Oxazolidinones

The oxazolidinones (linezolid and tedizolid) are bacterial protein synthesis inhibitors. Their unique binding site on the 23S ribosomal RNA of the 50S ribosome gives them zero cross-resistance with other antibiotics. These medications are readily absorbed and widely distributed in the body, and they are indicated for gram-positive infections, including MRSA and vancomycin-resistant Enterococcus. Adverse effects include GI upset, myelosuppression, peripheral or optic neuropathy, and lactic acidosis. Linezolid is a weak monoamine oxidase inhibitor, which can increase the risk for serotonin syndrome when coadministered with other serotonergic medications.

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Chemistry and Pharmacodynamics

Chemical structure

  • Oxazolidinone medications contain the same 5-membered ring (2-oxazolidone) containing nitrogen (N) and oxygen (O).
  • Similar to a N- and O-containing azole (oxazole), with a carbon oxidized to a ketone

Mechanism of action

  • Inhibits bacterial protein synthesis
    • Binds to the bacterial 23S ribosomal RNA (rRNA) of the 50S subunit 
    • Blocks the formation of the 70S initiation complex → prevents translation
  • Prevents: 
    • Bacterial growth
    • Toxin production
  • Primarily bacteriostatic (exception: bactericidal against most streptococcal strains)
  • Resistance: 
    • Can occur because of a mutation at the binding site on 23S rRNA
    • No cross-resistance with other protein synthesis inhibitor antibiotics
Linezolid site of action Oxazolidinones

Linezolid site of action on the 50S ribosomal subunit:
This construction inhibits the initiation of protein synthesis and prevents bacterial replication.

Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics

Absorption and distribution

  • 90%–100% bioavailability after ingestion
  • Tedizolid is a prodrug → converted to active form by phosphatases
  • Protein binding:
    • Linezolid: poor
    • Tedizolid: highly bound
  • Readily distributes into well-perfused tissues
  • Volume of distribution for linezolid is similar to total body water (↑ for tedizolid).

Metabolism

  • Hepatic:
    • Linezolid: metabolized by nonenzymatic oxidation into 2 inactive metabolites
    • Tedizolid: sulfation into inactive sulfate conjugates
  • Neither induce nor inhibit cytochrome P450 enzymes

Excretion

  • Linezolid: urine > feces
  • Tedizolid: feces > urine

Indications

Antimicrobial coverage

  • Oxazolidinones are used to treat infections caused by gram-positive bacteria, including:
    • Streptococcus
    • Enterococcus, including vancomycin-resistant Enterococcus (VRE)
    • Coagulase-negative Staphylococcus
    • Staphylococcus aureus, including MRSA
    • Bacillus 
    • Corynebacterium
    • Listeria
  • Activity has also been demonstrated in vitro against Mycobacterium species.

Types of infections

These medications are FDA-approved for:

  • Linezolid:
    • Skin and soft tissue infections
    • Pneumonia
    • VRE infections
  • Tedizolid: skin and soft tissue infections

Adverse Effects

Adverse effects

  • GI upset
  • Myelosuppression (all blood cell lineages)
  • Peripheral and optic neuropathy
  • Lactic acidosis
  • Hepatotoxicity
  • Hypoglycemia
  • Note: The more severe side effects occur more frequently with prolonged use.

Warnings

Linezolid may cause a hypertensive crisis in the following conditions:

  • Uncontrolled hypertension
  • Hyperthyroidism/thyrotoxicosis
  • Pheochromocytoma

Drug interactions

  • Serotonergic agents: linezolid can reversibly inhibit monoamine oxidase → ↑ risk of serotonin syndrome
    • Selective serotonin reuptake inhibitors
    • Serotonin–norepinephrine reuptake inhibitors
    • Monoamine oxidase inhibitors
  • Warfarin: ↑ PT
  • Sympathomimetic, vasopressor, or dopaminergic medications: ↑ blood pressure

Comparison of Antibiotics

Table: Comparison of several classes of bacterial protein synthesis inhibitor antibiotics
Drug classMechanism of actionCoverageAdverse effects
Amphenicols
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram positives
  • Gram negatives
  • Atypicals
  • GI upset
  • Optic neuritis
  • Aplastic anemia
  • Gray baby syndrome
Lincosamides
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram-positive cocci:
    • MSSA
    • MRSA
    • Streptococcus
  • Anaerobes
  • GI upset
  • Allergic reactions
  • Pseudomembranous colitis
Macrolides
  • Bind to the 50S subunit
  • Prevent transpeptidation
  • Gram positives
  • Gram negatives
  • Atypicals
  • Mycobacterium avium complex
  • GI upset
  • QT prolongation
  • Hepatotoxicity
  • Myasthenia gravis exacerbation
Oxazolidinones
  • Bind to the 23S rRNA of the 50S subunit
  • Prevent initiation complex formation
Gram-positive cocci:
  • MSSA
  • MRSA
  • VRE
  • Streptococcus
  • Myelosuppression
  • Neuropathy
  • Lactic acidosis
  • Serotonin syndrome
rRNA: ribosomal RNA
VRE: vancomycin-resistant Enterococcus
Antibiotic sensitivity chart

Antibiotic sensitivity:
Chart comparing the microbial coverage of different antibiotics for gram-positive cocci, gram-negative bacilli, and anaerobes.

Image by Lecturio. License: CC BY-NC-SA 4.0

References

  1. Norrby R. (2001). Linezolid—a review of the first oxazolidinone. Expert Opin Pharmacother 2:293–302. https://pubmed.ncbi.nlm.nih.gov/11336587/
  2. Hamel JC, Stapert D, Moerman JK, Ford CW. (200). Linezolid, critical characteristics. Infection 28:60–64. https://pubmed.ncbi.nlm.nih.gov/10697798/
  3. Diekema DI, Jones RN. (200). Oxazolidinones: a review. Drugs 59:7–16. https://pubmed.ncbi.nlm.nih.gov/10718097/
  4. Deck DH, Winston LG. (2012). Tetracyclines, macrolides, clindamycin, chloramphenicol, streptogramins, & oxazolidinones. In Katzung BG, Masters SB, Trevor AJ (Eds.), Basic & Clinical Pharmacology, 12th ed., pp. 809–819. https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf
  5. Drew RH, Peel T. (2020). Linezolid and tedizolid (oxazolidinones): An overview. In Baron, E.L. (Ed.), UpToDate. Retrieved June 28, 2021, from https://www.uptodate.com/contents/linezolid-and-tedizolid-oxazolidinones-an-overview
  6. Azzouz A, Preuss CV. (2021). Linezolid. StatPearls. Retrieved June 28, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK539793/
  7. Werth BJ. (2020). Lincosamides, oxazolidinones, and streptogramins. MSD Manual Professional Version. Retrieved June 28, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/lincosamides,-oxazolidinones,-and-streptogramins
  8. Pandit N, Singla RK, Shrivastava B. (2012). Current updates on oxazolidinone and its significance. International Journal of Medicinal Chemistry. https://doi.org/10.1155/2012/159285

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