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| | First of a new class of synthetic antibacterials: oxazolidinones
Mode of action
- Inhibits ribosomal protein synthesis by inhibiting formation of the initiation complex
Spectrum of activity
- in vitro activity against most pathogenic Gram positives
- bacteriostatic against most organisms but bacteriacidal against
pneumococcus
- spectrum of activity includes MRSA and vancomycin resistant
enterococci
- borderline activity against Bacteroides fragilis
- clinical efficacy similar to vancomycin for pneumonia and complicated
soft tissue infections
- relatively good in vitro activity against mycobacteria including Mycobacterium
tuberculosis and Mycobacterium avium complex. Clinical
significance of this activity unknown
- excellent in vitro activity against Nocardia species
- sub-inhibitory concentrations inhibit expression of virulence factors by
staphylococci and streptococci and potentiate susceptibility of S. aureus
and Strep. pyogenes to phagocytosis by neutrophils
Pharmacokinetics
- Administration: IV or PO (100% bioavailability in healthy volunteers)
- Wide tissue distribution
- good lung penetration: concentration in epithelial lining fluid 4.5 x
plasma
- CSF penetration much better than vancomycin
- ~30% protein bound
- Elimination by predominantly by hepatic metabolism, although 30-35%
excreted unchanged in urine
- parent drug does not accumulate significantly in renal failure but
metabolites do. Clinical significance of this unknown.
- elimination half life ~4.5-5.5 h
- both linezolid and metabolites eliminated by haemodialysis
- no dosage adjustment recommended for patients with renal and hepatic
insufficiency but inadequate data on patients with severe hepatic
insufficiency to be sure this recommendation applies to these patients.
- Dosage adjustment for critical illness not necessary
- Efficacy associated with ratio of area under concentration-time curve to
MIC
Clinical uses
- complicated skin and soft tissue infections caused by S. aureus (MRSA
or MSSA), Strep. pyogenes or Strep. agalactiae
- uncomplicated skin infections caused by MSSA or Strep. pyogenes
- nosocomial pneumonia caused by S. aureus (MRSA or MSSA) or Strep.
pneumoniae
- infections with glycopeptide resistant enterococci or staphylococci
- although clinical trials suggest that the efficacy of linezolid and
vancomycin are similar for patients with MRSA infection a meta-analysis with sub-group analysis suggests that
linezolid may be more effective for nosocomial pneumonia. Further
subgroup analysis suggests that linezolid is more effective in ventilator
associated pneumonia
Adverse effects
- not nephrotoxic
- myelosuppression causing anaemia, leucopaenia, pancytopaenia and
thrombocytopaenia. More common in:
- patients receiving >2 weeks of linezolid
- pre-existing myelosuppression
- concomitant administration of drugs which cause myelosuppression
- chronic infection in patients who have received previous or
concomitant antibiotics
- lactic acidosis (rare)
Drug interactions
- co-administration of serotinergic agents (eg MAOI) may result in serotonin
syndrome (rare)
- adrenergic agents, resulting in hypertension
Further reading
Moellering RC. Linezolid: the first oxazolidinone
antimicrobial. Ann Intern Med, 2003; 138:135-42
Kolleff M et al. Intensive Care Medicine, 2004
Potential conflict of interest
The Dept of Anaesthesia & Intensive Care, The Chinese
University of Hong Kong received sponsorship for educational activities from
Pharmacia in 2002 and Pfizer Corp. Hong Kong Ltd. in 2003 and 2004
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