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: Alexander J Lepak, Karen Marchillo, Solen Pichereau, William A Craig, David R Andes
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 56 Issue 11 Pg. 5916-22 (Nov 2012) ISSN: 1098-6596 [Electronic] United States
• PMID: 22964254 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetamides
• Anti-Bacterial Agents
• Blood Proteins
• Organophosphates
• Oxazoles
• Oxazolidinones
• Prodrugs
• Linezolid
• tedizolid phosphate

Topics

• Acetamides (blood, pharmacokinetics, pharmacology)
• Administration, Oral
• Animals
• Anti-Bacterial Agents (blood, pharmacokinetics, pharmacology)
• Area Under Curve
• Blood Proteins (chemistry)
• Colony Count, Microbial
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Linezolid
• Lung (drug effects, microbiology)
• Methicillin-Resistant Staphylococcus aureus (drug effects, growth & development)
• Mice
• Mice, Inbred ICR
• Microbial Sensitivity Tests
• Neutropenia (blood, complications, drug therapy, microbiology)
• Organophosphates (blood, pharmacokinetics, pharmacology)
• Oxazoles (blood, pharmacokinetics, pharmacology)
• Oxazolidinones (blood, pharmacokinetics, pharmacology)
• Pneumonia, Staphylococcal (blood, complications, drug therapy, microbiology)
• Prodrugs (metabolism, pharmacokinetics, pharmacology)
• Protein Binding
• Staphylococcus aureus (drug effects, growth & development)