Combined application of ciprofloxacin and tobramycin on mutant selective windows of ciprofloxacin against Pseudomonas aeruginosa

Abstract

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.