Tedizolid

Tedizolid (formerly torezolid, trade name Sivextro),[3] 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)).[4]

Tedizolid
Clinical data
Trade namesSivextro
Other namesTR-700
AHFS/Drugs.comMonograph
MedlinePlusa614038
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability91%
Protein binding70–90%
Elimination half-life12 hours
ExcretionFeces
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 InfoCard100.249.430
Chemical and physical data
FormulaC17H15FN6O3
Molar mass370.344 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 checkY
  • Key:XFALPSLJIHVRKE-GFCCVEGCSA-N checkY
 ☒NcheckY (what is this?)  (verify)

The most common side effects include nausea (feeling sick), headache, diarrhoea and vomiting.[2] These side effects were generally of mild or moderate severity.[2]

Tedizolid was approved for medical use in the United States in June 2014,[5][6] and for medical use in the European Union in March 2015.[2]

Medical uses

Tedizolid was approved by the U.S Food and Drug Administration (FDA) on June 20, 2014, with the indication for the treatment of acute bacterial Skin and skin structure infections (ABSSSI) caused by certain susceptible bacteria, including Staphylococcus aureus (including methicillin-resistant strains, 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.[5][6][7][1] Tedizolid is a second-generation oxazolidinone derivative that is 4-to-16-fold more potent against staphylococci and enterococci compared to linezolid.[8] 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).[1]

In the European Union tedizolid is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in adults.[2]

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.[1][9] 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.[1]

Tedizolid phosphate

Pharmacokinetic/pharmacodynamic (PK/PD) properties

Tedizolid tablets have an oral bioavailability >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 VRE and MRSA is time dependent. Correlations are closest between fAUC24/MIC and the tedizolid PK/PD index against MRSA and VRE. To achieve 1 log10 kill, 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.[10]

Clinical trials

Tedizolid proved its noninferiority to linezolid in two phase-III trials, known as the ESTABLISH trials.[11]

Tedizolid is the second treatment approved by the FDA under the new federal law Generating Antibiotic Incentives Now (known as the GAIN Act).[12][13] New antibiotics manufactured under this new act will be designed as a Qualified Infectious Disease Product (QIDP), allowing an expedited review by the FDA and an additional five years of market exclusivity.[13]

Adverse effects

The most common adverse effects found in the clinical trials were nausea, headache, diarrhea, vomiting, and dizziness.[1] 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.[1] Its safety in patients with decreased levels of white blood cells has not been established.[7] Patients on tedizolid are also at low risk of peripheral and optic neuropathy, similar to other members of the oxazolidinone class.[1]

References
  1. "Sivextro- tedizolid phosphate tablet, film coated Sivextro- tedizolid phosphate injection, powder, lyophilized, for solution". DailyMed. 22 June 2020. Retrieved 24 October 2020.
  2. "Sivextro EPAR". European Medicines Agency (EMA). Retrieved 5 July 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. "Trius grows as lead antibiotic moves forward". 31 Oct 2011.
  4. "Cubist Pharmaceuticals to Acquire Trius Therapeutics". July 2013.
  5. "Drug Approval Package: Sivextro (tedizolid phosphate) Tablets NDA #205435". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 5 July 2020.
  6. "Drug Approval Package: Sivextro (tedizolid phosphate) Injection NDA #205436". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 5 July 2020.
  7. "FDA approves Sivextro to treat skin infections" (Press release). June 2014. Archived from the original on 2017-01-21. Retrieved 2019-12-16.
  8. "Tedizolid (TR-701): a new oxazolidinone with enhanced potency". Accessed 2015-03-16.
  9. 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.
  10. 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.
  11. "Analysis of the Phase 3 ESTABLISH Trials of Tedizolid versus Linezolid in Acute Bacterial Skin and Skin Structure Infections". Accessed March 16, 2015
  12. "New FDA task force will support innovation in antibacterial drug development". September 2012.
  13. "Three encouraging steps towards new antibiotics". September 2014.
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