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This Manual has been designed for use in the NICU at London Health Sciences Centre (LHSC), London, Ontario, Canada, and represents clinical practice at this institution. The information contained within the Manual may not be applicable to other centres. If users of this Manual are not familiar with a drug, it is recommended that the official monograph be consulted before it is prescribed and administered. Any user of this information is advised that the contributors, Editor and LHSC are not responsible for any errors or omissions, and / or any consequences arising from the use of the information in this Manual.

LINEZOLID

Indication

  • For the treatment of multiresistant gram-positive cocci, particularly as an alternative in infections caused by vancomycin-resistant enterococci (Enterococcus faecium), penicillin-susceptible Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus
  • Also for the treatment of complicated skin and skin structure infections caused by Streptococcus pyogenes, Streptococcus agalactiae or Staphylococcus aureus (methicillin susceptile strains only)
  • The following organisms are susceptible to linezolid in vitro: Enterococcus faecalis (including vancomycin resistant strains) Enterococcus faecium (vancomycin susceptible strains), Staphyloccus epidermidis (including methicillin resistant strains), Staphylococcus haemolyticus, Streptococcus pneumoniae (penicillin resistant strains) and Viridans group streptococci.

Clinical Pharmacology

(based on Adult studies unless indicated otherwise)
  • Linezolid is a synthetic antibacterial agent of the oxazolidinone class and is structurally unrelated to any other commercially available class of antibiotics.
  • Linezolid works by inhibiting bacterial protein synthesis; is bacteriostatic against enterococci and staphylococci and bacteriocidal against most strains of streptococci.
  • Plasma protein binding of linezolid is approximately 31% and is concentration-independent.
  • Linezolid is rapidly and extensively absorbed from the GI tract with a bioavailability of 100%.
  • Approximately 30% of a dose is eliminated unchanged in the urine; an additional 10% of a dose appears in the urine as 'Metabolite A' and 40 % appears as 'Metabolite B'; virtually no linezolid appears in the faeces, but about 3% of a dose is present in the faeces as 'Metabolite A' and 6% as 'Metabolite B'.
  • Linezolid is primarily metabolized via oxidation reactions; it is not detectably metabolized by cytochrome P450; therefore, it is not expected to inhibit or induce the metabolism of other drugs that are metabolized by cytochrome P450.
  • Clearance of linezolid varies with age. See table I.

    Table 1. Half-life of linezolid in pediatric patients following a single IV infusion of 10 mg/kg.

    Age Group t1/2
    (hrs)
    Neonates
         Pre-term ** < 1 week
         Full-term *** < 1 week
         Full-term *** > 1 week to 28 days

    5.6 [2.4 - 9.8]
    3.0 [1.3 - 6.1]
    1.5 [1.2 - 1.9]
    Infants
         > 28 days to < 3 months

    1.8 [1.2 - 2.8]
    Paediatrics
         3 months through 11 years

    2.9 [0.9 - 8.0]
    Adolescents
         12 through 17 years

    4.1 [1.3 - 8.1]
     
    ** "pre-term" is defined as < 34 weeks gestational age (Note: Only 1 patient enrolled was pre-term with a postnatal age between 1 week and 28 days
    *** "full-term" is defined as > 34 weeks gestational age

Warnings:

  • Myelosuppression (including anemia, leukopenia, pancytopenia and thrombocytpenia) has been reported in patients receiving linezolid
  • Complete blood counts should be monitored at least weekly in patients who receive linezolid
  • Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression

Side Effects

  • Most commonly reported adverse events are diarrhea (incidence of 2.8 to 11% in clinical trials), nausea (3.4 to 9.6%), headache (0.5 to 11.3%), constipation (2.2%) and rash (2%)
  • NEUTROPENIA and EOSINOPHILIA has been reported with rates of 6.4% (n=78) and 17.9% (n=14) respectively in children ages 1 to 12 years while receiving treatment with linezolid 10 mg/kg for community-acquired pneumonia.
  • Lactic acidosis has been reported with the use of linezolid. This has manifested as repeated episodes of nausea and vomiting. Unexplained acidosis or a low bicarbonate level should be investigated.
  • Skin rash has occasionally been reported during oral therapy.

Miscellaneous

  • Linezolid penetrates into well perfused tissues and has been reported to have been found in saliva, CSF, and intrapleural fluids.
  • Some patients may experience a reversible enhancement of the pressor response to agents such as dopamine, dobutamine or epinephrine. Doses of these adrenergic agents should be titrated to the desired response.
  • Nursing Mothers: Linezolid and its metabolites are excreted in the milk of lactating rats, with milk concentrations similar to those in plasma. It is not known whether linezolid is excreted in human milk.

Dose

  • Pre-term neonates < 7 days of age have slower linezolid clearance and higher mean AUC values than full term neonates and older infants. Starting at 7 days of age, clearance of linezolid gradually increases, which necessitates a more frequent dosing interval.
  • Similar mean daily AUC values were observed in full-term neonates and pediatric patients dosed every 8 hours (q8h) relative to adolescents or adults dosed every 12 hours (q12h).

    Pre-term neonates (gestational age < 34 weeks) < 7 days of age:

    10 mg/kg q12h

    (consider 10mg/kg q8h regimen if clinical response is sub-optimal)

    Full term neonates and pre-term neonates >7 days of age:

    10 mg/kg q8h

    Infuse over 30 to 120 minutes

  • Dosing in renal insufficiency
    • The pharmacokinetics of the parent drug, linezolid, are not affected
    • However, the secondary metabolites of linezolid (i.e. Metabolite A and metabolite B) will accumulate

Supplied

  • 2mg/mL syringe, prepared by Pharmacy
  • the solution may exhibit a yellow colour. This does not affect the potency.

References

  1. Kaplan SL, Patterson L, Edwards KM et al: Linezolid for the treatment of community-acquired pneumonia in hospitalized children. Pediatr Infect Dis J 2001; 20(5):488-494.
  2. Kearns GL, Abdel-Rahman SM, Blumer JL et al: Single dose pharmacokinetics of linezolid in infants and children. Pediatr Infect Dis J 2000; 19:1178-1184.
  3. Lyseng-Williamson KA and Goa KL. Linezolid in Infants and children with severe gram-positive infections. Pediatr Drugs 2003;5(6):419-29.
  4. U.S. Product monograph 2003
  5. Micromedex 2003

Aug/03 -C. Reynaert/L. Vanderhaeghe, Pharmacy Dept. (66004)
Sep/03-DKnoppert (modified)




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