Tedizolid

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Tedizolid
Tedizolid.svg
Tedizolid 3D molecule.png
Clinical data
Trade names Sivextro
Other namesTR-700, torezolid [1]
AHFS/Drugs.com Monograph
MedlinePlus a614038
License data
Routes of
administration 		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 91%
Protein binding 70–90%
Elimination half-life 12 hours
Excretion Feces
Identifiers
  • (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.249.430 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H15FN6O3
Molar mass 370.344 g·mol−1
3D model (JSmol)
  • O=C4O[C@H](CN4c3cc(F)c(c1ccc(nc1)c2nn(nn2)C)cc3)CO
  • InChI=1S/C17H15FN6O3/c1-23-21-16(20-22-23)15-5-2-10(7-19-15)13-4-3-11(6-14(13)18)24-8-12(9-25)27-17(24)26/h2-7,12,25H,8-9H2,1H3/t12-/m1/s1 Yes check.svgY
  • Key:XFALPSLJIHVRKE-GFCCVEGCSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Tedizolid, sold under the brand name Sivextro (by Merck) is an oxazolidinone-class antibiotic. Tedizolid phosphate is a phosphate ester prodrug of the active compound tedizolid. It was developed by Cubist Pharmaceuticals, following acquisition of Trius Therapeutics (originator: Dong-A Pharmaceuticals), and is marketed for the treatment of acute bacterial skin and skin structure infections (also known as complicated skin and skin-structure infections (cSSSIs)). [5] [ medical citation needed ]

Contents

The most common side effects include nausea (feeling sick), headache, diarrhea and vomiting. [4] These side effects were generally of mild or moderate severity. [4]

Tedizolid was approved for medical use in the United States in June 2014, [6] [7] and authorized for medical use in the European Union in March 2015. [4] Tedizolid phosphate is a therapeutic alternative on the World Health Organization's List of Essential Medicines. [8]

Medical uses

Tedizolid is indicated for the treatment of acute bacterial Skin and skin structure infections (ABSSSI) caused by certain susceptible bacteria, including Staphylococcus aureus (including methicillin-resistant strains, methicillin-resistant Staphylococcus aureus (MRSA), and methicillin-susceptible strains), various Streptococcus species ( S. pyogenes , S. agalactiae , and S. anginosus group including S. anginosus , S. intermedius , and S. constellatus ), and Enterococcus faecalis . [6] [7] [9] [3] Tedizolid is a second-generation oxazolidinone derivative that is 4-to-16-fold more potent against staphylococci and enterococci compared to linezolid. [10] The recommended dosage for treatment is 200 mg once daily for a total duration of six days, either orally (with or without food) or through an intravenous injection (if patient is older than 18 years old). [3]

In the European Union, tedizolid is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in adults. [4]

Mechanism of action

Tedizolid phosphate (TR-701) is a prodrug activated by plasma or intestinal phosphatases to tedizolid (TR-700) following administration of the drug either orally or intravenously. [3] [11] Once activated, tedizolid exerts its bacteriostatic microbial activity through inhibition of protein synthesis by binding to the 50S ribosomal subunit (on the acceptor site) of the bacteria. [3]

Tedizolid phosphate molecular structure. Tedizolid phosphate.svg
Tedizolid phosphate molecular structure.
A 3D ball and stick representation of a tedizolid phosphate molecule. Tedizolid phosphate 3D.png
A 3D ball and stick representation of a tedizolid phosphate molecule.

Pharmacokinetic/pharmacodynamic (PK/PD) properties

Tedizolid tablets have an oral bioavailability of >90%. Tedizolid has higher binding to plasma proteins (80%), longer half-life, and a larger volume of distribution compared to linezolid. It is primarily metabolized by the liver as an inactive sulphate conjugate (phase II reaction), with no metabolism by cytochrome P-450 enzymes. Less than 20% of the drug is excreted unchanged in the urine. Tedizolid bactericidal activity on vancomycin-resistant Enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) is time dependent. Correlations are closest between fAUC24/MIC and the tedizolid PK/PD index against MRSA and VRE. To achieve 1 kill (90% of organisms killed in every step), tedizolid fAUC24/MIC in neutropenic mouse models with a thigh infection with VRE and MRSA should be 14.2 and 138.5, respectively. The post-antibiotic effects of tedizolid against VRE and MRSA are 2.39 and 0.99 h, respectively. [12]

Clinical trials

Tedizolid proved its noninferiority to linezolid in two phase-III trials, known as the ESTABLISH trials. [13]

Tedizolid is the second treatment approved by the US Food and Drug Administration (FDA) under the Generating Antibiotic Incentives Now (known as the GAIN Act) federal law. [14] [15] New antibiotics manufactured under the act will be designated as a Qualified Infectious Disease Product (QIDP), allowing an expedited review by the FDA and an additional five years of market exclusivity. [15]

Adverse effects

The most common adverse effects found in the clinical trials were nausea, headache, diarrhea, vomiting, and dizziness. [3] Tedizolid has also been found to have hematologic (blood) effects, as shown in Phase-I studies in which subjects exposed to doses longer than 6 days showed a possible dose and duration effect on hematologic parameters. [3] Its safety in patients with decreased levels of white blood cells has not been established. [9] Patients on tedizolid are also at low risk of peripheral and optic neuropathy, similar to other members of the oxazolidinone class. [3]

References

  1. ↑ "Trius grows as lead antibiotic moves forward". 31 October 2011.
  2. ↑ "Health Canada New Drug Authorizations: 2015 Highlights". Health Canada . 4 May 2016. Retrieved 7 April 2024.
  3. 1 2 3 4 5 6 7 8 "Sivextro- tedizolid phosphate tablet, film coated Sivextro- tedizolid phosphate injection, powder, lyophilized, for solution". DailyMed. 22 June 2020. Retrieved 24 October 2020.
  4. 1 2 3 4 5 "Sivextro EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 5 July 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  5. ↑ "Cubist Pharmaceuticals to Acquire Trius Therapeutics". July 2013. Archived from the original on 2 April 2015. Retrieved 17 March 2015.
  6. 1 2 "Drug Approval Package: Sivextro (tedizolid phosphate) Tablets NDA #205435". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 5 July 2020.
  7. 1 2 "Drug Approval Package: Sivextro (tedizolid phosphate) Injection NDA #205436". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 5 July 2020.
  8. ↑ World Health Organization (2025). The selection and use of essential medicines, 2025: WHO Model List of Essential Medicines, 24th list. Geneva: World Health Organization. hdl: 10665/382243 .
  9. 1 2 "FDA approves Sivextro to treat skin infections" (Press release). June 2014. Archived from the original on 21 January 2017. Retrieved 16 December 2019.
  10. ↑ "Tedizolid (TR-701): a new oxazolidinone with enhanced potency". Accessed 2015-03-16.
  11. ↑ Schaadt R, Sweeney D, Shinabarger D, Zurenko G (August 2009). "In vitro activity of TR-700, the active ingredient of the antibacterial prodrug TR-701, a novel oxazolidinone antibacterial agent". Antimicrobial Agents and Chemotherapy. 53 (8): 3236–3239. doi:10.1128/AAC.00228-09. PMC   2715649 . PMID   19528279.
  12. ↑ Carcione D, Intra J, Andriani L, Campanile F, Gona F, Carletti S, et al. (September 2023). "New Antimicrobials for Gram-Positive Sustained Infections: A Comprehensive Guide for Clinicians". Pharmaceuticals. 16 (9): 1304. doi: 10.3390/ph16091304 . PMC   10536666 . PMID   37765112.
  13. ↑ "Analysis of the Phase 3 ESTABLISH Trials of Tedizolid versus Linezolid in Acute Bacterial Skin and Skin Structure Infections". Accessed March 16, 2015
  14. ↑ "New FDA task force will support innovation in antibacterial drug development". September 2012. Archived from the original on 25 September 2012.
  15. 1 2 "Three encouraging steps towards new antibiotics". September 2014. Archived from the original on 7 March 2015. Retrieved 17 March 2015.
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