In vitro pharmacodynamic activities of ABT-492, a novel quinolone, compared to those of levofloxacin against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis

Abstract

ABT-492 is a novel quinolone with potent activity against gram-positive, gram-negative, and atypical pathogens, making this compound an ideal candidate for the treatment of community-acquired pneumonia. We therefore compared the in vitro pharmacodynamic activity of ABT-492 to that of levofloxacin, an antibiotic commonly used for the treatment of pneumonia, through MIC determination and time-kill kinetic analysis. ABT-492 demonstrated potent activity against penicillin-sensitive, penicillin-resistant, and levofloxacin-resistant Streptococcus pneumoniae strains (MICs ranging from 0.0078 to 0.125 micro g/ml); beta-lactamase-positive and beta-lactamase-negative Haemophilus influenzae strains (MICs ranging from 0.000313 to 0.00125 micro g/ml); and beta-lactamase-positive and beta-lactamase-negative Moraxella catarrhalis strains (MICs ranging from 0.001 to 0.0025 micro g/ml), with MICs being much lower than those of levofloxacin. Both ABT-492 and levofloxacin demonstrated concentration-dependent bactericidal activities in time-kill kinetics studies at four and eight times the MIC with 10 of 12 bacterial isolates exposed to ABT-492 and with 12 of 12 bacterial isolates exposed to levofloxacin. Sigmoidal maximal-effect models support concentration-dependent bactericidal activity. The model predicts that 50% of maximal activity can be achieved with concentrations ranging from one to two times the MIC for both ABT-492 and levofloxacin and that near-maximal activity (90% effective concentration) can be achieved at concentrations ranging from two to five times the MIC for ABT-492 and one to six times the MIC for levofloxacin.

FIG. 1.

Time-kill curves for four clinical isolates. Curves on the left represent the activity of ABT-492, and the curves on the right represent the activity of levofloxacin against the same isolate. ▴, control; ⋄, 0.0625 times the MIC; ♦, 0.125 times the MIC; □, 0.25 times the MIC; ▪, 0.5 times the MIC; ▿, 1 times the MIC; ▾, 2 times the MIC; ○, 4 times the MIC; •, 8 times the MIC.

FIG. 2.

Composite concentration-response curves for penicillin-sensitive S. pneumoniae (SPS) and penicillin-resistant S. pneumoniae (SPR) isolates following antibiotic exposure to ABT-492 (left-hand side) and levofloxacin (right-hand side) at 4, 6, and 12 h.