F1-329. Efficacy of AFN-1252 and Vancomycin in the Mouse Subcutaneous Abscess Model with a Methicillin-Resistant S. aureus
Session: Poster Session: Fatty Acid Biosynthesis and Protein Biosynthesis Inhibitors
Saturday, October 25, 2008: 12:00 AM
Room: Hall C
Background: AFN-1252, a novel antibiotic inhibitor of the bacterial fatty acid biosynthesis (FAS II) pathway, is currently under clinical development as an oral and intravenous agent for susceptible and multi-drug resistant staphylococcal infections. AFN-1252 specifically targets the essential enzyme FabI (enoyl-ACP reductase). The current study was performed to determine the efficacy of AFN-1252 (AFN) and vancomycin (Van) in a mouse model of skin and skin structure MRSA infection. Methods: Female CD-1 mice were rendered neutropenic by a single IP injection of cyclophosphamide (150 mg/kg) on day -4 prior to infection. Abscesses were formed on the flanks of mice by the subcutaneous injection of 105 CFU of an S. aureus (MRSA) culture mixed with Cytodex (dextran) beads. Treatment with AFN (orally) or Van (intraperitoneal) was initiated 2 hrs post-infection and continued for three days either once-per-day (qd) or twice-per-day (bid). Abscesses were removed, homogenized and plated 18 hrs after the last dose. Efficacy was determined as the change in CFU/abscess as compared to vehicle treated controls. Results: The MICs of AFN and Van for the MRSA strain used in this study were determined to be 0.008 and 1 ug/mL, respectively. Abscesses in vehicle treated control animals exhibited a mean bacterial density of 8.7 log CFU/abscess at the end of the study. AFN, administered orally at 100, 30 or 10 mg/kg, demonstrated log reductions of 5.9, 5.2 and 2.5 CFU when administered bid and 5.2, 4.1 and 2.4 CFU when dosed qd, respectively, as compared to the vehicle treated control animals. Van dosed at 30 mg/kg IP bid exhibited a 4.4 log CFU reduction. Conclusions: The results of this study demonstrate the in vivo efficacy of AFN-1252 in a murine subcutaneous abscess model with an MRSA strain and support its further study and development for both susceptible and resistant S. aureus skin infections.
Barry Hafkin, MD1, Mark Pulse2, Nachum Kaplan, PhD3, Phung Nguyen2, William Weiss4 and  W. J. Weiss, None., (1)Affinium Pharmaceuticals, (2)UNT Health Science Center, (3)Affinium Pharmaceuticals, Toronto, ON, Canada, (4)UNT Health Science Center, Fort Worth, TX