Treatment of tuberculosis using a combination of sustained-release rifampin-loaded microspheres and oral dosing with isoniazid

Citation
Dc. Quenelle et al., Treatment of tuberculosis using a combination of sustained-release rifampin-loaded microspheres and oral dosing with isoniazid, ANTIM AG CH, 45(6), 2001, pp. 1637-1644
Citations number
31
Categorie Soggetti
Microbiology
Journal title
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN journal
00664804 → ACNP
Volume
45
Issue
6
Year of publication
2001
Pages
1637 - 1644
Database
ISI
SICI code
0066-4804(200106)45:6<1637:TOTUAC>2.0.ZU;2-S
Abstract
Previously, we reported on the use of rifampin-loaded microspheres to effec tively treat Mycobacterium tuberculosis-infected macrophages and mice. Usin g similar biocompatible polymeric excipients of lactide and glycolide copol ymers, we have increased the rifampin loading of small microsphere formulat ions (1 to 10 mum) by fourfold. Improved formulations were evaluated indivi dually and in combination with oral regimens of isoniazid for the treatment of Mycobacterium tuberculosis H37Rv-infected mice. Groups (10 mice per gro up) consisted of mice that received (i) oral dosages of isoniazid (25 to 0. 19 mg/kg of body weight/day), (ii) two intraperitoneal injections of rifamp in-loaded microspheres on days 0 and 7, (iii) a combination of small rifamp in-loaded microspheres on days 0 and 7 and isoniazid orally for 25 days (12 .5 to 0.39 mg/kg/day), (iv) placebo injections, and (v) no treatment. Treat ment with rifampin-loaded microspheres alone resulted in significant reduct ions in the numbers of CFU in the lungs and spleens by day 26, A bioassay r evealed that plasma rifampin levels from the microspheres exceeded the MICs by more than twofold throughout the 26-day experimental period. Susceptibi lity testing demonstrated continued sensitivity to rifampin during the trea tment period. Whereas isoniazid alone significantly reduced the numbers of CFU for dosages ranging from 12.5 to 1.56 mg/kg, combination therapy with r ifampin-loaded microspheres increased the effective range to 0.39 mg/kg. In many cases, complete elimination of CFU was obtained with the combination therapy, something not achieved nith most of the single therapies. These re sults demonstrate the ability to use small microsphere formulations alone t o achieve significant results in a murine tuberculosis model and also the a bility to use them safely in combination with another antimycobacterial age nt.