Comparative pharmacodynamics of ABT492 and ciprofloxacin (CIP) with Escherichia coli and Pseudomonas aeruginosa in an in vitro dynamic model
Abstract number: 902_p1024
To compare the pharmacodynamics of ABT492 relative to CIP, the kinetics of killing of Gram-negative organisms were studied using a dynamic model that simulates human pharmacokinetics of the fluoroquinolones.
Clinical isolates of E. coli and P. aeruginosa (MICABTs 0.01 and 0.12; MICCIPs 0.01 and 0.19 mg/L, respectively) were exposed to bi-exponentially decreasing concentrations of ABT492 (T1/2, alpha 2.1 h, T1/2, beta 23 h) and mono-exponentially decreasing concentrations of CIP (T1/2 4 h). Single dose simulations were performed with ABT492 vs. two 12-h doses CIP at different ratios of the area under the curve (AUC) to MIC, which varied from 60 to 480 h. Both E. coli and P. aeruginosa were also exposed to the clinically achievable AUC/MIC ratios of ABT492 (1740 and 140 h, respectively) and CIP (2200 and 120 h, respectively) that correspond to a 400-mg dose of ABT492 and two 500-mg doses of CIP. In addition, an 800-mg dose of ABT492 was simulated against P. aeruginosa as a single dose (AUC/MIC 280 h) and as two 400-mg doses given with a 12-h interval (AUC/MIC 2 × 140 h).
The maximal reductions in the starting inoculum of antibiotic-exposed E. coli and P. aeruginosa were greater with ABT492 than with CIP at most of the simulated AUC/MICs, but the times to regrowth were shorter with ABT492. Species-independent AUC/MIC relationships of the intensity of the antimicrobial effect (IE area between the control growth and the time-kill/regrowth curves) were specific for ABT492 and CIP. Despite greater IEs produced by CIP at a given AUC/MIC ratio (from 120 to 480 h), the effect of the clinically achievable AUC/MIC of ABT492 (1740 h) on E. coli was more pronounced than the respective AUC/MIC of CIP (2200 h). With P. aeruginosa, a 140-h AUC/MIC of ABT492 (400 mg as a single dose) provided an 1.8-fold smaller IE than a 120-h AUC/MIC of CIP. However, two 12-h doses of ABT492 (AUC/MIC 2 × 140 h) were even more efficient than CIP.
These findings predict comparable efficacies of clinically achievable AUC/MICs of ABT492 and CIP against E. coli (q.d. vs. b.i.d. quinolone dosing) and P. aeruginosa (b.i.d. dosing) but suggest lower efficacy of q.d. ABT492 against P. aeruginosa."
|Session name:||XXIst ISTH Congress|
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