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JAC Advance Access published online on September 13, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl369
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received March 1, 2006
Revised July 17, 2006
Accepted August 15, 2006

Original article

Evaluation of dosing regimen of respirable rifampicin biodegradable microspheres in the treatment of tuberculosis in the guinea pig

L. Garcia-Contreras 1, V. Sethuraman 1, M. Kazantseva 1, V. Godfrey 1, and A. J. Hickey 1 *

1 School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA

* To whom correspondence should be addressed.
A. J. Hickey, E-mail: ahickey{at}unc.edu


  Abstract

Objectives: The efficacy of rifampicin-loaded polymeric microspheres (RPLGA) delivered to guinea pigs infected with Mycobacterium tuberculosis (H37Rv) was compared with a daily dose of nebulized rifampicin suspension.

Methods: Aerosol-infected animals were subjected to multiple dose or single dose treatment with RPLGA, PLGA microspheres or micronized rifampicin suspension aerosols. For comparison with treatment with suspensions of microspheres, additional groups received daily doses of rifampicin-only suspensions for 20 (20-RIF) and 10 (10-RIF) days.

Results: Drug and polymer treated multiple dose groups exhibited significantly lower wet lung weights than untreated animals. Spleen wet weights and viable bacterial counts (VBCs) were much lower for drug microsphere treated animals than for all other groups. In multiple dose studies with rifampicin-only suspensions, wet lung weights for 10-RIF and 20-RIF treated animals were much smaller than controls. Likewise, wet spleen weights of 10-RIF and 20-RIF treated animals were much smaller than controls, consistent with reduced inflammation. Spleen VBC of 20-RIF treated animals was much smaller than controls. No statistical differences were observed in the lung VBC among single dose groups. However, a trend similar to that of the wet weights was observed.

Conclusions: Aerosolized RPLGA reduced most measures of tuberculosis (TB) infection. These studies are further evidence for the potential of inhaled aerosol therapy for the treatment of TB. However, additional studies are required to elucidate underlying mechanisms of action and optimize this route of drug delivery.

Keywords: aerosols; nebulized suspensions; PLGA; lung deposition.
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