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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI033833-01A2
Application #
3148868
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1993-09-30
Project End
1996-08-31
Budget Start
1993-09-30
Budget End
1994-08-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Duzgunes, N; Flasher, D; Reddy, M V et al. (1996) Treatment of intracellular Mycobacterium avium complex infection by free and liposome-encapsulated sparfloxacin. Antimicrob Agents Chemother 40:2618-21
Gangadharam, P R; Ashtekar, D R; Flasher, D L et al. (1995) Therapy of Mycobacterium avium complex infections in beige mice with streptomycin encapsulated in sterically stabilized liposomes. Antimicrob Agents Chemother 39:725-30