Tedizolid: A Novel Oxazolidinone with Potent Activity Against Multidrug-Resistant Gram-Positive Pathogens

Abstract

Tedizolid phosphate is a novel oxazolidinone prodrug (converted to the active form tedizolid by phosphatases in vivo) that has been developed and recently approved (June 2014) by the United States FDA for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by susceptible Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Tedizolid is an oxazolidinone, but differs from other oxazolidinones by possessing a modified side chain at the C-5 position of the oxazolidinone nucleus which confers activity against certain linezolid-resistant pathogens and has an optimized C- and D-ring system that improves potency through additional binding site interactions. The mechanism of action of tedizolid is similar to other oxazolidinones and occurs through inhibition of bacterial protein synthesis by binding to 23S ribosomal RNA (rRNA) of the 50S subunit of the ribosome. As with other oxazolidinones, the spontaneous frequency of resistance development to tedizolid is low. Tedizolid is four- to eightfold more potent in vivo than linezolid against all species of staphylococci, enterococci, and streptococci, including drug-resistant phenotypes such as MRSA and vancomycin-resistant enterococci (VRE) and linezolid-resistant phenotypes. Importantly, tedizolid demonstrates activity against linezolid-resistant bacterial strains harboring the horizontally transmissible cfr gene, in the absence of certain ribosomal mutations conferring reduced oxazolidinone susceptibility. With its half-life of approximately 12 h, tedizolid is dosed once daily. It demonstrates linear pharmacokinetics, has a high oral bioavailability of approximately 90 %, and is primarily excreted by the liver as an inactive, non-circulating sulphate conjugate. Tedizolid does not require dosage adjustment in patients with any degree of renal dysfunction or hepatic dysfunction. Studies in animals have demonstrated that the pharmacodynamic parameter most closely associated with the efficacy of tedizolid is fAUC(0-24h)/MIC. In non-neutropenic animals, a dose-response enhancement was observed with tedizolid and lower exposures were required compared to neutropenic cohorts. Two Phase III clinical trials have demonstrated non-inferiority of a once-daily tedizolid 200 mg dose for 6-10 days versus twice-daily 600 mg linezolid for the treatment of ABSSSIs. Both trials used the primary endpoint of early clinical response at 48-72 h; however, one trial compared oral formulations while the other initiated therapy with the parenteral formulation and allowed oral sequential therapy following initial clinical response. Throughout its development, tedizolid has demonstrated that it is well tolerated and animal studies have shown a lower propensity for neuropathies with long-term use than its predecessor linezolid. Data from the two completed Phase III clinical trials demonstrated that the studied tedizolid regimen (200 mg once daily for 6 days) had significantly less impact on hematologic parameters as well as significantly...

Activities of Tedizolid and Linezolid Determined by the Reference Broth Microdilution Method against 3,032 Gram-Positive Bacterial Isolates Collected in Asia-Pacific, Eastern Europe, and Latin American Countries in 2014

“…Surprisingly, the Taiwanese isolates of the S. anginosus group were uniformly susceptible to linezolid despite only 38.7% susceptibility to tedizolid (9). Notably, a linezolid-susceptible and tedizolid-resistant phenotype had not been reported in previous in vitro surveillance surveys (1,2,5,8,10).…”

“…Surprisingly, the Taiwanese isolates of the S. anginosus group were uniformly susceptible to linezolid despite only 38.7% susceptibility to tedizolid (9). Notably, a linezolid-susceptible and tedizolid-resistant phenotype had not been reported in previous in vitro surveillance surveys (1,2,5,8,10).The study of Chen et al (9) differed from previous studies of tedizolid in the use of an agar dilution method rather than the Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution (BMD) method (11) to determine the susceptibility of tested isolates to tedizolid and linezolid. Furthermore, Chen et al (9) did not provide methodological details concerning the inoculum concentration, the duration of incubation, or the criteria used for MIC endpoint determination.…”

“…Structural modifications in the molecule result in enhanced binding to the 23S rRNA target and provide enhanced activity of tedizolid compared to that of linezolid; furthermore, tedizolid potency is not affected by strains harboring the transmissible cfr resistance gene (1,2,6).…”

“…edizolid is an oxazolidinone derivative that exhibits greater potency and a broader spectrum than linezolid when tested against a broad array of Gram-positive cocci, including those with drug-resistant phenotypes, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), and linezolid-resistant phenotypes (1,2). Tedizolid was approved by the U.S. Food and Drug Administration (FDA) in 2014 for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and is undergoing phase III clinical trials for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilated nosocomial pneumonia (VNP) (2).…”

Comparative Efficacies of Tedizolid Phosphate, Linezolid, and Vancomycin in a Murine Model of Subcutaneous Catheter-Related Biofilm Infection Due to Methicillin-Susceptible and -Resistant Staphylococcus aureus

“…Tedizolid is a novel oxazolidinone derivative that has potent activity against staphylococci and enterococci (7,8). It exerts bacteriostatic microbial activity through inhibition of protein synthesis by binding to the 50S ribosomal subunit of the bacteria.…”