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Linezolid [Zyvox]

linezolid molecule

Actions and Uses

Linezolid (Zyvox® by Pharmacia & Upjohn) is the first member of a new class of antibiotics known as oxazolidinones to be introduced to the US market (FDA approved on 4/17/2000). Linezolid is a bacteriostatic agent indicated for the treatment of nosocomial infections involving Gram-positive organisms including methicillin-resistant Staph aureus (MRSA or ORSA), multi-resistant strains of Strep pneumoniae, and vancomycin-resistant enterococcus faecium (VRE).

Linezolid inhibits initiation of protein synthesis at the level of the ribosomes. It prevents the formation of the fmet- tRNA:mRNA:30S subunit ternary complex. It also binds to the 50S ribosomal subunit in a region shared with chloramphenicol. However, unlike chloramphenicol, the oxazolidinones are not inhibitors of peptidyl transferase.

The FDA-approved indications are:

  1. VRE faecium infections including VRE bacteremia.
  2. Nosocomial pneumonia caused by methicillin-resistant and methicillin-susceptible strains of Staph aureus (MRSA & MSSA), or Strep pneumoniae (penicillin-susceptible only)(PSSP).
  3. Complicated skin and skin structure infections caused by Staph aureus (MRSA & MSSA), Strep pyogenes, or Strep agalactiae.
  4. Uncomplicated skin and skin structure infections caused by methicillin-susceptible Staph aureus (MSSA) or Strep pyogenes.
  5. Community aquired pneumonia caused by PSSP (including cases of concurrent bacteremia), or MSSA.

Efficacy of linezolid in the treatment of diabetic foot infection or decubitus ulcers has not been evaluated. Linezolid is not approved for use in the pediatric population; safety and effecacy of linezolid in children are yet to be determined.

Linezolid is bacteriostatic in most cases and should not be used for the treatment of endocarditis.

There have been at least a half dozen reports of linezolid-resistant VRE in immunosuppressed patients including liver transplant recipients. Therefore, resistance studies should be done routinely before commencing VRE treatment with linezolid.

Pharmacokinetics

  • Absorption of oral form of linezolid is rapid (time-to-peak <2 hrs) and complete and there is no need for dose adjustment when switching from the intravenous to oral route.
  • Linezolid is widely distributed (Vd = 0.6 L/kg; plasma protein binding = 30%). Its concentration is saliva is the same as in plasma, whereas its level in the sweat is only half the plasma level.
  • There is no information on its distribution into the CNS / CSA.
  • About one third of dose is eliminated unchanged in the urine. The elimination half life of the parent compound is about 6.5 hrs in healthy volunteers and 8.5 hrs in hemodialysis patients.
  • There are limited data in the pediatric population, but the elimination half-life is significantly shorter than in adults, suggesting that a q8h dosing regimen may be more appropriate for these patients (1 yr < age < 12 yr) (note that the drug is not approved for children).
  • Linezolid undergoes oxidation and opening of its morpholino ring resulting in the formation of two virtually inactive carboxylic acid metabolites (known as metabolites A and B).
  • Urinary excretion of metabolites A & B accounts for 50% of the dose, whereas about 30% of the dose appears in the urine as linezolid. About 10% of the dose appears in the feces as metabolites.
  • The elimination half-life of the metabolites is approximately 6.5 hrs in healthy subjects and about 10 hrs in patients with severe renal impairment (10 < CLcr < 30 mL/min).

Contraindications and Warnings

  • Linezolid is contrindicated in patients with a history of allergy to linezolid products.
  • Linezolid has a relatively weak monoamine oxidase inhibitor action. Therefore, MAOI precautions should be followed to avoid potentially serious food-drug or drug-drug interactions.
Available As

  • Intravenous (2 mg/mL minibags): 200, 400, and 600-mg bags
  • Oral Tablets: 400 and 600 mg
  • Oral Suspension (to be reconsistuted): 150 mL x 20 mg/mL

Dose and Administration

  • For most indications: 600 mg (iv or po) q12h.
  • For uncomplicated skin infections: 400 mg q12h.
  • There appears to be no need for renal dose adjustment.
  • No dose adjustment is required for patients with mild-to-moderate hepatic insufficiency.
  • When given IV, it should be infused over 30 - 120 minutes (usually 1 hr).
  • Oral dose is the same as IV dose, and the oral form may be taken with or w/o food.
  • Although the drug is not approved for children, a 10 mg/kg has been suggested.
Main Side Effects

  • Hematologic: Thrombocytopenia
  • Liver: elevated liver and pancreatic enzymes (Amylase, AST, ALT, Alk Phos, Lipase) (2 - 10% of pts)
  • GI: Pseudomembraneous colitis, diarrhea; nausea and vomiting.
  • CNS: heache; dizziness

Drug Interactions

  • Linezolid is a reversible, non-selective inhibitor of monoamine oxidase. Patients receiving linezolid should avoid food rich in tyramine. Patients receiving pressors together with linezolid need to be monitored closely. The pressor response to such over-the-counter drugs as phenylpropanolamine may be significantly enhanced by linezolid.
  • Linezolid is neither an inducer nor an inhibitor of the P450 system.

References

  1. Lundstrom TS, Sobel JD. Antibiotics for gram-positive bacterial infections. Vancomycin, teicoplanin, quinupristin/dalfopristin, and linezolid. Infect Dis Clin North Am. 2000;14(2):463-74.
  2. Clemett D, Markham A. Linezolid. Drugs. 2000;59(4):815-27
  3. Diekema DI, Jones RN. Oxazolidinones: a review. Drugs. 2000 Jan;59(1):7-16.
  4. Zyvox PI

 

 
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