Open AccessEnrichment of Fluoroquinolone-Resistant Staphylococcus aureus : Oscillating Ciprofloxacin Concentrations Simulated at the Upper and Lower Portions of the Mutant Selection Window
Author(s) -
Alexander A. Firsov,
Irene Yu Lubenko,
Maria Smirnova,
Ele. Strukova,
Stephen H. Zinner
Publication year - 2008
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.01371-07
Subject(s) - staphylococcus aureus , ciprofloxacin , microbiology and biotechnology , liter , micrococcaceae , antibiotics , mutant , minimum inhibitory concentration , antibacterial agent , area under the curve , biology , chemistry , bacteria , pharmacology , biochemistry , genetics , gene , endocrinology
The time inside the mutant selection window (MSW),T MSW , appears to be less predictive of the selection of fluoroquinolone-resistantStaphylococcus 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 thatT 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-resistantS. 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 sameT MSW . Two methicillin-resistant strains ofS. 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. WithS. 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). WithS. 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 4× MIC of CIP in the upper case was three times smaller than that in the lower case for bothS. aureus strains. Similar differences were seen at the higher (8× MIC) and lower (2× MIC) CIP concentrations. These data highlight differences in the selection of resistantS. aureus , depending on the position of simulated concentrations inside the MSW at a givenT MSW . This explains whyT MSW -based predictions of resistance are less accurate than those based on AUC/MIC and AUC/MPC.