Clinical Pharmacokinetics and Pharmacodynamics of Oxazolidinones

Claire Roger, Jason A. Roberts, Laurent Muller

Oxazolidinones are a class of synthetic antimicrobial agents with potent activity against a wide range of multidrug-resistant Gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Oxazolidinones exhibit their antibacterial effects by inhibiting protein synthesis acting on the ribosomal 50S subunit of the bacteria and thus preventing formation of a functional 70S initiation complex. Currently, two oxazolidinones have been approved by the US Food and Drug Administration: linezolid and more recently tedizolid. Other oxazolidinones are currently under investigation in clinical trials. These antimicrobial agents exhibit a favourable pharmacokinetic profile with an excellent bioavailability and a good tissue and organ penetration. In-vitro susceptibility studies have shown that oxazolidinones are bacteriostatic against enterococci and staphylococci, and bactericidal for the majority of strains of streptococci. In the context of emergence of resistance to glycopeptides, oxazolidinones have become an effective alternative to vancomycin treatment frequently associated with nephrotoxicity. However, oxazolidinones, and linezolid in particular, are associated with significant adverse events, myelosuppression representing the main unfavourable side effect. More recently, tedizolid has been shown to effectively treat acute bacterial skin and skin structure infections. This newer oxazolidinone offers the advantages of once-daily dosing and a better safety profile in healthy volunteer studies (fewer gastrointestinal and haematological side effects). The potential use of tedizolid for other infections that could require longer therapy warrants further studies for positioning this new oxazolidinone in the available antimicrobial armamentarium. Moreover, other oxazolidinones are currently under active investigation.