F1-2021. In Vitro and In Vivo Antibacterial Activities of ACH-702 against Gram-Positive Pathogens
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.
Barton Bradbury, PhD1, Christy Thoma1, Jane Thanassi1, Jijun Cheng, PhD1, Michael Pucci, PhD2, Milind Deshpande, PhD1, Steven Podos, PhD2 and  M. J. Pucci,
Achillion Pharmaceuticals Role(s): Employee, Received: Salary., (1)Achillion Pharmaceuticals, (2)Achillion Pharmaceuticals, New Haven, CT


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