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

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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 fAUC0–24h/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 less gastrointestinal treatment-emergent adverse effects (TEAEs) than its comparator linezolid. As with linezolid, tedizolid is a weak, reversible MAO inhibitor; however, a murine head twitch model validated to assess serotonergic activity reported no increase in the number of head twitches with tedizolid even at doses that exceeded the C max in humans by up to 25-fold. Tyramine and pseudoephedrine challenge studies in humans have also reported no meaningful MAO-related interactions with tedizolid. With its enhanced in vitro activity against a broad-spectrum of Gram-positive aerobic bacteria, convenient once-daily dosing, a short 6-day course of therapy, availability of both oral and intravenous routes of administration, and an adverse effect profile that appears to be more favorable than linezolid, tedizolid is an attractive agent for use in both the hospital and community settings. Tedizolid is currently undergoing additional Phase III clinical trials for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilated nosocomial pneumonia (VNP).

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Notes

  1. CE population: Patients receiving at least 5 days of study therapy, having a TOC assessment, and no other confounding events or factors. Twenty-eight patients were excluded from the CE group due to indeterminate clinical status (N = 16), visit window violation (N = 4), concomitant medication (N = 4), confounding medical event (N = 1), and Gram-negative pathogen (N = 1). Two patients had multiple reasons.

  2. cMITT population: All randomized patients with a diagnosis of cSSSI (including ten patients who discontinued the study drug: 200 mg N = 4, 300 mg N = 3, 400 mg N = 3).

  3. ITT population: All patients randomized to treatment.

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Acknowledgments

The authors are grateful to Cubist Pharmaceuticals, Inc. for their assistance with literature retrieval.

Conflict of interest

Dr. Zhanel has received research grants from Cubist Pharmaceuticals, Inc. Drs Love, Adam, Golden, Zelenitsky, Schweizer, Gorityala, Lagace-Weins, Rubinstein, Gin, Walkty, Gilmour, Hoban, Lynch, and Karlowsky have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada

    George G. Zhanel, Heather Adam, Alyssa Golden, Frank Schweizer, Philippe R. S. Lagacé-Wiens, Ethan Rubinstein, Andrew Walkty, Alfred S. Gin, Matthew Gilmour, Daryl J. Hoban & James A. Karlowsky

  2. Faculty of Pharmacy, University of Manitoba, Winnipeg, MB, Canada

    Riley Love, Sheryl Zelenitsky & Alfred S. Gin

  3. Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB, Canada

    Frank Schweizer & Bala Gorityala

  4. Department of Medicine, Health Sciences Centre, Winnipeg, MB, Canada

    George G. Zhanel, Ethan Rubinstein & Andrew Walkty

  5. Department of Pharmacy, Health Sciences Centre, Winnipeg, MB, Canada

    Alfred S. Gin

  6. Department of Clinical Microbiology, Health Sciences Centre, MS673-820 Sherbrook Street, Winnipeg, MB, R3A 1R9, Canada

    George G. Zhanel, Heather Adam, Matthew Gilmour & Daryl J. Hoban

  7. Department of Clinical Microbiology, Saint Boniface Hospital, Winnipeg, MB, Canada

    Philippe R. S. Lagacé-Wiens & James A. Karlowsky

  8. Division of Pulmonary, Critical Care, Allergy and Clinical Immunology, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Joseph P. Lynch 3rd

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  1. George G. Zhanel
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Correspondence to George G. Zhanel.

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Zhanel, G.G., Love, R., Adam, H. et al. Tedizolid: A Novel Oxazolidinone with Potent Activity Against Multidrug-Resistant Gram-Positive Pathogens. Drugs 75, 253–270 (2015). https://doi.org/10.1007/s40265-015-0352-7

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