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
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.