title: In Vivo Pharmacodynamic Evaluation of an FtsZ Inhibitor, TXA-709, and Its Active Metabolite, TXA-707, in a Murine Neutropenic Thigh Infection Model.
abstract: Antibiotics with novel mechanisms of action are urgently needed. Processes of cellular division are attractive targets for new drug development. FtsZ, an integral protein involved in cell cytokinesis, is a representative example. In the present study, the pharmacodynamic (PD) activity of an FtsZ inhibitor, TXA-709, and its active metabolite, TXA-707, was evaluated in the neutropenic murine thigh infection model against 5 Staphylococcus aureus isolates, including both methicillin-susceptible and methicillin-resistant isolates. The pharmacokinetics (PK) of the TXA-707 active metabolite were examined after oral administration of the TXA-709 prodrug at 10, 40, and 160 mg/kg of body weight. The half-life ranged from 3.2 to 4.4 h, and the area under the concentration-time curve (AUC) and maximum concentration of drug in serum (Cmax) were relatively linear over the doses studied. All organisms exhibited an MIC of 1 mg/liter. Dose fractionation demonstrated the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) to be the PD index most closely linked to efficacy (R(2) = 0.72). Dose-dependent activity was demonstrated against all 5 isolates, and the methicillin-resistance phenotype did not alter the pharmacokinetic/pharmacodynamic (PK/PD) targets. Net stasis was achieved against all isolates and a 1-log10 kill level against 4 isolates. PD targets included total drug 24-h AUC/MIC values of 122 for net stasis and 243 for 1-log10 killing. TXA-709 and TXA-707 are a promising novel antibacterial class and compound for S. aureus infections. These results should prove useful for design of clinical dosing regimen trials.
authors.affiliation: Department of Medicine, University of Wisconsin, and William S. Middleton VA Hospital, Madison, Wisconsin, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lepak
authors.affiliation: TAXIS Pharmaceuticals, Inc., North Brunswick, New Jersey, USA.
authors.forename: Ajit
authors.initials: A
authors.lastname: Parhi
authors.affiliation: Department of Medicine, University of Wisconsin, and William S. Middleton VA Hospital, Madison, Wisconsin, USA.
authors.forename: Michaela
authors.initials: M
authors.lastname: Madison
authors.affiliation: Department of Medicine, University of Wisconsin, and William S. Middleton VA Hospital, Madison, Wisconsin, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Marchillo
authors.affiliation: Department of Medicine, University of Wisconsin, and William S. Middleton VA Hospital, Madison, Wisconsin, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: VanHecker
authors.affiliation: Department of Medicine, University of Wisconsin, and William S. Middleton VA Hospital, Madison, Wisconsin, USA dra@medicine.wisc.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Andes
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D051379:Mice; D009503:Neutropenia / Q000188:drug therapy* / Q000378:metabolism*; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity; D013848:Thigh / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents