Selection of a moxifloxacin dose that suppresses drug resistance in Mycobacterium tuberculosis, by use of an in vitro pharmacodynamic infection model and mathematical modeling

J Infect Dis. 2004 Nov 1;190(9):1642-51. doi: 10.1086/424849. Epub 2004 Sep 24.


Background: Moxifloxacin is a quinolone antimicrobial that has potent activity against Mycobacterium tuberculosis. To optimize moxifloxacin dose and dose regimen, pharmacodynamic antibiotic-exposure targets associated with maximal microbial kill and complete suppression of drug resistance in M. tuberculosis must be identified.

Methods: We used a novel in vitro pharmacodynamic infection model of tuberculosis in which we exposed M. tuberculosis to moxifloxacin with a pharmacokinetic half-life of decline similar to that encountered in humans. Data obtained from this model were mathematically modeled, and the drug-exposure breakpoint associated with the suppression of drug resistance was determined. Monte-Carlo simulations were performed to determine the probability that 10,000 clinical patients taking different doses of moxifloxacin would achieve or exceed the drug-exposure breakpoint needed to suppress resistance to moxifloxacin in M. tuberculosis.

Results: The ratio of the moxifloxacin-free (non-protein-bound) area under the concentration-time curve from 0 to 24 h to the minimum inhibitory concentration associated with complete suppression of the drug-resistant mutant population was 53. For patients taking moxifloxacin doses of 400, 600, or 800 mg/day, the calculated target-attainment rates to suppress drug resistance were 59%, 86%, and 93%, respectively.

Conclusion: A moxifloxacin dose of 800 mg/day is likely to achieve excellent M. tuberculosis microbial kill and to suppress drug resistance. However, tolerability of this higher dose is still unknown.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / administration & dosage
  • Antitubercular Agents / pharmacokinetics
  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / therapeutic use
  • Aza Compounds / administration & dosage
  • Aza Compounds / pharmacokinetics*
  • Aza Compounds / pharmacology*
  • Aza Compounds / therapeutic use
  • Colony Count, Microbial
  • Drug Resistance, Bacterial
  • Fluoroquinolones
  • Humans
  • Microbial Sensitivity Tests
  • Models, Biological
  • Monte Carlo Method
  • Moxifloxacin
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / growth & development
  • Quinolines / administration & dosage
  • Quinolines / pharmacokinetics*
  • Quinolines / pharmacology*
  • Quinolines / therapeutic use
  • Tuberculosis / drug therapy
  • Tuberculosis / microbiology


  • Antitubercular Agents
  • Aza Compounds
  • Fluoroquinolones
  • Quinolines
  • Moxifloxacin