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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{triangledown}

Alexander A. Firsov,1* Irene Y. Lubenko,1,2 Maria V. Smirnova,1 Elena N. Strukova,1 and Stephen H. Zinner3

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), TMSW, 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 TMSW 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 TMSW. 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 (TMSW 75% of the dosing interval). With S. aureus ATCC 43300, the simulated AUC24/MICs were 30 and 100 h (TMSW 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 TMSW. This explains why TMSW-based predictions of resistance are less accurate than those based on AUC/MIC and AUC/MPC.

* Corresponding author. Mailing address: Department of Pharmacokinetics and Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 Bolshaya Pirogovskaya St., Moscow 119021, Russia. Phone: 7 (495) 708-3341. Fax: 7 (495) 245-0295. E-mail: firsov{at}dol.ru

{triangledown} Published ahead of print on 31 March 2008.

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.



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