Antimicrob Agents Chemother. 2017 Jul 25;61(8). pii: e00448-17. doi: 10.1128/AAC.00448-17. Print 2017 Aug.
The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Francisella tularensis SCHU S4 Infection in BALB/c Mice and Cynomolgus Macaques.
Grossman TH1, Anderson MS2, Christ D3, Gooldy M4, Henning LN2, Heine HS5, Kindt MV6, Lin W7, Siefkas-Patterson K7, Radcliff AK4, Tam VH8, Sutcliffe JA9.
Author information
1Tetraphase Pharmaceuticals, Inc., Watertown, Massachusetts, USA tgrossman@yahoo.com.2Battelle, Columbus, Ohio, USA.3SNC Partners, LLC, Newark, Delaware, USA.4CUBRC, Inc., Buffalo, New York, USA.5United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.6Pathways Toxicology Consulting, LLC, Lahaska, Pennsylvania, USA.7IIT Research Institute, Chicago, Illinois, USA.8University of Houston College of Pharmacy, Houston, Texas, USA.9Tetraphase Pharmaceuticals, Inc., Watertown, Massachusetts, USA.
Abstract
TP-271 is a novel, fully synthetic fluorocycline in development for complicated bacterial respiratory infections. TP-271 was active in vitroagainst a panel of 29 Francisella tularensis isolates, showing MICs against 50% and 90% of isolates of 0.25 and 0.5 µg/ml, respectively. In a mouse model of inhalational tularemia, animals were exposed by aerosol to 91 to 283 50% lethal doses (LD50)/mouse of F. tularensis SCHU S4. Following 21 days of once-daily intraperitoneal dosing with TP-271 at 3, 6, 12, and 18 mg/kg of body weight/day, initiating at 24 h postchallenge, survival was 80%, 100%, 100%, and 100%, respectively. When treatment was initiated at 72 h postchallenge, survival was 89%, 100%, 100%, and 100% in the 3-, 6-, 12-, and 18-mg/kg/day TP-271 groups, respectively. No mice treated with the vehicle control survived. Surviving mice treated with TP-271 showed little to no relapse during 14 days posttreatment. In a nonhuman primate model of inhalational tularemia, cynomolgus macaques received an average aerosol exposure of 1,144 CFU of F. tularensis SCHU S4. Once-daily intravenous infusion with 1 or 3 mg/kg TP-271, or vehicle control, for 21 days was initiated within 6 h of confirmed fever. All animals treated with TP-271 survived to the end of the study, with no relapse during 14 days after the last treatment, whereas no vehicle control-treated animals survived. The protection and low relapse afforded by TP-271 treatment in these studies support continued investigation of TP-271 for use in the event of aerosolized exposure to F. tularensis. |
