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: Mary A Banevicius, Nachum Kaplan, Barry Hafkin, David P Nicolau
• Journal: Journal of chemotherapy (Florence, Italy) (J Chemother) Vol. 25 Issue 1 Pg. 26-31 (Feb 2013) ISSN: 1973-9478 [Electronic] England
• PMID: 23433441 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• API 1252
• Acetamides
• Anti-Bacterial Agents
• Benzofurans
• Oxazolidinones
• Pyrones
• Linezolid

Topics

• Acetamides (pharmacology)
• Animals
• Anti-Bacterial Agents (pharmacokinetics, pharmacology)
• Benzofurans (pharmacokinetics, pharmacology)
• Community-Acquired Infections (drug therapy, metabolism, microbiology)
• Female
• Linezolid
• Methicillin-Resistant Staphylococcus aureus (drug effects)
• Mice
• Mice, Inbred ICR
• Microbial Sensitivity Tests
• Oxazolidinones (pharmacology)
• Pyrones (pharmacokinetics, pharmacology)
• Staphylococcal Infections (drug therapy, metabolism, microbiology)
• Staphylococcus aureus (drug effects)
• Thigh (microbiology)