氟喹诺酮药物对金黄色葡萄球菌同源耐药突变株的耐药突变选择窗研究

Mutant selection windows of fluoroquinolones for isogenic resistant mutants of Staphylococcus aureus

目的通过测定不同氟喹诺酮(FQ)药物对同源金黄色葡萄球菌耐药突变株的MIC和防耐药突变浓度(mutant prevention concentration,M PC),分析不同药物的抗菌活性及限制耐药突变株选择的能力。方法分别采用环丙沙星和加替沙星琼脂平板筛选金黄色葡萄球菌ATCC25923同源的第一步和第二步耐药突变株。采用琼脂平板稀释法测定各耐药突变株的M IC和M PC,计算选择指数(MPCM/IC)。结果加替沙星和莫西沙星对金黄色葡萄球菌ATCC25923第一步耐药突变的M PC值(1～2μg/m l)明显低于环丙沙星、左氧氟沙星和帕珠沙星(4～16μg/ml),以上5种FQ药物对第一步耐药突变的M PC值和选择指数分别为ATCC25923的2～8倍和1～4倍。加替沙星和莫西沙星对第二步耐药突变的M PC值为8～16μgm/l。结论对于金黄色葡萄球菌ATCC25923同源的第一步耐药突变株,加替沙星和莫西沙星限制下一步耐药突变株选择的能力强于环丙沙星、左氧氟沙星和帕珠沙星,结合药动学参数,环丙沙星、左氧氟沙星和帕珠沙星很容易选择出下一步耐药突变株;而加替沙星和莫西沙星则能够限制下一步耐药突变株的选择。对于第二步耐药突变株,加替沙星和莫西沙星则很容易筛选出对这两种药物也耐药的菌株。临床上为延长加替沙星和莫西沙星的应用时间,对于已对左氧氟沙星耐药的菌株应避免应用加替沙星和莫西沙星单药治疗。

Objective The antibacterial activities and the abilities of restricting selection of resistant mutants of fluoroquinolones were studied by measuring minimal inhibitory concentrations （MIC） and mutant prevention concentrations （MPC） of fluoroquinolones against isogenic resistant mutants of Staphylococcus aureus strain ATCC25923. Methods The first-step and second-step resistant mutants of Staphylococcus aureus strain ATCC25923 were selected by ciprofloxacin and gatifloxacin respectively. MICs and MPCs of 5 fluoroquinolones for isogenic resistant mutants of Staphylococcus aureus strain ATCC25923 were determined by agar plates dilution method, and selection index was defined as the ratio of MPC/MIC. Results For first-step resistant mutants, MPCs of gatifloxacin and moxifloxacin （1 -2μg/ml） were significant lower than those of ciprofloxacin, levofloxacin and pazufloxacin （4 - 16μg/ml）. MPCs and selection indices of ciprofloxacin, levofloxacin, pazufloxacin, gatifloxacin and moxifloxacin for first - step resistant mutants of S taphylococcus aureus strain ATCC25923 were 2 - 8 times and 1 - 4 times higher than those for strain ATCC25923 respectively. MPCs of gatifloxacin and moxifloxacin for second-step resistant mutants were 8 - 16μg/ml. Conclusion For first-step resistant mutants of Staphylococcus aureus strain ATCC25923, the abilities of gatifloxacin and moxifloxacin for restricting the selection of next-step resistant mutants were stronger than those of ciprofloxacin, levofloxacin and pazufloxacin. Combined with pharmacokinetic parameters, gatifloxacin and moxifloxacin may restrict the selective enrichment of next-step resistant mutants and ciprofloxacin, levofloxacin and pasufloxacin are expected to selectively enrich next-step mutants easily. For second-step resistant mutants, gatifloxacin and moxifloxacin are expected to selectively enrich next-step mutants easily too. Thus, in order to extend the lifespan of moxifloxacin and gatifloxacin in clinic, moxifloxacin and gatifloxacin should avoid to be used against levofloxacin-resistant mutants.