Florea Naomi R, Tessier Pamela R, Zhang Cuilian, Nightingale Charles H, Nicolau David P
Loma Linda University School of Pharmacy, Loma Linda, California, USA.
Antimicrob Agents Chemother. 2004 Apr;48(4):1215-21. doi: 10.1128/AAC.48.4.1215-1221.2004.
Recent clinical failures associated with levofloxacin treatment for Streptococcus pneumoniae infections and growing evidence of frequent mutations in the isolate population have led to increased concerns regarding fluoroquinolone resistance. Our objective was to characterize the efficacies of levofloxacin and moxifloxacin against various genotypes of S. pneumoniae after simulated bronchopulmonary exposures. An in vitro model was used to simulate a levofloxacin concentration of 500 mg and a moxifloxacin concentration of 400 mg, which were previously determined to be the concentrations in the epithelial lining fluid of older adults receiving once-daily dosing. The effects of the drugs were tested against six S. pneumoniae containing various mutations. Bacterial density and resistance were quantitatively assessed over 48 h. The S. pneumoniae isolate with no mutation displayed a 4-log reduction in CFU after treatment with both agents and did not develop resistance. Isolates containing the parC or parE mutation or both mutations regrew and developed resistance when they were exposed to levofloxacin, despite an unbound area under the concentration-time curve (AUC):MIC ratio of approximately 100. When the isolate containing the parC and gyrA mutations was exposed to levofloxacin, there was a half-log reduction in the number of CFU compared to that for the control, but the isolate subsequently regrew. Likewise, levofloxacin did not kill the isolate containing the parC, gyrA, and parE mutations. Moxifloxacin sustained the killing of all bacterial isolates tested without the development of resistance. Levofloxacin did not sustain bacterial killing and did not prevent the emergence of further resistance in mutants with the parC or parE mutation or both mutations, even though an unbound AUC:MIC ratio for exposure well above the breakpoint of 30 to 40 established in the literature for S. pneumoniae was maintained. Moxifloxacin was effective against all isolates tested, despite the presence of isolates with two- and three-step mutations, for which the MICs were increased.
近期与左氧氟沙星治疗肺炎链球菌感染相关的临床失败案例以及分离菌群体中频繁出现突变的证据不断增加，引发了人们对氟喹诺酮耐药性的更多担忧。我们的目的是在模拟支气管肺暴露后，表征左氧氟沙星和莫西沙星对不同基因型肺炎链球菌的疗效。使用体外模型模拟左氧氟沙星浓度为500毫克和莫西沙星浓度为400毫克，这两种浓度先前被确定为接受每日一次给药的老年人上皮衬液中的浓度。测试了这两种药物对六种含有不同突变的肺炎链球菌的效果。在48小时内对细菌密度和耐药性进行了定量评估。未发生突变的肺炎链球菌分离株在用两种药物治疗后CFU减少了4个对数，并且未产生耐药性。含有parC或parE突变或两种突变的分离株在暴露于左氧氟沙星时会重新生长并产生耐药性，尽管浓度-时间曲线下未结合面积（AUC）：MIC比值约为100。当含有parC和gyrA突变的分离株暴露于左氧氟沙星时，与对照组相比CFU数量减少了半个对数，但该分离株随后重新生长。同样，左氧氟沙星未能杀死含有parC、gyrA和parE突变的分离株。莫西沙星持续杀死了所有测试的细菌分离株，且未产生耐药性。尽管维持了高于文献中为肺炎链球菌确定的30至40的断点的暴露未结合AUC：MIC比值，但左氧氟沙星未能持续杀死细菌，也未能阻止具有parC或parE突变或两种突变的突变体中进一步耐药性的出现。莫西沙星对所有测试的分离株均有效，尽管存在具有两步和三步突变且MIC增加的分离株。
