Paradoxical effect of isoniazid on the activity of rifampin-pyrazinamide combination in a mouse model of tuberculosis

Deepak Almeida, Eric Nuermberger, Rokeya Tasneen, Ian Rosenthal, Sandeep Tyagi, Kathy Williams, Charles Peloquin, Jacques Grosset

Research output: Contribution to journalArticle

Abstract

To investigate the antagonism between isoniazid (INH) and rifampin (rifampicin) (RIF)-pyrazinamide (PZA) combination observed in Mycobacterium tuberculosis-infected mice, extensive pharmacokinetic studies of INH were performed and followed by experiments to assess the impact of increasing doses of INH on the antimicrobial activity of RIF-PZA combination. INH at 6.25 mg/kg of body weight produced a maximum concentration of drug in serum (C max) value of 4 μg/ml and an area under the concentration-time curve from 0 to 24 h (AUC0-24) value of 4.9 μg·h/ml, the former being close to the Cmax value observed after the standard 5-mg/kg dose in humans. INH at 25 mg/kg produced a Cmax value of 22 μg/ml and an AUC0-24 value of 29 μg·h/ml, the latter being close to the AUC observed after a 5-mg/kg dose of INH in humans with the slow acetylation phenotype. Beginning 2 weeks after aerosol infection with M. tuberculosis, mice were treated for 8 weeks with INH at twofold-increasing doses, ranging from 1.56 to 50 mg/kg, either alone or in combination with RIF-PZA. Given alone, INH exhibited dose-dependent activity. Combined with RIF-PZA, INH exhibited dose-dependent antagonism of RIF-PZA activity. To determine the individual components of RIF-PZA combination with which INH was antagonistic, mice were treated for 8 weeks with RIF alone, PZA alone, RIF-PZA, and INH at 3.125, 12.5, or 50 mg/kg either alone or combined with RIF or PZA. Addition of INH to RIF had additive activity, whereas addition of INH to PZA resulted in a negative interaction. Finally, a 10-mg/kg dose of INH in mice may best represent the 5-mg/kg dose in humans and decrease the antagonism of INH with RIF-PZA.

Original languageEnglish (US)
Pages (from-to)4178-4184
Number of pages7
JournalAntimicrobial agents and chemotherapy
Volume53
Issue number10
DOIs
StatePublished - Oct 1 2009

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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