Comparison of the pharmacokinetics of two dosage regimens of linezolid in multidrug-resistant and extensively drug-resistant tuberculosis patients

Clin Pharmacokinet. 2010 Aug;49(8):559-65. doi: 10.2165/11532080-000000000-00000.


Background and objectives: For the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB), potent new drugs are urgently needed. Linezolid is a promising drug, but its use is limited by adverse effects with prolonged administration of 600 mg twice daily. In order to reduce its adverse effects and maintain efficacy, we investigated whether linezolid in a reduced dosage resulted in drug serum concentrations exceeding a ratio of the in vitro minimum inhibitory concentration (MIC) to the area under the serum concentration-time curve (AUC) over 24 hours (AUC(24)) [AUC(24)/MIC] of >100.

Patients and methods: This open-label, prospective pharmacokinetic study evaluated two doses (300 and 600 mg) of linezolid in MDR-TB patients, who received linezolid as part of their treatment. They received linezolid 300 mg twice daily for 3 days, followed by 600 mg twice daily. Blood samples taken at predefined intervals for measuring serum linezolid concentrations were processed by a validated liquid chromatography-tandem mass spectrometry procedure. The AUC(24)/MIC ratio was used as a predictive model of efficacy. Adverse effects of linezolid, including peripheral neuropathy, were evaluated by clinical and laboratory assessments.

Results: Eight patients were included in this study. The median duration of linezolid treatment was 56 days (interquartile range [IQR 44-82] days), with a median cumulative dose of 51,000 mg (IQR 33,850-60,450 mg). The median linezolid AUC over 12 hours (AUC(12)) values were 57.6 mg x h/L (IQR 38.5-64.2 mg x h/L) with the 300 mg dose and 145.8 mg x h/L (IQR 101.2-160.9 mg x h/L) with the 600 mg dose. The AUC(24)/MIC ratios were 452 (IQR 343-513) with the 300 mg dose and 1151 (IQR 656-1500) with the 600 mg dose. Linezolid was well tolerated.

Conclusion: Seemingly effective serum concentrations were reached after 3 days of administration of linezolid 300 mg twice daily, i.e. the AUC(24)/MIC ratio was at least 100 in 7 of 8 patients. Larger numbers of patients should be studied to confirm the efficacy of the linezolid 300 mg twice-daily dosage in MDR-TB or XDR-TB treatment.

Publication types

  • Clinical Trial
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / administration & dosage*
  • Acetamides / adverse effects
  • Acetamides / blood
  • Acetamides / pharmacokinetics*
  • Adult
  • Antitubercular Agents / administration & dosage*
  • Antitubercular Agents / adverse effects
  • Antitubercular Agents / blood
  • Antitubercular Agents / pharmacokinetics*
  • Extensively Drug-Resistant Tuberculosis / drug therapy*
  • Extensively Drug-Resistant Tuberculosis / metabolism
  • Female
  • Humans
  • Linezolid
  • Male
  • Oxazolidinones / administration & dosage*
  • Oxazolidinones / adverse effects
  • Oxazolidinones / blood
  • Oxazolidinones / pharmacokinetics*
  • Tuberculosis, Multidrug-Resistant / drug therapy*
  • Tuberculosis, Multidrug-Resistant / metabolism


  • Acetamides
  • Antitubercular Agents
  • Oxazolidinones
  • Linezolid