TARGETED THERAPY OF MYCOBACTERIUM AVIUM INFECTIONS

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Mycobacterium avium-intracellulare complex (MAC) causes serious disseminated bacterial infection in patients with the acquired immunodeficiency syndrome (AIDS). MAC infection in AIDS patients is largely resistant to currently available antimycobacterial drugs. These pathogens localize primarily in the macrophages of the reticuloendothelial system (RES). Liposomes are phospholipid vesicles that can encapsulate antibiotics, and are avidly taken up by the RES. Based on previous studies indicating the superior efficacy of several liposome-encapsulated antibiotics against MAC infections in beige mice and cultured macrophages, the central hypothesis of this projects is that targeting antibiotics to the intracellular sites of MAC infection increases their efficacy and reduces their toxicity. The proposed research will establish targeted therapy of MAC in beige mice, an established animal model of this disease. The optimal dose, schedule of administration and combination of liposome- encapsulated antibiotics, including streptomycin, amikacin and clofazimine, will be determined, to achieve maximal antimycobacterial effects in MAC-infected beige mice. The in vivo therapeutic effect of promising new drugs encapsulated in liposomes, including ciprofloxacin, sparfloxacin and clarithromycin, will be investigated. The effect of liposome-encapsulated antibiotics on the growth of MAC in human peripheral blood monocytes will be investigated, to ascertain whether liposomal delivery enhances the anti-MAC activity of these antibiotics and their combinations, as well as to evaluate other new antimycobacterial drugs.