Glucan particles (GPs) are 2–4 mm spherical, hollow, porous shells extracted from Baker’s yeast, Saccharomyces cerevisae. The surface of the GPs is composed primarily of 1,3-b-glucan and the particles are efficiently phagocytosed via receptor-mediated cell uptake by macrophages, phagocytic cells expressing glucan receptors. The hollow cavity of the GPs allows for efficient absorption and encapsulation of payload molecules. Rifampicin (Rif), a drug used in tuberculosis treatment, was encapsulated by precipitation in GPs and trapped using a calcium alginate or chitosan hydrogel to seal the pores of GPs and slow Rif release. Unplugged GP formulations immediately released Rif following particle resuspension in aqueous buffer. Alginate and chitosan sealing of GPs loaded with Rif was able to extend drug release for 24–72 h. GP-Rif formulations containing 10% w/w Rif/GP plugged with a calcium alginate hydrogel were effective at reducing colony forming units of M. tuberculosis strain mc²6020 in infected bone marrow macrophages ~80–90% at 24 and 72 hours. The amount of Rif delivered in the GP formulations was below the free Rif minimal inhibitory concentration demonstrating that GP targeted Rif delivery to macrophages enhances Rif antimicrobial effects.