title: Comparative pharmacodynamics of the new oxazolidinone tedizolid phosphate and linezolid in a neutropenic murine Staphylococcus aureus pneumonia model.
abstract: Tedizolid phosphate (TR-701) is a novel oxazolidinone prodrug (converted to the active form tedizolid [TR-700]) with potent Staphylococcus aureus activity. The current studies characterized and compared the in vivo pharmacokinetic/pharmacodynamic (PD) characteristics of TR-701/TR-700 and linezolid against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) in the neutropenic murine pneumonia model. The pharmacokinetic properties of both drugs were linear over a dose range of 0.625 to 40 mg/kg of body weight. Protein binding was 30% for linezolid and 85% for TR-700. Mice were infected with one of 11 isolates of S. aureus, including MSSA and community- and hospital-acquired MRSA strains. Each drug was administered by oral-gastric gavage every 12 h (q12h). The dosing regimens ranged from 1.25 to 80 mg/kg/12 h for linezolid and 0.625 to 160 mg/kg/12 h for TR-701. At the start of therapy, mice had 6.24 ± 0.40 log(10) CFU/lungs, which increased to 7.92 ± 1.02 log(10) CFU/lungs in untreated animals over a 24-h period. A sigmoid maximum-effect (E(max)) model was used to determine the antimicrobial exposure associated with net stasis (static dose [SD]) and 1-log-unit reduction in organism relative to the burden at the start of therapy. The static dose pharmacodynamic targets for linezolid and TR-700 were nearly identical, at a free drug (non-protein-bound) area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) of 19 and 20, respectively. The 1-log-unit kill endpoints were also similar, at 46.1 for linezolid and 34.6 for TR-700. The exposure targets were also comparable for both MSSA and MRSA isolates. These dosing goals support further clinical trial examination of TR-701 in MSSA and MRSA pneumonia.
authors.affiliation: University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lepak
authors.forename: Karen
authors.initials: K
authors.lastname: Marchillo
authors.forename: Solen
authors.initials: S
authors.lastname: Pichereau
authors.forename: William A
authors.initials: WA
authors.lastname: Craig
authors.forename: David R
authors.initials: DR
authors.lastname: Andes
mesh_terms: D000081:Acetamides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood* / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001798:Blood Proteins / Q000737:chemistry; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D000069349:Linezolid; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000097:blood* / Q000150:complications / Q000188:drug therapy / Q000382:microbiology; D010755:Organophosphates / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D010080:Oxazoles / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D023303:Oxazolidinones / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011023:Pneumonia, Staphylococcal / Q000097:blood* / Q000150:complications / Q000188:drug therapy / Q000382:microbiology; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D010755:Organophosphates; D010080:Oxazoles; D023303:Oxazolidinones; D011355:Prodrugs; D000069349:Linezolid; C515040:tedizolid phosphate