Comparison of the 'Denver regimen' against acute tuberculosis in the mouse and guinea pig

Zahoor Ahmad, Eric L. Nuermberger, Rokeya Tasneen, Michael L. Pinn, Kathy N. Williams, Charles A. Peloquin, Jacques H. Grosset, Petros C. Karakousis

Research output: Contribution to journalArticle

Abstract

Objectives: In this study, we sought to compare the sterilizing activity of human-equivalent doses of the 'Denver regimen' against acute tuberculosis (TB) infection in the standard mouse model and in the guinea pig. Methods: Pharmacokinetic studies in guinea pigs were used to establish human-equivalent doses for rifampicin, isoniazid and pyrazinamide. Guinea pigs and mice were aerosol-infected with Mycobacterium tuberculosis CDC1551 and treatment was started 2 weeks later with rifampicin/isoniazid/pyrazinamide for up to 6 months. For the first 2 weeks of therapy, the dosing frequency was 5 days/week, and for the remaining period, twice weekly. Treatment was discontinued in groups of 30 mice and 10 guinea pigs at 5 months and at 6 months, and these animals were held for a further 3 months in order to assess relapse rates. Results: Guinea pig lungs became culture-negative after 3 months of predominantly twice-weekly treatment and relapse rates were 0% (0/10) both after 5 months and after 6 months of treatment. In contrast, all mice remained culture-positive despite 6 months of the same treatment, and 93% (28/30) and 69% (20/29) of mice relapsed after treatment for 5 and 6 months, respectively. Conclusions: Treatment with rifampicin/isoniazid/pyrazinamide administered at human-equivalent doses is much more potent against acute TB infection in guinea pigs than in mice. Our findings have important implications for the use of alternative animal models in testing novel TB drug regimens and for modelling M. tuberculosis persistence.

Original languageEnglish (US)
Article numberdkq007
Pages (from-to)729-734
Number of pages6
JournalJournal of Antimicrobial Chemotherapy
Volume65
Issue number4
DOIs
StatePublished - Jan 31 2010

Keywords

  • Chemotherapy
  • Isoniazid
  • Mycobacterium tuberculosis
  • Persistence
  • Pyrazinamide
  • Rifampicin

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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