In Vivo Pharmacodynamics of Torezolid Phosphate (TR-701), a New Oxazolidinone Antibiotic, against Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus Strains in a Mouse Thigh Infection Model

Abstract

Torezolid phosphate (TR-701) is the phosphate monoester prodrug of the oxazolidinone TR-700 which demonstrates potent in vitro activity against Gram-positive bacteria, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). The pharmacodynamics of TR-701 or TR-700 (TR-701/700) against S. aureus is incompletely defined. Single-dose pharmacokinetic studies were conducted in mice for TR-701/700. Forty-eight-hour dose range and 24-hour dose fractionation studies were conducted in a neutropenic mouse thigh model of S. aureus infection using MRSA ATCC 33591 to identify the dose and schedule of administration of TR-701/700 that was linked with optimized antimicrobial effect. Additional dose range studies compared the efficacies of TR-701/700 and linezolid for one MSSA strain and one community-associated MRSA strain. In dose range studies, TR-701/700 was equally bactericidal against MSSA and MRSA. Mean doses of 37.6 and 66.9 mg/kg of body weight/day of TR-701/700 resulted in stasis and 1 log CFU/g decreases in bacterial densities, respectively, at 24 h, and mean doses of 35.3, 46.6, and 71.1 mg/kg/day resulted in stasis and 1 and 2 log CFU/g reductions, respectively, at 48 h. Linezolid administered at doses as high as 150 mg/kg/day did not achieve stasis at either time point. Dose fractionation studies demonstrated that the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the pharmacodynamic index for TR-701/700 that was linked with efficacy. TR-701/700 was highly active against MSSA and MRSA, in vivo, and was substantially more efficacious than linezolid, although linezolid's top exposure has half the human exposure. Dose fractionation studies showed that AUC/MIC was the pharmacodynamic index linked with efficacy, indicating that once-daily dosing in humans is feasible.

Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model

“…One small difference was the level of protein binding utilized for calculating free drug (non-protein-bound) exposures. The current study used 85% as the protein-bound fraction, whereas the previous study used 80% (35). Accounting for this difference alone would make the fAUC/MIC PD targets more congruent.…”

“…Clinical success was more common when the linezolid plasma fAUC/MIC value was near 30. More recently, the murine thigh infection model was used to explore the treatment efficacy of TR-701 against a single MRSA isolate (35). Similar to linezolid, the AUC/MIC ratio was the predictive index for efficacy, and net stasis in infectious burden was noted at a fAUC/MIC of 43 at the 24-h study endpoint.…”

“…Prior PK/PD study with oxazolidinones, including TR-701, has demonstrated potency against both MSSA and MRSA and the relevance of the AUC/MIC index (2,22,23,27,34,35,37,44,53,55). For example, Louie et al (35) performed a dose fractionation PK/PD evaluation of TR-701 against MRSA and MSSA using the murine thigh infection model.…”

“…For example, Louie et al (35) performed a dose fractionation PK/PD evaluation of TR-701 against MRSA and MSSA using the murine thigh infection model. The total daily dose ranged from 0 to 100 mg/kg and was fractionated into every 24 h (q24h), q12h, and q6h dosing regimens.…”

“…The dose needed to achieve net stasis (SD) and 1-log-unit kill was determined using the formula for each drug against each strain tested. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) has been shown in previous studies to be the pharmacodynamic (PD) parameter predictive of treatment efficacy for oxazolidinones (8,35). Therefore, the total drug AUC/MIC (tAUC/MIC ratio) and free drug (non-protein-bound) AUC/MIC (fAUC/MIC ratio) for each drug-organism combination was also determined.…”