Use of Translational PK/PD Infection Models to Understand Impact of Neutropenia on Efficacy of Tedizolid Phosphate [Pharmacology]

Tedizolid phosphate, the prodrug of the active antibiotic tedizolid, is an oxazolidinone for the treatment of acute bacterial skin and skin structure infections. Studies in a mouse thigh infection model demonstrated improved potency and pharmacokinetics-pharmacodynamics (PK/PD) vs linezolid. Subsequent studies showed that the efficacy of tedizolid was enhanced in immune competent (IC) compared with neutropenic (IS) mice, with stasis at clinically relevant doses being achieved only in the presence of granulocytes. The tedizolid label therefore contains a warning about use in neutropenic patients. This study reevaluated the PK/PD of tedizolid and linezolid in the mouse thigh infection model in IC and IS mice using a methicillin-resistant Staphylococcus aureus (MRSA) strain (ATCC 33591) and a methicillin-susceptible S. aureus (MSSA) strain (ATCC 29213). The antistaphylococcal effect of doses ranging from 1–150 mg/kg of tedizolid (once daily) or linezolid (twice daily) was determined at 24, 48, and 72 hours after initiating treatment. In IC mice, stasis was achieved in the absence of antibiotics, and both tedizolid and linezolid reduced the burden further beyond a static effect. In IS mice, tedizolid achieved stasis at 72 hours at a human clinical dose of 200 mg against MRSA ATCC 33591 and MSSA ATCC 29213, several-fold lower than in earlier studies. Linezolid achieved a static effect against MRSA ATCC 33591 in IS mice at a dose lower than that used clinically. This study demonstrates that with time both tedizolid and linezolid at clinically relevant exposures achieve stasis in neutropenic mice with MRSA or MSSA thigh infection.

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