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

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 (Cmax) value of 4 microg/ml and an area under the concentration-time curve from 0 to 24 h (AUC(0-24)) value of 4.9 microg x 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 microg/ml and an AUC(0-24) value of 29 microg x 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.

FIG. 1.

Serum concentration-time curves for mice treated with three different doses of isoniazid compared with human data (dashed lines) from the work of Peloquin et al. (19). Conc., concentration.

FIG. 2.

Change in lung CFU counts in mice treated with increasing doses of isoniazid (H) given alone (A) or in combination with 10 mg/kg rifampin (R) and 150 mg/kg pyrazinamide (Z) (B).

FIG. 3.

Change in lung CFU counts in mice treated with increasing doses of isoniazid (H) given alone or in combination with rifampin (R) (A) or pyrazinamide (Z) (B).

FIG. 4.

Comparative activities of 10 mg/kg rifampin (R) alone, 150 mg/kg pyrazinamide (Z) alone, and rifampin-pyrazinamide (RZ) in the lungs of mice treated 5 days a week.