Treatment of Tuberculosis Using a Combination of Sustained-Release Rifampin-Loaded Microspheres and Oral Dosing with Isoniazid

Abstract

Previously, we reported on the use of rifampin-loaded microspheres to effectively treat Mycobacterium tuberculosis-infected macrophages and mice. Using similar biocompatible polymeric excipients of lactide and glycolide copolymers, we have increased the rifampin loading of small microsphere formulations (1 to 10 m) by fourfold. Improved formulations were evaluated individually and in combination with oral regimens of isoniazid for the treatment of Mycobacterium tuberculosis H37Rv-infected mice. Groups (10 mice per group) 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 rifampin-loaded microspheres on days 0 and 7, (iii) a combination of small rifampin-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. Treatment with rifampin-loaded microspheres alone resulted in significant reductions in the numbers of CFU in the lungs and spleens by day 26. A bioassay revealed that plasma rifampin levels from the microspheres exceeded the MICs by more than twofold throughout the 26-day experimental period. Susceptibility testing demonstrated continued sensitivity to rifampin during the treatment period. Whereas isoniazid alone significantly reduced the numbers of CFU for dosages ranging from 12.5 to 1.56 mg/kg, combination therapy with rifampin-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 with most of the single therapies. These results demonstrate the ability to use small microsphere formulations alone to achieve significant results in a murine tuberculosis model and also the ability to use them safely in combination with another antimycobacterial agent.

Polylactide-co-glycolide-rifampicin-nanoparticles efficiently clearMycobacterium bovisBCG infection in macrophages and remain membrane-bound in phago-lysosomes

“…6C when free rifampicin was administered for the same time as the rifampicin NPs it was less effective than the NPs. This agrees with many earlier studies with both BCG and M.tb in macrophages (Barrow et al, 1998;Hirota et al, 2010;Kisich et al, 2007;Quenelle et al, 2001;Yoshida et al, 2006) and in many mammalian models of M.tb (Griffiths et al, 2010).…”

“…A number of studies have addressed the interactions of rifampicin PLGA MPs or NPs with primary macrophages, or macrophage cell lines infected with mycobacteria, including M.tb (Anisimova et al, 2000;Barrow et al, 1998;Hirota et al, 2010;Makino et al, 2004;Quenelle et al, 2001;Sharma et al, 2001;Yoshida et al, 2006). Other antibiotics, such as moxifloxacin, combined with other polymers (polybutyl-cyanoacrylate, PBCA), have also been successfully used for NP-based therapy of M.tb in macrophages (Kisich et al, 2007).…”

In vitrosusceptibility ofMycobacterium tuberculosisto extracts ofEucalyptus camaldulensisandEucalyptus torellianaand isolated compounds

“…This leads to poor patient compliance and, consequently, the development of resistance and has been a contributing factor to emerging drug-resistant Mtb strains. There is now an urgent need to discover and develop new anti-Mtb drugs particularly to target drug resistance, and improve the treatment of latent TB by targeting tubercle bacilli that are thought to remain within the lungs in a non-replicating state of persistence (Quenelle et al, 2001). The use of traditional herbal remedies (ethnomedicines) for the treatment of TB is increasing in developing countries, and these plants are an excellent starting point for the development of new effective anti-Mtb drugs.…”

Chemical and Biological Factors in the Control of Brucella and Brucellosis

“…These major hurdles may be solved by the use of Drug Delivery Systems. These vectors have been proposed for delivering antimicrobial agents and targeting intracellular sites of infection, thereby helping to increase the therapeutic index of antimicrobials in intracellular niches [21][22][23][24]. At the end of this manuscript, we review the work on the development of new approaches to an effective pharmaceutical dosage form of gentamicin for the treatment of brucellosis.…”