Paradoxical effect of isoniazid on the activity of rifampin-pyrazinamide combination in a mouse model of tuberculosis.
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.
Almeida
Deepak
D
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Nuermberger
Eric
E
Tasneen
Rokeya
R
Rosenthal
Ian
I
Tyagi
Sandeep
S
Williams
Kathy
K
Peloquin
Charles
C
Grosset
Jacques
J
D000818:Animals; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D007538:Isoniazid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011718:Pyrazinamide / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012293:Rifampin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin