title: Low-dose aerosol infection model for testing drugs for efficacy against Mycobacterium tuberculosis.
abstract: As a paradigm for chronic infectious diseases, tuberculosis exhibits a variety of clinical presentations, ranging from primary pulmonary tuberculosis to reactivation tuberculosis and cavitary disease. To date, the animal models used in evaluating chemotherapy of tuberculosis have been high-dose intravenous models that mimic the disseminated forms of the disease. In the present study, we have used a low-dose aerosol exposure model which we feel better reflects newly diagnosed tuberculosis in patients converting to tuberculin positivity. As appropriate examples of chemotherapy, four rifamycins (rifampin, rifabutin, rifapentine, and KRM-1648) were tested, first in an in vitro murine macrophage model and then in the low-dose aerosol infection model, for their activity against Mycobacterium tuberculosis. In both models, KRM-1648 had the highest level of activity of the four compounds. In the infected-lung model, rifabutin, rifapentine, and KRM-1648 all had sterilizing activity when given orally at 5 mg/kg of body weight per day. When given at 2.5 mg/kg/day, KRM-1648 had the highest level of activity of the four drugs, reducing the bacterial load by 2.7 logs over 35 days of therapy.
authors.affiliation: Department of Microbiology, Colorado State University, Fort Collins 80523, USA.
authors.forename: B P
authors.initials: BP
authors.lastname: Kelly
authors.forename: S K
authors.initials: SK
authors.lastname: Furney
authors.forename: M T
authors.initials: MT
authors.lastname: Jessen
authors.forename: I M
authors.initials: IM
authors.lastname: Orme
mesh_terms: D000336:Aerosols; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D008168:Lung / Q000382:microbiology; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000276:immunology; D012294:Rifamycins / Q000494:pharmacology / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000336:Aerosols; D000904:Antibiotics, Antitubercular; D012294:Rifamycins; C068980:KRM 1648