Comparative pharmacodynamics of the new fluoroquinolone ABT492 and ciprofloxacin with Escherichia coli and Pseudomonas aeruginosa in an in vitro dynamic model.
The killing kinetics of Escherichia coli and Pseudomonas aeruginosa were compared when exposed to ABT492 and ciprofloxacin. E. coli ATCC 25922 and a clinical isolate of P. aeruginosa 4226 were exposed to ABT492 (single dose) and ciprofloxacin (two 12 h doses) at the ratios of area under the curve (AUC) to MIC varying from 60 to 480 h and at clinically achievable AUC/MIC ratios of ABT492 (1,740 and 140 h, respectively) and ciprofloxacin (2,200 and 120 h, respectively) that correspond to a 400 mg dose of ABT492 and two 500 mg doses of ciprofloxacin. In addition, a double dose of ABT492 (800 mg; AUC/MIC 280 h) and two 12 h doses of ABT492 (2 x 400 mg) were used with P. aeruginosa. Maximal reductions in the starting inoculum of E. coli and P. aeruginosa were greater with ABT492 than with ciprofloxacin at a given AUC/MIC ratio (60-480 h), whereas the times to regrowth were shorter with ABT492. A specific AUC/MIC relationship of the antimicrobial effect was inherent in each quinolone-pathogen pair. With both E. coli and P. aeruginosa, AUC/MIC plots of the area between the control growth and the time-kill curves (I(E)) were steeper for ciprofloxacin than ABT492 and they were species-independent. The effect of ABT492 on E. coli at the clinically achievable AUC/MIC ratio (1740h) was more pronounced than the respective AUC/MIC of ciprofloxacin (2,200 h). With P. aeruginosa, a 140 h AUC/MIC of ABT492 (400 mg as a single dose) provided 1.8-fold less effect than a 120 h AUC/MIC of ciprofloxacin (2 x 500 mg). However, two 12 h doses of ABT492 (AUC/MIC 2 x 140 h) but not a double single dose (800 mg) were more efficient than ciprofloxacin. These findings predict comparable efficacies of clinically achievable AUC/MICs of ABT492 and ciprofloxacin against E. coli (q.d. versus b.i.d. quinolone dosing) and P. aeruginosa at b.i.d. but not at q.d. ABT492.
Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, USA.
Stephen H
SH
Zinner
Sergey N
SN
Vostrov
Irene V
IV
Alferova
Irene Yu
IY
Lubenko
Yury A
YA
Portnoy
Alexander A
AA
Firsov
D000890:Anti-Infective Agents / Q000494:pharmacology*; D019540:Area Under Curve; D002939:Ciprofloxacin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects* / Q000254:growth & development; D024841:Fluoroquinolones / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D015363:Quinolones / Q000494:pharmacology*
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D015363:Quinolones; D002939:Ciprofloxacin; C477891:delafloxacin