Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6117912 | International Journal of Antimicrobial Agents | 2014 | 5 Pages |
Abstract
The time inside the mutant selection window (TMSW) has been shown to be less predictive of selection of fluoroquinolone-resistant bacteria than the ratio of the area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC). To explore the different predictive powers of TMSW and AUC/MIC, enrichment of ciprofloxacin-resistant mutants of four Escherichia coli strains was studied in an in vitro dynamic model at widely ranging TMSW values. Each organism was exposed to twice-daily ciprofloxacin for 3 days. Peak antibiotic concentrations were simulated to be close to the MIC, between the MIC and the mutant prevention concentration (MPC), and above the MPC, with TMSW varying from 0% to 100% of the dosing interval. Amplification of resistant mutants was monitored by plating on medium with 8Ã MIC of the antibiotic. For each organism, TMSW plots of the area under the bacterial mutant concentration-time curve (AUBCM) exhibited a hysteresis loop: at a given TMSW that corresponds to the points on the ascending portion of the bell-shaped AUBCM-AUC/MIC curve [when the time above the MPC (T>MPC) was zero], the AUBCM was greater than at the same TMSW related to the descending portion (T>MPCÂ >Â 0). A sigmoid function fits these separate data sets well for combined data with the four organisms (r2Â =Â 0.81 and 0.92, respectively), in contrast to fitting the whole data pool while ignoring the AUC/MIC-resistance relationship (r2Â =Â 0.61). These data allow the appropriate use of TMSW as a predictor of bacterial resistance.
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Authors
Alexander A. Firsov, Yury A. Portnoy, Elena N. Strukova, Darya S. Shlykova, Stephen H. Zinner,