A simple in vitro PK/PD model system to determine time-kill curves of drugs against Mycobacteria

Nageshwar R. Budha, Robin B. Lee, Julian G. Hurdle, Richard E. Lee, Bernd Meibohm

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

In vivo tuberculosis is exposed to continually changing drug concentrations for which static minimum inhibitory concentration (MIC) testing may be a poor surrogate. While in vitro approaches to determine time-kill curves for antibiotics have been widely applied in assessing antimicrobial activity against fast growing microorganisms, their availability and application for slow-growing microorganisms including Mycobacterium tuberculosis has so far been scarce. Thus, we developed a novel simple in vitro pharmacokinetic/pharmacodynamic (PK/PD) model for establishing time-kill curves and applied it for evaluating the antimicrobial activity of different dosing regimens of isoniazid (INH) against Mycobacterium bovis BCG as a surrogate for virulent M. tuberculosis. In the in vitro model M. bovis BCG was exposed to INH concentration-time profiles as usually encountered during multiple dose therapy with 25, 100 and 300 mg/day in humans who are fast or slow INH metabolizers. Bacterial killing was followed over time by determining viable counts and the resulting time-kill data was analyzed using a semi-mechanistic PK/PD model with an adaptive IC50 function to describe the emergence of insensitive populations of bacteria over the course of treatment. In agreement with previous studies, the time-kill data suggest that AUC0-24/MIC is the PK/PD index that is the most explanatory of the antimicrobial effect of INH. The presented in vitro PK/PD model and associated modeling approach were able to characterize the time-kill kinetics of INH in M. bovis BCG, and may in general serve as a potentially valuable, low cost tool for the assessment of antibacterial activity in slow-growing organisms in drug development and applied pharmacotherapy.

Original languageEnglish (US)
Pages (from-to)378-385
Number of pages8
JournalTuberculosis
Volume89
Issue number5
DOIs
StatePublished - Sep 1 2009

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Mycobacterium
Mycobacterium bovis
Pharmacokinetics
Pharmaceutical Preparations
Microbial Sensitivity Tests
Mycobacterium tuberculosis
Isoniazid
In Vitro Techniques
Inhibitory Concentration 50
Tuberculosis
Anti-Bacterial Agents
Bacteria
Costs and Cost Analysis
Drug Therapy
Therapeutics
Population

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

Cite this

A simple in vitro PK/PD model system to determine time-kill curves of drugs against Mycobacteria. / Budha, Nageshwar R.; Lee, Robin B.; Hurdle, Julian G.; Lee, Richard E.; Meibohm, Bernd.

In: Tuberculosis, Vol. 89, No. 5, 01.09.2009, p. 378-385.

Research output: Contribution to journalArticle

Budha, Nageshwar R. ; Lee, Robin B. ; Hurdle, Julian G. ; Lee, Richard E. ; Meibohm, Bernd. / A simple in vitro PK/PD model system to determine time-kill curves of drugs against Mycobacteria. In: Tuberculosis. 2009 ; Vol. 89, No. 5. pp. 378-385.
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