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 (~106 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 fAUC/minimum inhibitory concentration (MIC) best describing the pharmacodynamic profile of AFN-1252. The 80, 50 and 5% maximum effects were observed with fAUC/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. © 2013 Edizioni Scientifiche per l'Informazione su Farmaci e Terapia.