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Antimicrobial Agents and Chemotherapy, June 2008, p. 1924-1928, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01371-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Enrichment of Fluoroquinolone-Resistant Staphylococcus aureus: Oscillating Ciprofloxacin Concentrations Simulated at the Upper and Lower Portions of the Mutant Selection Window

Department of Pharmacokinetics and Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia,¹ P. K. Anokhin Institute of Normal Physiology, Russian Academy of Medical Sciences, 11/4 Mokhovaya Street, Moscow 103009, Russia,² Mount Auburn Hospital, Harvard Medical School, 330 Mount Auburn Street, Cambridge, Massachusetts 02138³

Received 24 October 2007/ Returned for modification 25 February 2008/ Accepted 25 March 2008

The time inside the mutant selection window (MSW), T_MSW, appears to be less predictive of the selection of fluoroquinolone-resistant Staphylococcus aureus than is the ratio of the area under the concentration-time curve (AUC) to the MIC. This observation might be attributed to the fact that T_MSW does not consider the actual position of simulated antibiotic concentrations inside the MSW, which also might influence the amplification of resistant mutants. To test this hypothesis, the enrichment of ciprofloxacin-resistant S. aureus was studied at ciprofloxacin (CIP) concentrations that oscillate near the mutant prevention concentration (MPC), i.e., closer to the top of the MSW ("upper case"), and closer to the MIC, i.e., at the lower limit of the MSW ("lower case") at the same T_MSW. Two methicillin-resistant strains of S. aureus, ATCC 6538 and ATCC 43300 (MICs of 0.25 and 0.5 mg/liter, respectively, and MPCs of 4 and 2 mg/liter, respectively), were exposed to twice-daily CIP treatments for three consecutive days. With S. aureus ATCC 6538, the simulated ratios of the AUC at 24 h (AUC₂₄) to the MIC were 50 and 260 h (T_MSW 75% of the dosing interval). With S. aureus ATCC 43300, the simulated AUC₂₄/MICs were 30 and 100 h (T_MSW 56%). With each organism, mutants resistant to CIP were enriched in an AUC₂₄/MIC-dependent manner: the higher the AUC₂₄/MIC ratio, the lower the growth on CIP-containing plates. For example, the area under the time-kill curve of mutants resistant to 4x MIC of CIP in the upper case was three times smaller than that in the lower case for both S. aureus strains. Similar differences were seen at the higher (8x MIC) and lower (2x MIC) CIP concentrations. These data highlight differences in the selection of resistant S. aureus, depending on the position of simulated concentrations inside the MSW at a given T_MSW. This explains why T_MSW-based predictions of resistance are less accurate than those based on AUC/MIC and AUC/MPC.

Published ahead of print on 31 March 2008.