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Antimicrobial Agents and Chemotherapy, April 2007, p. 1373-1379, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01050-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Determination of Antibiotic Efficacy against Bacillus anthracis in a Mouse Aerosol Challenge Model{triangledown}

Henry S. Heine,1* Jennifer Bassett,1 Lynda Miller,1 Justin M. Hartings,2 Bruce E. Ivins,1 M. Louise Pitt,2 David Fritz,1 Sarah L. Norris,3 and W. Russell Byrne1

Division of Bacteriology,1 Division of Aerobiology,2 Biostatistical Services, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland 21702-50113

Received 21 August 2006/ Returned for modification 30 November 2006/ Accepted 25 January 2007

An anthrax spore aerosol infection mouse model was developed as a first test of in vivo efficacy of antibiotics identified as active against Bacillus anthracis. Whole-body, 50% lethal dose (LD50) aerosol challenge doses in a range of 1.9 x 103 to 3.4 x 104 CFU with spores of the fully virulent Ames strain were established for three inbred and one outbred mouse strain (A/J, BALB/c, C57BL, and Swiss Webster). The BALB/c strain was further developed as a model for antibiotic efficacy. Time course microbiological examinations of tissue burdens in mice after challenge showed that spores could remain dormant in the lungs while vegetative cells disseminated to the mediastinal lymph nodes and then to the spleen, accompanied by bacteremia. For antibiotic efficacy studies, BALB/c mice were challenged with 50 to 100 LD50 of spores followed by intraperitoneal injection of either ciprofloxacin at 30 mg/kg of body weight (every 12 h [q12h]) or doxycycline at 40 mg/kg (q6h). A control group was treated with phosphate-buffered saline (PBS) q6h. Treatment was begun 24 h after challenge with groups of 10 mice for 14 or 21 days. The PBS-treated control mice all succumbed (10/10) to inhalation anthrax infection within 72 h. Sixty-day survival rates for ciprofloxacin and doxycycline-treated groups were 8/10 and 9/10, respectively, for 14-day treatment and 10/10 and 7/10 for 21-day treatment. Delayed treatment with ciprofloxacin initiated 36 and 48 h postexposure resulted in 80% survival and was statistically no different than early (24 h) postexposure treatment. Results using this mouse model correlate closely with clinical observations of inhalational anthrax in humans and with earlier antibiotic studies in the nonhuman primate inhalational anthrax model.

* Corresponding author. Mailing address: Division of Bacteriology, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter St., Fort Detrick, MD 21702-5011. Phone: (301) 619-4887. Fax: (301) 619-8351. E-mail: henry.heine{at}amedd.army.mil

{triangledown} Published ahead of print on 12 February 2007.

Antimicrobial Agents and Chemotherapy, April 2007, p. 1373-1379, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01050-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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