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- Title
The Mutant Selection Window in Rabbits Infected with Staphylococcus aureus.
- Authors
Junchang Cui; Youning Liu; Rui Wang; Weihang Tong; Drlica, Karl; Xilin Zhao
- Abstract
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 AUC24/MPC value of ∼25 h, where AUC24 is the area under the drug concentration time curve in a 24-h interval. The lower boundary was estimated as an AUC24/MIC value of ∼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.
- Subjects
BACTERIAL diseases; STAPHYLOCOCCUS aureus infections; STAPHYLOCOCCAL diseases; RABBITS; ANTI-infective agents; MICROBIAL mutation
- Publication
Journal of Infectious Diseases, 2006, Vol 194, Issue 11, p1601
- ISSN
0022-1899
- Publication type
Article
- DOI
10.1086/508752