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Antimicrob Agents Chemother. 2017 Sep 22;61(10). pii: e01103-17. doi: 10.1128/AAC.01103-17. Print 2017 Oct.

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Bacillus anthracis Infection in BALB/c Mice and Cynomolgus Macaques.

Author information

1
Tetraphase Pharmaceuticals, Inc., Watertown, Massachusetts, USA tgrossman@yahoo.com.
2
Battelle, Columbus, Ohio, USA.
3
IIT Research Institute, Chicago, Illinois, USA.
4
CUBRC, Inc., Buffalo, New York, USA.
5
United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
6
Tetraphase Pharmaceuticals, Inc., Watertown, Massachusetts, USA.

Abstract

The fluorocycline TP-271 was evaluated in mouse and nonhuman primate (NHP) models of inhalational anthrax. BALB/c mice were exposed by nose-only aerosol to Bacillus anthracis Ames spores at a level of 18 to 88 lethal doses sufficient to kill 50% of exposed individuals (LD50). When 21 days of once-daily dosing was initiated at 24 h postchallenge (the postexposure prophylaxis [PEP] study), the rates of survival for the groups treated with TP-271 at 3, 6, 12, and 18 mg/kg of body weight were 90%, 95%, 95%, and 84%, respectively. When 21 days of dosing was initiated at 48 h postchallenge (the treatment [Tx] study), the rates of survival for the groups treated with TP-271 at 6, 12, and 18 mg/kg TP-271 were 100%, 91%, and 81%, respectively. No deaths of TP-271-treated mice occurred during the 39-day posttreatment observation period. In the NHP model, cynomolgus macaques received an average dose of 197 LD50 of B. anthracis Ames spore equivalents using a head-only inhalation exposure chamber, and once-daily treatment of 1 mg/kg TP-271 lasting for 14 or 21 days was initiated within 3 h of detection of protective antigen (PA) in the blood. No (0/8) animals in the vehicle control-treated group survived, whereas all 8 infected macaques treated for 21 days and 4 of 6 macaques in the 14-day treatment group survived to the end of the study (56 days postchallenge). All survivors developed toxin-neutralizing and anti-PA IgG antibodies, indicating an immunologic response. On the basis of the results obtained with the mouse and NHP models, TP-271 shows promise as a countermeasure for the treatment of inhalational anthrax.

KEYWORDS:

Bacillus anthracis; TP-271; anthrax; fluorocycline

PMID:
28784679
PMCID:
PMC5610513
DOI:
10.1128/AAC.01103-17
[Indexed for MEDLINE]
Free PMC Article

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