SUMMARY:Anthrax is considered a serious biowarfare and bioterrorism threat because of its high lethality, especially by the inhalation route. Rhesus macaques (Macaca mulatta) are the most commonly used nonhuman primate model of human inhalation anthrax exposure. The nonavailability of rhesus macaques necessitated development of an alternate model for vaccine testing and immunologic studies. This report describes the median lethal dose (LD 50 ) and pathology of inhalation anthrax in cynomolgus macaques (Macaca fascicularis). Gross and microscopic tissue changes were reviewed in 14 cynomolgus monkeys that died or were killed after aerosol exposure of spores of Bacillus anthracis (Ames strain). The LD 50 and 95% confidence intervals were 61,800 (34,000 to 110,000) colony-forming units. The most common gross lesions were mild splenomegaly, lymph node enlargement, and hemorrhages in various organs, particularly involving the meninges and the lungs. Mediastinitis, manifested as hemorrhage or edema, affected 29% of the monkeys. Microscopically, lymphocytolysis occurred in the intrathoracic lymph nodes and spleens of all animals, and was particularly severe in the spleen and in germinal centers of lymph nodes. Hemorrhages were common in lungs, bronchial lymph nodes, meninges, gastrointestinal tract, and mediastinum. These results demonstrate that the Ames strain of B. anthracis is lethal by the inhalation route in the cynomolgus macaque. The LD 50 of the Ames strain of B. anthracis was within the expected experimental range of previously reported values in the rhesus monkey in an aerosol challenge. The gross and microscopic pathology of inhalation anthrax in the cynomolgus monkey is remarkably similar to that reported in rhesus monkeys and humans. The results of this study are important for the establishment of an alternative nonhuman primate model for evaluation of medical countermeasures against inhalational anthrax. (Lab Invest 2003, 83:1201-1209.A nthrax is caused by Bacillus anthracis, a Grampositive, aerobic or facultative anaerobic, rodshaped spore-forming bacterium. Infection follows dermal, gastrointestinal, or inhalation routes of entry, each with slightly different clinical manifestations; however, the final outcome, regardless of portal of entry, is often septicemia. The inhalation route is most lethal, with nonspecific initial clinical signs such as fever, malaise, headache, nausea, and vomiting. The spores are phagocytosed by pulmonary macrophages and germinate in the draining mediastinal and thoracic lymph nodes. Rapid progression to chest pain and respiratory distress leads to an almost 100% case fatality rate in humans. The incubation period in humans varies from 12 hours to 5 days, depending on the dose received, and can be longer following exposure to low doses or removal of therapeutics. Death is thought to be due to effects of the two major anthrax exotoxins, lethal toxin and edema toxin. Species differ in susceptibility, with ruminants most susceptible and carnivores generally less susceptible. Hig...

This trial provides evidence of the efficacy of paromomycin-gentamicin and paromomycin alone for ulcerative L. major disease. (Funded by the Department of the Army; ClinicalTrials.gov number, NCT00606580.).

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