title: Pharmacokinetics, pharmacodynamics and efficacy of novel FabI inhibitor AFN-1252 against MSSA and MRSA in the murine thigh infection model.
abstract: AFN-1252, a new antimicrobial agent, specifically and potently inhibits fatty acid synthesis in Staphylococcus aureus. We characterized in vivo pharmacokinetic and pharmacodynamic profiles of AFN-1252 administered orally to neutropenic mice inoculated in thighs (∼10(6)  CFU) with methicillin-susceptible S. aureus (MSSA) ATCC 29213. Efficacy was also assessed in mice inoculated with MSSA, hospital-acquired Methicillin-resistant Staphylococcus aureus (HA-MRSA) or community-acquired (CA)-MRSA, and administered AFN-1252 or linezolid orally. Bacterial  density was determined after 24 hours and efficacy defined as the change in CFU/thigh versus untreated controls at time 0. With MSSA, antibacterial reductions of ≥1 log were observed at ≥20 mg/kg doses, with ƒAUC/minimum inhibitory concentration (MIC) best describing the pharmacodynamic  profile of AFN-1252. The 80, 50 and 5% maximum effects were observed with ƒAUC/MIC values of 22·3, 17·0, and 9·6, respectively. Similar values were obtained for CA-MRSA and HA-MRSA. AFN-1252 was 4-40 fold more effective than linezolid against CA-MRSA and HA-MRSA.  These data demonstrate the excellent in vivo potency of AFN-1252 against phenotypically diverse S. aureus.
authors: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
authors: Mary A
authors: MA
authors: Banevicius
authors: Nachum
authors: N
authors: Kaplan
authors: Barry
authors: B
authors: Hafkin
authors: David P
authors: DP
authors: Nicolau
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001572:Benzofurans / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017714:Community-Acquired Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D005260:Female; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D023303:Oxazolidinones / Q000494:pharmacology; D011753:Pyrones / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000378:metabolism* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects; D013848:Thigh / Q000382:microbiology
chemical_list: C521531:API 1252; D000081:Acetamides; D000900:Anti-Bacterial Agents; D001572:Benzofurans; D023303:Oxazolidinones; D011753:Pyrones; D000069349:Linezolid