseudomonas aeruginosa in rabbits.
Firstly the minimal inhibitory concentration (MIC), mutant prevention concentration (MPC), mutant selective windows (MSW, MPC-MIC) and selective indices (SI, MPC/MIC) of ciprofloxacin and tobramycin were measured in vitro respectively with standard strain ATCC27853. And the MIC was detected for the combination of ciprofloxacin and tobramycin. The rabbit tissue cage model was constructed to determine the pharmacokinetic parameters of ciprofloxacin by HPLC (high performance liquid chromatography). Fifty-five rabbits were randomly divided by a random number table into 11 groups: physiological saline in 1 group, ciprofloxacin alone in 5 groups and ciprofloxacin plus tobramycin in another 5 groups. The rabbits received ciprofloxacin 10 times a day at a 2-hour dosing interval. In 2 dosing groups, the steady state concentrations of ciprofloxacin reached to 0.25, 0.5, 1.0, 2.0 and 4.0 mg/L respectively. The dose of tobramycin was 2.0 mg×kg(-1)×d(-1) and its peak concentration reached around 2.0 mg/L. At Day 3, the tissue juice was extracted, diluted and coated on agar plates with ciprofloxacin at a concentration of 0.25 mg/L so as to observe the growing condition of mutants.
Against Pseudomonas aeruginosa, the values of MIC, MPC and SI of ciprofloxacin were 0.25 mg/L, 4.0 mg/L and 16 while 0.25 mg/L, 8.0 mg/L and 32 for tobramycin respectively. Single groups: the mutants were found in 0.25, 0.5, 1.0 and 2.0 mg/L groups, but none in 4.0 mg/L group. The MPC of ciprofloxacin was the same for in vivo and in vitro. Both were at 16. Combination groups: the mutants were only found in the group with a concentration of ciprofloxacin at 0.25 mg/L while no mutants in the other groups. And MPC was 0.5 mg/L and MIC 0.125 mg/L for ciprofloxacin plus tobramycin. And the value of SI was 4.
The combined use of ciprofloxacin and tobramycin may reduce the mutant selective windows of ciprofloxacin against P. aeruginosa in rabbits so as to reduce the occurrence of mutants to control its drug resistance.
观察环丙沙星与妥布霉素联合应用后对兔铜绿假单胞菌突变选择窗（MSW）的影响。
首先采用标准菌株ATCC27853分别测定环丙沙星和妥布霉素的最低抑菌浓度（MIC）、突变预防浓度（MPC）、突变选择窗（MSW，MPC - MIC）和选择指数（SI，MPC/MIC）。并检测环丙沙星与妥布霉素联合后的MIC。构建兔组织笼模型，采用高效液相色谱法（HPLC）测定环丙沙星的药代动力学参数。55只家兔按随机数字表法随机分为11组：1组为生理盐水组，5组为环丙沙星单独给药组，另5组为环丙沙星加妥布霉素联合给药组。家兔每天给药10次，给药间隔2小时。2个给药组中环丙沙星稳态血药浓度分别达到0.25、0.5、1.0、2.0和4.0 mg/L。妥布霉素剂量为2.0 mg×kg⁻¹×d⁻¹，峰浓度达2.0 mg/L左右。第3天抽取组织液，稀释后接种于含0.25 mg/L环丙沙星的琼脂平板上，观察突变菌生长情况。
对铜绿假单胞菌，环丙沙星的MIC、MPC和SI值分别为0.25 mg/L、4.0 mg/L和16，妥布霉素分别为0.25 mg/L、8.0 mg/L和32。单药组：0.25、0.5、1.0和2.0 mg/L组均发现有突变菌，4.0 mg/L组未发现。环丙沙星体内外MPC相同，均为16。联合组：仅在环丙沙星浓度为0.25 mg/L组发现有突变菌，其他组未发现。环丙沙星与妥布霉素联合后的MPC为0.5 mg/L，MIC为0.125 mg/L，SI值为4。
环丙沙星与妥布霉素联合应用可降低环丙沙星对兔铜绿假单胞菌的突变选择窗，从而减少突变菌的产生，控制其耐药性。
