Tedizolid

This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

Summary

Tedizolid is an oxazolidinone class antibiotic that inhibits bacterial protein synthesis and is proven to be effective in the treatment of certain Gram-positive bacterial infections.

Generic Name
Tedizolid
DrugBank Accession Number
DB14569
Background

Drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and penicillin-resistant Streptococcus penumoniae, represent a massive public health threat.5,8 Tedizolid is a member of the oxazolidinone class of antibiotics, which includes the previously approved linezolid and is generally effective against multidrug-resistant Gram-positive bacteria. Tedizolid is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and is generally more effective and more tolerable than linezolid.14,5,1

Tedizolid was approved by the FDA on June 20, 2014, for sale by Cubist Pharmaceuticals as tedizolid phosphate (SIVEXTRO®). This product is currently available as both an oral tablet and as a powder for intravenous injection.14

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 370.344
Monoisotopic: 370.11896653
Chemical Formula
C17H15FN6O3
Synonyms
  • Tedizolid
  • Torezolid
External IDs
  • DA 7157
  • DA-7157
  • TR 700
  • TR-700

Pharmacology

Indication

Tedizolid is indicated for the treatment of acute bacterial infections of the skin and skin structure (ABSSSI). To prevent drug resistance, tedizolid should only be used for infections that are caused by susceptible bacteria.14

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Tedizolid is an oxazolidinone antibiotic that works by inhibiting protein synthesis by bacterial ribosomes.14,2,5 However, oxazolidinone antibiotics can also bind to human mitochondrial, but not cytoplasmic, ribosomes.3,7 Mitochondrial protein synthesis inhibition is associated with adverse patient effects such as neurological, hematological, and gastrointestinal toxicity, although tedizolid is tolerated better than the related linezolid.1 Alternative therapies should be considered when treating neutropenic patients with ABSSSI. Clostridium difficile-associated diarrhea has been reported in patients treated with tedizolid.14

Mechanism of action

Despite renewed efforts to combat the spread of antimicrobial resistance, multidrug-resistant organisms, including gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, remain a threat.8,5 Oxazolidinones represent a relatively new class of antibacterials inhibiting protein synthesis that is generally capable of overcoming resistance to other bacterial protein synthesis inhibitors.14,5,6

Protein synthesis involves the action of ribosomes, multi-subunit complexes composed of both protein and ribosomal RNA (rRNA) substituents. Translocation along the length of a messenger RNA and concomitant protein synthesis involves the action of the A, P, and E sites of the peptidyltransferase centre (PTC), which accepts charged aminoacyl-tRNAs and catalyzes the formation of peptide bonds between them. The bacterial 70S ribosome comprises a small (30S) and a large (50S) subunit.9

Early studies into the mechanism of action of oxazolidinone antibiotics suggested that they inhibit a step in the initiation of protein synthesis.4 However, this mechanism was inconsistent with mapped resistance mutations, and later studies involving cross-linking and direct structural determination of the binding site revealed that oxazolidinones, including both linezolid and tedizolid, bind in the A site of the PTC by interacting with the 23S rRNA component.3,2 The structural studies also revealed that oxazolidinone binding alters the conformation of a conserved nucleotide in the 23S rRNA (U2585 in Escherichia coli), which renders the PTC non-productive for peptide bond formation.2 Hence, tedizolid exerts its effect through inhibiting bacterial protein synthesis.14

TargetActionsOrganism
A23S ribosomal RNA
inhibitor
Enteric bacteria and other eubacteria
Absorption

Tedizolid reaches peak plasma concentrations within three hours for oral administration and within one hour following intravenous administration; the absolute oral bioavailability is approximately 91%. Food has no effect on absorption. When given once daily, either orally or intravenously, tedizolid reaches steady-state concentrations in approximately three days.14,10,11

The Cmax for tedizolid after a single dose/at steady-state is 2.0 ± 0.7/2.2 ± 0.6 mcg/mL for oral administration, and 2.3 ± 0.6/3.0 ± 0.7 mcg/mL for intravenous administration, respectively. Similarly, the Tmax has a median (range) of 2.5 (1.0 - 8.0)/3.5 (1.0 - 6.0) hrs for the oral route and 1.1 (0.9 - 1.5)/1.2 (0.9 - 1.5) hrs when given intravenous. The AUC is 23.8 ± 6.8/25.6 ± 8.4 mcg*hr/mL for oral and 26.6 ± 5.2/29.2 ± 6.2 mcg*hr/mL for intravenous.14,10,11

Volume of distribution

The volume of distribution for tedizolid following a single intravenous dose of 200 mg is between 67 and 80 L.14 In a study involving oral administration of 200 mg tedizolid to steady-state, the volume of distribution was 108 ± 21 L, while a single 600 mg oral dose resulted in an apparent volume of distribution of 113.3 ± 19.3 L.12,13 Tedizolid has been observed to penetrate the interstitial space of both adipose and skeletal muscle tissue and is also found in the epithelial lining fluid as well as in alveolar macrophages.14,12,13

Protein binding

Approximately 70 to 90% of tedizolid is bound to human plasma proteins.14,1,12,13

Metabolism

Tedizolid is administered as a phosphate prodrug that is converted to tedizolid (the circulating active moiety). Prior to excretion, the majority of tedizolid is converted to an inactive sulphate conjugate in the liver, though this is unlikely to involve the action of cytochrome P450-family enzymes.14,1

Route of elimination

When given as a single oral dose, approximately 82% of tedizolid is excreted via the feces and 18% in urine. The majority is found as the inactive sulphate conjugate, with only 3% recovered unchanged. Over 85% of the elimination occurs within 96 hours.14,1

Half-life

Tedizolid has a half-life of approximately 12 hours.14,11,10

Clearance

Tedizolid has an apparent oral clearance of 6.9 ± 1.7 L/hr for a single dose and 8.4 ± 2.1 L/hr at steady-state. The systemic clearance is 6.4 ± 1.2 L/hr for a single dose and 5.9 ± 1.4 L/hr at steady-state.14,11,10

Adverse Effects
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Toxicity

Toxicity information regarding tedizolid is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as nausea, headache, dizziness, diarrhea, and vomiting. Symptomatic and supportive measures are recommended.14

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcenocoumarolThe risk or severity of bleeding can be increased when Tedizolid is combined with Acenocoumarol.
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Tedizolid.
DicoumarolThe risk or severity of bleeding can be increased when Tedizolid is combined with Dicoumarol.
EstetrolThe therapeutic efficacy of Estetrol can be decreased when used in combination with Tedizolid.
FluindioneThe risk or severity of bleeding can be increased when Tedizolid is combined with Fluindione.
LactuloseThe therapeutic efficacy of Lactulose can be decreased when used in combination with Tedizolid.
PhenindioneThe risk or severity of bleeding can be increased when Tedizolid is combined with Phenindione.
PhenprocoumonThe risk or severity of bleeding can be increased when Tedizolid is combined with Phenprocoumon.
Picosulfuric acidThe therapeutic efficacy of Picosulfuric acid can be decreased when used in combination with Tedizolid.
Typhoid vaccineThe therapeutic efficacy of Typhoid vaccine can be decreased when used in combination with Tedizolid.
Interactions
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Food Interactions
No interactions found.

Products

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Categories

ATC Codes
J01XX11 — Tedizolid
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenylpyridines. These are polycyclic aromatic compounds containing a benzene ring linked to a pyridine ring through a CC or CN bond.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Phenylpyridines
Direct Parent
Phenylpyridines
Alternative Parents
Fluorobenzenes / Aryl fluorides / Oxazolidinones / Tetrazoles / Carbamate esters / Heteroaromatic compounds / Organic carbonic acids and derivatives / Azacyclic compounds / Oxacyclic compounds / Hydrocarbon derivatives
show 6 more
Substituents
3-phenylpyridine / Alcohol / Aromatic heteromonocyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzenoid / Carbamic acid ester / Carbonic acid derivative
show 19 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organofluorine compound, carbamate ester, tetrazoles, primary alcohol, pyridines, ring assembly, oxazolidinone (CHEBI:82717)
Affected organisms
  • Staphylococcus
  • Enterococcus
  • Streptococcus

Chemical Identifiers

UNII
97HLQ82NGL
CAS number
856866-72-3
InChI Key
XFALPSLJIHVRKE-GFCCVEGCSA-N
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
IUPAC Name
(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one
SMILES
CN1N=NC(=N1)C1=NC=C(C=C1)C1=C(F)C=C(C=C1)N1C[C@H](CO)OC1=O

References

Synthesis Reference

Katharina Reichenbacher, Robert J. Duguid, Jacqueline A. Ware, Douglas Phillipson. "Forms of R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate." U.S. Patent US9624250B2, issued April 18, 2017.

General References
  1. Roger C, Roberts JA, Muller L: Clinical Pharmacokinetics and Pharmacodynamics of Oxazolidinones. Clin Pharmacokinet. 2018 May;57(5):559-575. doi: 10.1007/s40262-017-0601-x. [Article]
  2. Wilson DN, Schluenzen F, Harms JM, Starosta AL, Connell SR, Fucini P: The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13339-44. doi: 10.1073/pnas.0804276105. Epub 2008 Aug 29. [Article]
  3. Leach KL, Swaney SM, Colca JR, McDonald WG, Blinn JR, Thomasco LM, Gadwood RC, Shinabarger D, Xiong L, Mankin AS: The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria. Mol Cell. 2007 May 11;26(3):393-402. doi: 10.1016/j.molcel.2007.04.005. [Article]
  4. Shinabarger DL, Marotti KR, Murray RW, Lin AH, Melchior EP, Swaney SM, Dunyak DS, Demyan WF, Buysse JM: Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions. Antimicrob Agents Chemother. 1997 Oct;41(10):2132-6. [Article]
  5. Koulenti D, Xu E, Mok IYS, Song A, Karageorgopoulos DE, Armaganidis A, Lipman J, Tsiodras S: Novel Antibiotics for Multidrug-Resistant Gram-Positive Microorganisms. Microorganisms. 2019 Aug 18;7(8). pii: microorganisms7080270. doi: 10.3390/microorganisms7080270. [Article]
  6. McCusker KP, Fujimori DG: The chemistry of peptidyltransferase center-targeted antibiotics: enzymatic resistance and approaches to countering resistance. ACS Chem Biol. 2012 Jan 20;7(1):64-72. doi: 10.1021/cb200418f. Epub 2011 Dec 30. [Article]
  7. McKee EE, Ferguson M, Bentley AT, Marks TA: Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones. Antimicrob Agents Chemother. 2006 Jun;50(6):2042-9. doi: 10.1128/AAC.01411-05. [Article]
  8. Laxminarayan R, Van Boeckel T, Frost I, Kariuki S, Khan EA, Limmathurotsakul D, Larsson DGJ, Levy-Hara G, Mendelson M, Outterson K, Peacock SJ, Zhu YG: The Lancet Infectious Diseases Commission on antimicrobial resistance: 6 years later. Lancet Infect Dis. 2020 Apr;20(4):e51-e60. doi: 10.1016/S1473-3099(20)30003-7. Epub 2020 Feb 11. [Article]
  9. Ling C, Ermolenko DN: Structural insights into ribosome translocation. Wiley Interdiscip Rev RNA. 2016 Sep;7(5):620-36. doi: 10.1002/wrna.1354. Epub 2016 Apr 27. [Article]
  10. Flanagan S, Fang E, Munoz KA, Minassian SL, Prokocimer PG: Single- and multiple-dose pharmacokinetics and absolute bioavailability of tedizolid. Pharmacotherapy. 2014 Sep;34(9):891-900. doi: 10.1002/phar.1458. Epub 2014 Jul 3. [Article]
  11. Flanagan SD, Bien PA, Munoz KA, Minassian SL, Prokocimer PG: Pharmacokinetics of tedizolid following oral administration: single and multiple dose, effect of food, and comparison of two solid forms of the prodrug. Pharmacotherapy. 2014 Mar;34(3):240-50. doi: 10.1002/phar.1337. Epub 2013 Aug 7. [Article]
  12. Housman ST, Pope JS, Russomanno J, Salerno E, Shore E, Kuti JL, Nicolau DP: Pulmonary disposition of tedizolid following administration of once-daily oral 200-milligram tedizolid phosphate in healthy adult volunteers. Antimicrob Agents Chemother. 2012 May;56(5):2627-34. doi: 10.1128/AAC.05354-11. Epub 2012 Feb 13. [Article]
  13. Sahre M, Sabarinath S, Grant M, Seubert C, Deanda C, Prokocimer P, Derendorf H: Skin and soft tissue concentrations of tedizolid (formerly torezolid), a novel oxazolidinone, following a single oral dose in healthy volunteers. Int J Antimicrob Agents. 2012 Jul;40(1):51-4. doi: 10.1016/j.ijantimicag.2012.03.006. Epub 2012 May 13. [Article]
  14. FDA Approved Products: Sivextro (tedizolid phosphate) tablet and injection [Link]
KEGG Drug
D09685
ChemSpider
9409096
BindingDB
50491954
RxNav
1540825
ChEBI
82717
ChEMBL
CHEMBL1257051
ZINC
ZINC000043100956
PDBe Ligand
U7V
Wikipedia
Tedizolid
PDB Entries
6wrs

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedOtherCystic Fibrosis (CF)1
3CompletedTreatmentBacterial Infections1
3CompletedTreatmentSkin and Subcutaneous Tissue Bacterial Infections1
3CompletedTreatmentSkin Diseases, Bacterial / Skin Diseases, Infectious1
2Active Not RecruitingTreatmentBone and Joint Infections1
2CompletedOtherCellulitis / Erysipelas / Major Cutaneous Abscess1
1CompletedBasic ScienceBacterial Infections1
1CompletedBasic ScienceHealthy Volunteers1
1CompletedOtherDiabetes / Healthy Volunteers / Wound Infections1
1CompletedOtherHealthy Volunteers1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous200 MG
Tablet, film coatedOral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)256.8https://pdf.hres.ca/dpd_pm/00032313.PDF
water solubility0.1 mg/mLhttps://pdf.hres.ca/dpd_pm/00032313.PDF
pKa1.8, 6.5https://pdf.hres.ca/dpd_pm/00032313.PDF
Predicted Properties
PropertyValueSource
Water Solubility0.382 mg/mLALOGPS
logP0.95ALOGPS
logP2.12ChemAxon
logS-3ALOGPS
pKa (Strongest Acidic)14.61ChemAxon
pKa (Strongest Basic)-1.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area106.26 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity115.06 m3·mol-1ChemAxon
Polarizability36.84 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets
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Kind
Nucleotide
Organism
Enteric bacteria and other eubacteria
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
Binding of tedizolid to 23S rRNA in the A pocket of the bacterial 70S ribosome inhibits bacterial protein synthesis.
In prokaryotes, the 23S rRNA is part of the large subunit (the 50S) that joins with the 30S small subunit to create the functional 70S ribosome. The ribosome is comprised of 3 RNAs: the 23S, the 16S and the 5S ribosomal RNAs. The 23S and the 5S associate with their respective proteins to make up the large subunit of the ribosome, while the 16S RNA associates with its proteins to make up the small subunit.
References
  1. Wilson DN, Schluenzen F, Harms JM, Starosta AL, Connell SR, Fucini P: The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13339-44. doi: 10.1073/pnas.0804276105. Epub 2008 Aug 29. [Article]
  2. Leach KL, Swaney SM, Colca JR, McDonald WG, Blinn JR, Thomasco LM, Gadwood RC, Shinabarger D, Xiong L, Mankin AS: The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria. Mol Cell. 2007 May 11;26(3):393-402. doi: 10.1016/j.molcel.2007.04.005. [Article]
  3. Shinabarger DL, Marotti KR, Murray RW, Lin AH, Melchior EP, Swaney SM, Dunyak DS, Demyan WF, Buysse JM: Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions. Antimicrob Agents Chemother. 1997 Oct;41(10):2132-6. [Article]
  4. FDA Approved Products: Sivextro (tedizolid phosphate) tablet and injection [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Tedizolid displays weak reversible inhibition of both MAO-A and MAO-B in vitro.
General Function
Serotonin binding
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...
Gene Name
MAOA
Uniprot ID
P21397
Uniprot Name
Amine oxidase [flavin-containing] A
Molecular Weight
59681.27 Da
References
  1. Flanagan S, Bartizal K, Minassian SL, Fang E, Prokocimer P: In vitro, in vivo, and clinical studies of tedizolid to assess the potential for peripheral or central monoamine oxidase interactions. Antimicrob Agents Chemother. 2013 Jul;57(7):3060-6. doi: 10.1128/AAC.00431-13. Epub 2013 Apr 22. [Article]
  2. FDA Approved Products: Sivextro (tedizolid phosphate) tablet and injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
Tedizolid displays weak reversible inhibition of both MAO-A and MAO-B in vitro.
General Function
Primary amine oxidase activity
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...
Gene Name
MAOB
Uniprot ID
P27338
Uniprot Name
Amine oxidase [flavin-containing] B
Molecular Weight
58762.475 Da
References
  1. Flanagan S, Bartizal K, Minassian SL, Fang E, Prokocimer P: In vitro, in vivo, and clinical studies of tedizolid to assess the potential for peripheral or central monoamine oxidase interactions. Antimicrob Agents Chemother. 2013 Jul;57(7):3060-6. doi: 10.1128/AAC.00431-13. Epub 2013 Apr 22. [Article]
  2. FDA Approved Products: Sivextro (tedizolid phosphate) tablet and injection [Link]

Drug created on July 20, 2018 20:44 / Updated on April 16, 2021 04:48