The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Francisella tularensis SCHU S4 Infection in BALB/c Mice and Cynomolgus Macaques
| Autor: | Joyce A. Sutcliffe, Kaylyn Siefkas-Patterson, Melanie Gooldy, Trudy H. Grossman, Anne K. Radcliff, Vincent H. Tam, Winston Lin, Lisa N. Henning, Henry S. Heine, M. Victoria Kindt, Michael S. Anderson, David Christ |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male 030106 microbiology Microbial Sensitivity Tests Body weight BALB/c Microbiology Tularemia 03 medical and health sciences Mice Medicine Animals Pharmacology (medical) Respiratory system Francisella tularensis Respiratory Tract Infections Aerosolization Pharmacology Mice Inbred BALB C biology business.industry biology.organism_classification medicine.disease Virology Nonhuman primate In vitro Anti-Bacterial Agents Disease Models Animal Macaca fascicularis 030104 developmental biology Infectious Diseases Tetracyclines Female business |
| Popis: | TP-271 is a novel, fully synthetic fluorocycline in development for complicated bacterial respiratory infections. TP-271 was active in vitro against 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 (LD 50 )/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 . |
| Databáze: | OpenAIRE |
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