Species differences in ciprofloxacin resistance among Gram-negative bacteria: can “anti-mutant” ratios of the area under the concentration–time curve to the MIC be achieved clinically?

Abstract

To explore if the ‘anti-mutant’ ratios of 24-h area under the concentration–time curve (AUC₂₄) to the MIC overlap the clinically attainable AUC₂₄/MICs, the selection of ciprofloxacin-resistant Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae mutants was studied in dynamic model that simulates human pharmacokinetics of ciprofloxacin. Four strains each of E. coli and P. aeruginosa and three strains of K. pneumoniae were exposed to ciprofloxacin over a 50–400-fold range of the AUC₂₄/MIC ratio. Based on population analysis data, areas under the bacterial mutant concentration–time curves (AUBC_Ms) were determined for subpopulations resistant to 4×, 8× and 16× MIC of the antibiotic. The emergence of resistance among three Gram-negative organisms was concentration dependent. Based on the AUBC_M vs. AUC₂₄/MIC curves, the predicted ‘anti-mutant’ AUC₂₄/MIC ratios were clinically attainable with E. coli but not with P. aeruginosa and K. pneumoniae. The emergence of fluoroquinolone resistance in a clinical setting can be predicted using dynamic models.

Keywords:

• Fluoroquinolones
• Gram-negative bacteria
• Resistant mutant enrichment
• In vitro dynamic model