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 q.d. for 3 days) over wide ranges of the 24-h AUC/MIC (AUC24/MIC) including clinically achievable AUC24/MIC ratios.

Results:

With each isolate, ABT492 at the 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 larger with ABT492 than levofloxacin. Moreover, at comparable AUC/MICs and AUC24/MICs maximal reductions in the starting inoculum of ABT492-exposed S. aureus were more pronounced than with levofloxacin. Loss in the susceptibility of S. aureus 201 exposed to both ABT492 and levofloxacin depended on the simulated AUC24/MIC. Although the maximal increase in MIC (MICfinal) related to its initial value (MICinitial) was seen at the 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.