JAC Advance Access published online on June 9, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh242
© 2004 by The British Society for Antimicrobial Chemotherapy
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1 Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 Bolshaya Pirogovskaya Street, Moscow, 119021
* To whom correspondence should be addressed. E-mail: firsov{at}dol.ru.
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--ABBC1+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). Conclusion: 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.
Revised March 18, 2004
Accepted March 19, 2004
Original article
ABT492 and levofloxacin: comparison of their pharmacodynamics
and their abilities to prevent the selection of resistant Staphylococcus aureus in an in vitro dynamic model
2 Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 Bolshaya Pirogovskaya Street, Moscow, 119021; Institute of Normal Physiology, Russian Academy of Medical Sciences, Moscow, Russia
3 Institute of Normal Physiology, Russian Academy of Medical Sciences, Moscow, Russia
4 Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, USA
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