Tedizolid

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]}

Tedizolid

Clinical data
Trade names	Sivextro
Other names	TR-700, torezolid[1]
AHFS/Drugs.com	Monograph
MedlinePlus	a614038
License data	US DailyMed: Tedizolid
Routes of administration	By mouth, intravenous
ATC code	J01XX11 (WHO)
Legal status
Legal status	CA: ℞-only[2] US: ℞-only[3] EU: Rx-only[4]
Pharmacokinetic data
Bioavailability	91%
Protein binding	70–90%
Elimination half-life	12 hours
Excretion	Feces
Identifiers
IUPAC name (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	856866-72-3 N Phosphate: 856867-55-5 Y
PubChem CID	11234049
DrugBank	DB09042 Y
ChemSpider	9409096 Y
UNII	97HLQ82NGL Phosphate: O7DRJ6R4DW Y
KEGG	D09685 Y Phosphate: D09686 Y
ChEBI	CHEBI:82717 Y
ChEMBL	ChEMBL1257051 N
CompTox Dashboard (EPA)	DTXSID10234975
ECHA InfoCard	100.249.430
Chemical and physical data
Formula	C17H15FN6O3
Molar mass	370.344 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C4O[C@H](CN4c3cc(F)c(c1ccc(nc1)c2nn(nn2)C)cc3)CO
InChI 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 Y Key:XFALPSLJIHVRKE-GFCCVEGCSA-N Y
NY (what is this?)  (verify)

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.

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 ${\textstyle log_{10}}$ 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]