Pharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with Gram-positive infections

J Antimicrob Chemother. 2003 May:51 Suppl 2:ii17-25. doi: 10.1093/jac/dkg248.

Abstract

The pharmacokinetics and pharmacodynamics of linezolid have been extensively investigated in laboratory models, healthy volunteers and patients. Three formulations exist: an intravenous (iv) form, film-coated tablets and an oral suspension. Linezolid can be assayed in serum and body fluids by HPLC and has good bioavailability with a Cmax at 0.5-2 h. The protein binding is 31%, and the volume of distribution is 30-50 L with adequate to good tissue penetration into skin blister fluids, bone, muscle, fat, alveolar cells, lung extracellular lining fluid and CSF. There are two major metabolites of linezolid (PNU-142586 and PNU-142300). Non-enzymic formation of PNU-142586 is the rate-limiting step in the clearance of linezolid, and linezolid and its two main metabolites plus several minor ones are all excreted in the urine. Dose linearity is evident in the Cmax and AUC across a wide range of doses. Gender and age have little effect on pharmacokinetics, but children have greater plasma clearance and volume of distribution and hence, have lower serum concentrations for equivalent doses in adults. No dose modification is needed in mild to moderate liver disease or any degree of renal impairment; however, both PNU-142586 and PNU-142300 accumulate in renal failure. Linezolid is bacteriostatic with a significant post-antibiotic effect against the key pathogens. In animal models of infection, the time the antibiotic concentration exceeds the MIC (t > MIC) helps to determine outcome, and a t > MIC of 40% is predictive of a bacteriostatic effect for both staphylococci and pneumococci. In man, t > MIC and AUC/MIC have been related to bacteriological and clinical outcomes. AUC and length of treatment are also related to the risk of thrombocytopenia.

Publication types

  • Review

MeSH terms

  • Acetamides / administration & dosage
  • Acetamides / pharmacokinetics*
  • Acetamides / pharmacology*
  • Acetamides / therapeutic use
  • Animals
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / pharmacokinetics*
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Gram-Positive Bacterial Infections / drug therapy*
  • Gram-Positive Bacterial Infections / metabolism
  • Gram-Positive Bacterial Infections / microbiology
  • Gram-Positive Cocci / drug effects
  • Humans
  • Linezolid
  • Microbial Sensitivity Tests
  • Oxazolidinones / administration & dosage
  • Oxazolidinones / pharmacokinetics*
  • Oxazolidinones / pharmacology*
  • Oxazolidinones / therapeutic use

Substances

  • Acetamides
  • Anti-Bacterial Agents
  • Oxazolidinones
  • Linezolid