Early Experience with Tedizolid: Clinical Efficacy, Pharmacodynamics, and Resistance

Abstract

Antimicrobial resistance among gram-positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) continues to limit therapeutic options. The oxazolidinones are a synthetic class of agents now commonly relied on for the treatment of serious MRSA and VRE infections. With increasing utilization of linezolid, resistant pathogens have once again begun to emerge. Tedizolid, a next-generation oxazolidinone, possesses a spectrum of activity including MRSA and VRE, with significantly enhanced potency also against linezolid-resistant strains. Preclinical and early clinical studies have reported positive results, demonstrating a favorable pharmacokinetic profile in combination with key potential safety advantages. In two phase III clinical trials, tedizolid was found noninferior to linezolid in the treatment of acute bacterial skin and skin structure infections. Investigations for treatment of ventilator-acquired and health care-associated pneumonia are currently underway. Tedizolid has been subjected to pharmacodynamics studies throughout its development that have highlighted properties unique to this agent. Considerable accumulations in epithelial lining fluid and antimicrobial activity greatly augmented by the presence of granulocytes suggest that slow but bactericidal activity may be possible in some clinical scenarios. Structural distinctions between tedizolid and linezolid suggest that tedizolid has decreased vulnerability to oxazolidinone resistance mechanisms. Tedizolid minimum inhibitory concentrations are essentially unchanged in organisms possessing the chloramphenicol-florfenicol resistance gene, a horizontally transferable linezolid resistance mechanism. Although the clinical experience with tedizolid remains limited, early data suggest a potential role in the treatment of serious infections due to multidrug-resistant gram-positive pathogens.

Vancomycin-Resistant Enterococci

“…95 Of note, the binding of tedizolid to the ribosome does not seem to be affected by Cfr-mediated methylation of the 23S rRNA, and this compound retains activity in vitro against enterococcal strains that carry the cfr gene. 96 The optrA gene encodes a putative ABC transporter associated with elevated MICs to the oxazolidinones in the absence of known 23S rRNA mutations or the gene cfr and has been recently identified in both E faecalis and E faecium from animal and human sources. 97 …”

Activity of Tedizolid in Methicillin-Resistant Staphylococcus aureus Experimental Foreign Body-Associated Osteomyelitis

“…Tedizolid is an expanded-spectrum oxazolidinone approved by the United States Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections; it has greater potency against methicillin-resistant Staphylococcus aureus (MRSA) than does linezolid, and data from comparative clinical trials suggest that it may have less toxicity, including fewer toxic effects resulting in thrombocytopenia and neuropathy, and fewer monoamine oxidase inhibitor interactions than linezolid (10)(11)(12). Moreover, once-daily dosing is possible.…”

Bacteremia due to Methicillin-Resistant Staphylococcus aureus

“…Tedizolid, the second drug of this class to become available, has key structural differences that allow additional target binding site interactions, accounting for its greater potency (with MICs 2-to 8-fold lower than linezolid against staphylococci) and retained activity despite linezolid resistance in some instances. 33 S aureus resistance to linezolid fortunately remains rare, having been detected in only 2 of 1454 isolates from 60 US centers; both carried cfr. 34 Most cfr-positive isolates, however, remain susceptible to tedizolid.…”