Negative impact of linezolid on human neutrophil functions in vitro

Chemotherapy. 2012;58(3):206-11. doi: 10.1159/000338390. Epub 2012 Jun 30.

Abstract

Background/aims: In a recent phase III clinical trial on linezolid, more patients in the linezolid treatment arm acquired Gram-negative catheter-related bloodstream infections despite the adequate therapy of infections caused by Gram-negative bacteria. We tested our hypothesis that linezolid impairs phagocytosis and the killing of Gram-negative bacteria by polymorphonuclear leukocytes (PMN).

Methods: The influence of clinically relevant concentrations (5, 20 and 50 mg/l) of linezolid on granulocyte function in vitro was tested. Phagocytosis was determined by flow cytometry, and killing of bacteria was evaluated by plate counting. Chemotaxis was examined by an under-agarose cell migration assay. Gram-positive and Gram-negative bacteria were used.

Results: Linezolid significantly impaired phagocytosis of a specific Escherichia coli strain in a concentration-dependent manner, whereas the effect on Pseudomonas aeruginosa was less prominent. No such effects were observed with a different E. coli strain or Staphylococcus aureus. Neither killing nor the chemotactic behaviour of PMN was significantly affected by linezolid.

Conclusions: The observed concentration-dependent impairment of the phagocytic function might contribute to the higher frequency of catheter-related Gram-negative bloodstream infections in patients treated with linezolid. Individual patient risk may also depend on the causative Gram-negative strain.

MeSH terms

  • Acetamides / pharmacology*
  • Acetamides / therapeutic use
  • Anti-Infective Agents / pharmacology*
  • Anti-Infective Agents / therapeutic use
  • Catheter-Related Infections / drug therapy
  • Chemotaxis / drug effects
  • Escherichia coli / drug effects
  • Flow Cytometry
  • Gram-Negative Bacterial Infections / drug therapy
  • Humans
  • Linezolid
  • Microbial Sensitivity Tests
  • Neutrophils / drug effects*
  • Neutrophils / immunology
  • Neutrophils / metabolism*
  • Oxazolidinones / pharmacology*
  • Oxazolidinones / therapeutic use
  • Phagocytosis / drug effects
  • Pseudomonas aeruginosa / drug effects
  • Staphylococcus aureus / drug effects

Substances

  • Acetamides
  • Anti-Infective Agents
  • Oxazolidinones
  • Linezolid