Subinhibitory Concentrations of Tedizolid Effectively Inhibit Extracellular Toxin Production by Methicillin-Sensitive and Methicillin-Resistant Staphylococcus aureus

Background: Staphylococcus aureus is a prevalent nosocomial and community-associated pathogen with the ability to cause mild to life-threatening infection. Extracellular protein toxins such as Alpha-hemolysin, Panton-Valentine leukocidin (PVL), and Toxic-shock syndrome toxin 1 (TSST-1) contribute significantly to the pathogenesis of S. aureus disease, thus, toxin production is an important consideration in the selection of an antimicrobial agent used to treat staphylococcal infections. Data from our laboratory and others have demonstrated that subinhibitory concentrations of beta-lactam antibiotics can increase S. aureus toxin transcript expression and toxin protein levels. Tedizolid, a novel oxazolidinone, has demonstrated potent efficacy against S. aureus, yet its effects on toxin gene expression and toxin production at subinhibitory levels has not been directly studied.

Methods: The current study evaluates the effects of subinhibitory concentrations of tedizolid on transcription and translation of staphylococcal exotoxins in both methicillin-resistant and methicillin-sensitive S. aureus. At 0, 3, 6, 9, 12, and 24 hours following treatment with subinhibitory concentrations of tedizolid, toxin transcript expression and protein production were quantified using real-time PCR and toxin-specific assays, respectively, and compared to samples treated with linezolid or nafcillin.

Results: Subinhibitory levels of tedizolid and linezolid effectively reduce the expression of Alpha-hemolysin, PVL and TSST-1 toxin during S. aureus growth. In contrast, subinhibitory concentrations of nafcillin only reduce toxin production when bacterial growth is severely impaired. The subinhibitory level of tedizolid, or linezolid, required to inhibit toxin production is strain-dependent and coincides with the quantity of toxin produced.

Conclusion: Tedizolid and linezolid are comparable in their ability to inhibit toxin production at similar MIC doses; however, tedizolid inhibits S. aureus growth at a concentration 4- to 8-fold lower than linezolid allowing tedizolid to more potently inhibit toxin production at a lower overall drug concentration.