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Antimicrobial Agents and Chemotherapy, August 2007, p. 2830-2836, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.01164-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Inhaled Large Porous Particles of Capreomycin for Treatment of Tuberculosis in a Guinea Pig Model{triangledown}

L. Garcia-Contreras,1 J. Fiegel,2 M. J. Telko,1 K. Elbert,2 A. Hawi,3 M. Thomas,2 J. VerBerkmoes,2 W. A. Germishuizen,2 P. B. Fourie,3 A. J. Hickey,1* and D. Edwards2,3*

The University of North Carolina, 1310 Kerr Hall, Chapel Hill, North Carolina 27599-7360,1 Harvard University, 322 Pierce Hall, 29 Oxford Street, Cambridge, Massachusetts 02138,2 Medicine in Need, 104 Mt. Auburn St., Suite 3, Cambridge, Massachusetts 021383

Received 18 September 2006/ Returned for modification 19 February 2007/ Accepted 8 May 2007

Capreomycin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB), but it is limited therapeutically by its severe side effects. The objectives of the present studies were (i) to design low-density porous capreomycin sulfate particles for efficient pulmonary delivery to improve local and systemic drug bioavailability and capacity to reduce the bacillary load in the lungs in a manner similar to that achieved with intramuscular injections; (ii) to determine pharmacokinetic parameters after pulmonary administration of these capreomycin particles; and (iii) to evaluate the efficacy of these particles in treating animals in a small-aerosol-inoculum guinea pig model of TB. Capreomycin particles were manufactured by spray drying and characterized in terms of size and drug content. Pharmacokinetic parameters were determined by noncompartmental methods with healthy guinea pigs after administration of capreomycin particles by insufflation. The efficacy of the particles was evaluated by histopathological analysis and in terms of wet organ weight and bacterial burden in TB-infected animals. Lungs of animals receiving a 14.5-mg/kg dose of capreomycin particles showed significantly lower wet weights and smaller bacterial burdens than those of animals receiving any other treatment. These results were supported by histopathological analysis. The feasibility of inhaling capreomycin in a novel powder form, with the ultimate objective of the treatment of MDR-TB, is demonstrated by pharmacokinetic and pharmacodynamic studies with guinea pigs. If applied to humans with MDR-TB, such a therapeutic approach might simplify drug delivery by eliminating injections and might reduce adverse effects through lowering the dose.

* Corresponding author. Mailing address for David A. Edwards: Harvard University, 322 Pierce Hall, 29 Oxford Street, Cambridge, MA 02138. Phone: (617) 495-1328. Fax: (617) 495-9837. E-mail: dedwards{at}seas.harvard.edu. Mailing address for Anthony J. Hickey: University of North Carolina at Chapel Hill, 1310 Kerr Hall, CB #7360, Chapel Hill, NC 27599. Phone: (919) 962-0223. Fax: (919) 966-0197. E-mail: ahickey{at}unc.edu

{triangledown} Published ahead of print on 21 May 2007.

Antimicrobial Agents and Chemotherapy, August 2007, p. 2830-2836, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.01164-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Sung, J. C., Garcia-Contreras, L., VerBerkmoes, J. L., Peloquin, C. A., Elbert, K. J., Hickey, A. J., Edwards, D. A. (2009). Dry Powder Nitroimidazopyran Antibiotic PA-824 Aerosol for Inhalation. Antimicrob. Agents Chemother. 53: 1338-1343 [Abstract] [Full Text]  


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