Chemistry:Tedizolid

Short description: Oxazolidinone-class antibiotic

Tedizolid

Clinical data
Trade names	Sivextro
Other names	TR-700
AHFS/Drugs.com	Monograph
MedlinePlus	a614038
Pregnancy category	US: N (Not classified yet)
Routes of administration	By mouth, intravenous
ATC code	J01XX11 (WHO)
Legal status
Legal status	US: ℞-only EU: Rx-only
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
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)

Tedizolid (formerly torezolid, trade name Sivextro), 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)).

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

Tedizolid was approved for medical use in the United States in June 2014, and for medical use in the European Union in March 2015.

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. Tedizolid is a second-generation oxazolidinone derivative that is 4-to-16-fold more potent against staphylococci and enterococci compared to linezolid. 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).

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

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. 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.

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.

Clinical trials

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

Tedizolid is the second treatment approved by the FDA under the new federal law Generating Antibiotic Incentives Now (known as the GAIN Act). 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.

Adverse effects

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

External links

• "Tedizolid". Drug Information Portal. U.S. National Library of Medicine. https://druginfo.nlm.nih.gov/drugportal/name/tedizolid. 
• "Tedizolid phosphate". Drug Information Portal. U.S. National Library of Medicine. https://druginfo.nlm.nih.gov/drugportal/name/tedizolid%20phosphate. 
• "Tedizolid Injection: MedlinePlus Drug Information". https://medlineplus.gov/druginfo/meds/a614039.html.