The mutant selection window in rabbits infected with Staphylococcus aureus

被引:83
作者
Cui, Junchang
Liu, Youning
Wang, Rui
Tong, Weihang
Drlica, Karl
Zhao, Xilin
机构
[1] Publ Hlth Res Inst, Newark, NJ 07103 USA
[2] Peoples Liberat Army Gen Hosp, Beijing, Peoples R China
基金
中国国家自然科学基金;
关键词
RESISTANT STREPTOCOCCUS-PNEUMONIAE; PREVENTION CONCENTRATION; MYCOBACTERIUM-SMEGMATIS; MODEL; CIPROFLOXACIN; LEVOFLOXACIN; MOXIFLOXACIN; SUSCEPTIBILITY; ERYTHROMYCIN; ANTIBIOTICS;
D O I
10.1086/508752
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background. The mutant selection window hypothesis, originally based on agar plate assays, may lead to new antimicrobial dosing strategies that severely restrict the acquisition of resistance. However, it has not been directly tested in an animal model of infection. Methods. Local infection with Staphylococcus aureus was established in rabbits, and the infected animals were treated orally with various doses of levofloxacin. Changes in levofloxacin concentration, levofloxacin susceptibility, and counts of total and resistant viable bacteria were monitored at the site of infection. Results. S. aureus lost levofloxacin susceptibility when drug concentrations at the site of infection fluctuated between the lower and upper boundaries of the window, defined in vitro as the minimum inhibitory concentration (MIC) 99 and the mutant prevention concentration (MPC), respectively. The upper boundary of the selection window in vivo was estimated as an AUC(24)/MPC value of similar to 25 h, where AUC(24) is the area under the drug concentration time curve in a 24-h interval. The lower boundary was estimated as an AUC(24)/MIC value of similar to 20 h. Conclusions. The mutant selection window exists in vivo, and its boundaries fit well with those determined in vitro. Maintenance of antimicrobial concentrations above the window is expected to suppress the outgrowth of resistant mutant subpopulations.
引用
收藏
页码:1601 / 1608
页数:8
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