Linezolid in vitro: mechanism and antibacterial spectrum

J Antimicrob Chemother. 2003 May:51 Suppl 2:ii9-16. doi: 10.1093/jac/dkg249.

Abstract

Oxazolidinones are prominent among the new Gram-positive antimicrobial agents now becoming available. They were discovered by DuPont Pharmaceuticals in the late 1980s but linezolid, the first analogue suitable for development, was found only when the family was re-examined by Pharmacia in the 1990s. Oxazolidinones bind to the 50S subunit of the prokaryotic ribosome, preventing formation of the initiation complex for protein synthesis. This is a novel mode of action; other protein synthesis inhibitors either block polypeptide extension or cause misreading of mRNA. Linezolid MICs vary slightly with the test method, laboratory, and significance attributed to thin hazes of bacterial survival, but all workers find that the susceptibility distributions are narrow and unimodal, with MIC values between 0.5 and 4 mg/L for streptococci, enterococci and staphylococci. Full activity is retained against Gram-positive cocci resistant to other antibiotics, including methicillin-resistant staphylococci and vancomycin-resistant enterococci. MICs are 4-8 mg/L for Moraxella, Pasteurella and Bacteroides spp. but other Gram-negative bacteria are resistant as a result of endogenous efflux activity. Resistance is difficult to select in vitro but has been reported during therapy in a few enterococcal infections and in two MRSA cases to date; the mechanism entails mutation of the 23S rRNA that forms the binding site for linezolid. Risk factors for selection of resistance include indwelling devices, undrained foci, protracted therapy and underdosage.

Publication types

  • Review

MeSH terms

  • Acetamides / pharmacology*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Colony Count, Microbial
  • Drug Resistance, Bacterial / genetics
  • Gram-Negative Bacteria / drug effects*
  • Gram-Negative Bacteria / genetics
  • Gram-Negative Bacteria / growth & development
  • Gram-Negative Bacterial Infections / drug therapy
  • Gram-Negative Bacterial Infections / microbiology
  • Gram-Positive Bacterial Infections / drug therapy
  • Gram-Positive Bacterial Infections / microbiology
  • Gram-Positive Cocci / drug effects*
  • Gram-Positive Cocci / genetics
  • Gram-Positive Cocci / growth & development
  • Humans
  • Linezolid
  • Microbial Sensitivity Tests
  • Oxazolidinones / pharmacology*

Substances

  • Acetamides
  • Anti-Bacterial Agents
  • Oxazolidinones
  • Linezolid