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 (AUC(24)/MIC) including clinically achievable AUC(24)/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 AUC(24)/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 AUC(24)/MIC. Although the maximal increase in MIC (MICfinal) related to its initial value (MICinitial) was seen at a higher AUC(24)/MIC ratio of ABT492 (120 h) than levofloxacin (50 h), similar AUC(24)/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 (AUC(24)/MIC 870 h) but not with 500 mg levofloxacin (AUC(24)/MIC 70 h). Conclusion: Overall, these findings predict greater efficacy of clinically achievable AUC/MIC (or AUC(24)/MIC) of ABT492 both in terms of the anti-staphylococcal effect and prevention of the selection of resistant mutants.