Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis

Antimicrob Agents Chemother. 2017 Jul 25;61(8):e00751-17. doi: 10.1128/AAC.00751-17. Print 2017 Aug.


Linezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates. The dose that would maximize efficacy and minimize toxicity is unknown. We performed linezolid dose-effect and dose-scheduling studies in the hollow fiber system model of tuberculosis (HFS-TB) for sterilizing effect. HFS-TB units were treated with several doses to mimic human-like linezolid intrapulmonary pharmacokinetics and repetitively sampled for drug concentration, total bacterial burden, linezolid-resistant subpopulations, and RNA sequencing over 2 months. Linezolid-resistant isolates underwent whole-genome sequencing. The expression of genes encoding efflux pumps in the first 1 to 2 weeks revealed the same exposure-response patterns as the linezolid-resistant subpopulation. Linezolid-resistant isolates from the 2nd month of therapy revealed mutations in several efflux pump/transporter genes and a LuxR-family transcriptional regulator. Linezolid sterilizing effect was linked to the ratio of unbound 0- to 24-h area under the concentration-time curve (AUC0-24) to MIC. Optimal microbial kill was achieved at an AUC0-24/MIC ratio of 119. The optimal sterilizing effect dose for clinical use was identified using Monte Carlo simulations. Clinical doses of 300 and 600 mg/day (or double the dose every other day) achieved this target in 87% and >99% of 10,000 patients, respectively. The susceptibility breakpoint identified was 2 mg/liter. The simulations identified that a 300-mg/day dose did not achieve AUC0-24s associated with linezolid toxicity, while 600 mg/day achieved those AUC0-24s in <20% of subjects. The linezolid dose of 300 mg/day performed well and should be compared to 600 mg/day or 1,200 mg every other day in clinical trials.

Keywords: RNA sequencing; efflux pump regulators; efflux pumps; mutations; optimal dose; whole-genome sequencing.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antitubercular Agents / adverse effects
  • Antitubercular Agents / therapeutic use*
  • Dose-Response Relationship, Drug
  • Drug Resistance, Bacterial / genetics
  • Genome, Bacterial / genetics
  • Humans
  • Linezolid / adverse effects
  • Linezolid / therapeutic use*
  • Membrane Transport Proteins / genetics
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects*
  • Protein Synthesis Inhibitors / therapeutic use*
  • Repressor Proteins / genetics
  • Trans-Activators / genetics
  • Tuberculosis, Pulmonary / drug therapy*


  • Antitubercular Agents
  • Membrane Transport Proteins
  • Protein Synthesis Inhibitors
  • Repressor Proteins
  • Trans-Activators
  • LuxR autoinducer binding proteins
  • Linezolid