Comparative pharmacodynamics of the new fluoroquinolone ABT492 and levofloxacin with Streptococcus pneumoniae in an in vitro dynamic model

Abstract 

The kinetics of killing of Streptococcus pneumoniae exposed to ABT492 or levofloxacin were compared. S. pneumoniae ATCC 49619 and four ciprofloxacin-resistant clinical isolates, S. pneumoniae 1149, 391, 79 and 804, were exposed to ABT492 and levofloxacin as a single dose in a dynamic model that simulates human pharmacokinetics of the quinolones. With S. pneumoniae ATCC 49619 eight-fold ranging AUC/MIC ratios (60–500h) were simulated for each quinolone. In addition, two larger AUC/MICs, i.e., 1080 and 2150h for ABT492 and 1460 and 3660h for levofloxacin which correspond to 100 and 200mg doses of ABT492 and 200 and 500mg doses of levofloxacin, respectively, were mimicked. Each ciprofloxacin-resistant organism was exposed to the clinical doses of ABT492 (400mg) and levofloxacin (500mg); the respective AUC/MIC ratios were from 580 to 3470h and from 28 to 110h. At comparable AUC/MICs (from 60 to 500h), regrowth of S. pneumoniae ATCC 49619 followed initial killing, and the times to regrowth were longer with levofloxacin than ABT492. However, no regrowth of S. pneumoniae ATCC 49619 occurred at the higher AUC/MICs of ABT492 (1080 and 2150h) and levofloxacin (1460 and 3660h). Killing of S. pneumoniae 1149, 391 and 79 without bacterial regrowth, was provided by ABT492 (AUC/MIC 3470, 2310 and 1160h, respectively) but not levofloxacin (AUC/MIC 55, 110 and 28h, respectively). Regrowth of S. pneumoniae 804 was observed with both ABT492 and levofloxacin (AUC/MIC 580 and 55h, respectively). Areas between the control growth curve and the time-kill curve (ABBCs) for ABT492 against S. pneumoniae 1149, 391 and 79 were 2.6–4.2 times larger than the respective ABBCs for levofloxacin, whereas similar ABBCs were found with S. pneumoniae 804 exposed to both quinolones.: These findings predict significantly greater efficacy of ABT492 than levofloxacin at clinically achievable AUC/MIC ratios against ciprofloxacin-resistant S. pneumoniae and similar efficacies of the two quinolones against susceptible organisms.

Keywords: ABT492, Pharmacodynamics, In vitro models