ABT492 and levofloxacin: comparison of their pharmacodynamics and their abilities to prevent the selection of resistant Staphylococcus aureus in an in vitro dynamic model.
OBJECTIVE
To compare the kinetics of killing/regrowth of differentially susceptible clinical isolates of Staphylococcus aureus exposed to ABT492 and levofloxacin and to explore their relative abilities to prevent the selection of resistant mutants.


METHODS
Three clinical isolates of S. aureus--including two ciprofloxacin-susceptible S. aureus, 201 and 480--and a ciprofloxacin-resistant S. aureus 866, were exposed to clinically achievable ratios of area under the curve (AUC) to MIC in a dynamic model that simulated human pharmacokinetics of ABT492 (400 mg) and levofloxacin (500 mg) as a single dose. In addition, S. aureus 201 was exposed to single and multiple doses of ABT492 and levofloxacin (both once daily for 3 days) over wide ranges of 24 h AUC/MIC (AUC24/MIC) including clinically achievable AUC24/MIC ratios.


RESULTS
With each isolate, ABT492 at clinically achievable AUC/MICs produced greater anti-staphylococcal effects than levofloxacin. Areas between the control growth and the time--kill curves (ABBC in single dose simulations and the sum of ABBCs determined after the first, second and third dosing in multiple dose simulations--ABBC(1+2+3)) were higher with ABT492 than levofloxacin. Moreover, at comparable AUC/MICs and AUC24/MICs, the maximal reductions in the starting inoculum of ABT492-exposed S. aureus were more pronounced than with levofloxacin. Loss in susceptibility of S. aureus 201 exposed to ABT492 or levofloxacin depended on the simulated AUC24/MIC. Although the maximal increase in MIC (MICfinal) related to its initial value (MICinitial) was seen at a higher AUC24/MIC ratio of ABT492 (120 h) than levofloxacin (50 h), similar AUC24/MICs (240 and 200 h, respectively) were protective against the selection of resistant S. aureus. These threshold values are readily achievable with 400 mg ABT492 (AUC24/MIC 870 h) but not with 500 mg levofloxacin (AUC24/MIC 70 h).


CONCLUSIONS
Overall, these findings predict greater efficacy of clinically achievable AUC/MIC (or AUC24/MIC) of ABT492 both in terms of the anti-staphylococcal effect and prevention of the selection of resistant mutants.
Firsov
Alexander A
AA
Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 Bolshaya Pirogovskaya Street, Moscow, 119021. firsov@dol.ru
Vostrov
Sergey N
SN
Lubenko
Irene Yu
IY
Arzamastsev
Alexander P
AP
Portnoy
Yury A
YA
Zinner
Stephen H
SH
D000465:Algorithms; D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones; D006207:Half-Life; D006801:Humans; D064704:Levofloxacin; D008954:Models, Biological; D015242:Ofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D015363:Quinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D015363:Quinolones; C477891:delafloxacin; D064704:Levofloxacin; D015242:Ofloxacin