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Antimicrobial Agents and Chemotherapy, October 2009, p. 4178-4184, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00830-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Paradoxical Effect of Isoniazid on the Activity of Rifampin-Pyrazinamide Combination in a Mouse Model of Tuberculosis{triangledown}

Deepak Almeida,1 Eric Nuermberger,1 Rokeya Tasneen,1 Ian Rosenthal,1 Sandeep Tyagi,1 Kathy Williams,1 Charles Peloquin,2,{dagger} and Jacques Grosset1*

Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland,1 Infectious Disease Pharmacokinetics Laboratory, National Jewish Medical and Research Center, Denver, Colorado2

Received 19 June 2009/ Returned for modification 6 July 2009/ Accepted 10 July 2009

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 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.

* Corresponding author. Mailing address: Center for Tuberculosis Research, 1550 Orleans Street, Room 105, Baltimore, MD 21231. Phone: (410) 502-8234. Fax: (410) 614-8173. E-mail: jgrosse4{at}jhmi.edu

{triangledown} Published ahead of print on 20 July 2009.

{dagger} Present address: Infectious Disease Pharmacokinetics Laboratory, University of Florida, College of Pharmacy, Gainesville, FL.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4178-4184, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00830-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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