Session: Poster Session: New Topoisomerase Inhibitors
Monday, October 27, 2008: 12:00 AM
Room: Hall C
Background: ACH-702 is an isothiazoloquinolone that exhibits excellent activity against most gram-positive pathogens. Methods: The antibacterial activity of ACH-702 was assessed against gram-positive and gram-negative clinical isolates by several standard in vitro and in vivo methods. Results: MIC assays revealed that ACH-702 displayed broad-spectrum activity, especially against gram-positive bacteria, with MICs for most strains ≤2 µg/ml. These included antibiotic-resistant isolates such as methicillin-resistant S. aureus (MRSA), vancomycin non-susceptible staphylococci, and quinolone-resistant strains. For gram-negative bacteria, reduced activity was observed against some Enterobacteriacea strains, but there was exceptional potency against H. influenzae, M. catarrhalis, and Neisseria sp. with MICs ≤0.06 µg/ml for all strains tested. Good antibacterial activity was also seen against several anaerobes as well as L. pneumophila and M. pneumoniae. Excellent bactericidal effects were observed against staphylococci in time-kill assays with a ≥3-log drop in CFU/ml after 4 hours of exposure. Postantibiotic effects (PAEs) of 1.2-4.6 h were seen in staphylococci including clinical isolates after treatment with 10× MIC ACH-702, similar in most cases to those observed for moxifloxacin at 10× MIC. In vivo efficacy was demonstrated against S. aureus in murine sepsis, lung, and thigh infection models. PD50 values were ≤1 mg/kg in sepsis infections while, in thigh infections, decreases in CFU/thigh were equal to or greater than those observed after vancomycin treatment. Conclusions: ACH-702 displays potent, bactericidal activity especially against gram-positive pathogens and demonstrates efficacy in animal infection models as well.
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