Mycobacterium tuberculosis (Mtb) infects via the respiratory tract where organisms are taken up by alveolar macrophages and proliferate intracellularly. Antibiotic therapy for Mtb is administered orally. This method is usually successful but complications occur due to organ toxicities and noncompliance. Noncompliance is of particular importance because inadequate treatment can favor the development of antibiotic resistant strains of Mtb. Treatment of Mtb infections by aerosolization techniques may provide an effective means for concentrating antibiotics in Mtb-infected lungs thus potentially decreasing systemic side effects, or improving compliance if the efficacy of anti-Mtb activity can be improved and a shorter treatment plan designed. Liposome technology is a potential method for improving anti-Mtb activity of aerosolized antibiotics because liposomes are preferentially taken up by phagocytic macrophages which harbor Mtb and liposomes can also prolong a drug's half-life. Aerosol therapy may be particularly useful as a prophylactic therapy or for treating acute Mtb exposures in susceptible individuals when Mtb is likely localized to the lung. These investigators have developed a virulent Mtb lung infection model in mice. They intend to apply this model for aerosolizing anti-tuberculous drugs and determine: (1) the optimal size of particle for delivering drugs to the lower airways; (2) the organ distribution and intracellular location using autoradiographic techniques: and (3) the pharmacological analysis of aerosolized drugs using high performance liquid chromatography. Other experiments will determine whether aerosolization of anti-tuberculous agents can kill Mtb in infected mice at different stages of Mtb infection and determine the maximal Mtb burden for which aerosolized drug therapy is efficacious. They will also compare the effectiveness of aerosolized soluble and liposome-associated antibiotics, on clearance of Mtb from infected immunocompetent and immunodeficient mice to determine whether the immune response is required for treatment of Mtb infections during aerosol therapy. Another aim will be to examine a role for aerosolizing known Mo activating cytokines and effector molecules to enhance native Mtb defenses. These techniques may serve as a viable method for enhancing host resistance against Mtb and complement antibiotic therapy in immunocompromised hosts.
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