AAC Accepts, published online ahead of print on 7 July 2008

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00360-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Efficacy of Oritavancin in a Murine Model of Bacillus anthracis Spore Inhalation Anthrax

H. S. Heine^*, J. Bassett, L. Miller, A. Bassett, B. E. Ivins, D. Lehoux, F. F. Arhin, T. R. Parr JR., and G. Moeck

United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD; Targanta Therapeutics, St-Laurent, Canada

^* To whom correspondence should be addressed. Email: henry.heine{at}amedd.army.mil.

The inhaled form of Bacillus anthracis infection may be fatal to humans. The current standard of care for inhalational anthrax postexposure prophylaxis is ciprofloxacin therapy twice daily for 60 days. The potent in vitro activity of oritavancin, a semisynthetic lipoglycopeptide, against B. anthracis (minimum inhibitory concentration against Ames strain, 0.015 µg/ml) prompted us to test its efficacy in a mouse aerosol-anthrax model. In postexposure prophylaxis dose-ranging studies, a single intravenous (i.v.) dose of oritavancin of 5, 15 or 50 mg/kg 24 h after challenge with 50 to 75 times the median lethal dose of Ames strain spores provided 40, 70, and 100% proportional survival, respectively, at 30 days postchallenge. Untreated animals died within 4 days of challenge whereas 90% of control animals receiving ciprofloxacin at 30 mg/kg intraperitoneally twice daily for 14 days starting 24 h after challenge survived. Oritavancin demonstrated significant activity postsymptom development: a single i.v. dose of 50 mg/kg administered 42 h after challenge provided 56% proportional survival at 30 days. In a preexposure prophylaxis study, a single i.v. dose of 50 mg/kg oritavancin administered 1, 7, 14, or 28 days before lethal challenge protected 90, 100, 100, and 20% of mice at 30 days; mice treated with ciprofloxacin 24 h or 24 and 12 h before challenge all died within 5 days. Efficacy in pre- and postexposure models of inhalation anthrax together with a demonstrated low propensity to engender resistance promote further study of oritavancin pharmacokinetics and efficacy in non-human primate models.

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