The fluorocycline TP-271 is efficacious in models of aerosolized Francisella tularensis SCHU S4 infection in BALB/c mice and cynomolgus macaques [PublishAheadOfPrint]

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 minimal inhibitory concentrations against 50% and 90% of isolates of 0.25 and 0.5μg/mL, respectively. In a mouse model of inhalational tularemia, animals were exposed by aerosol to 91 to 283 LD₅₀/mouse of F. tularensis SCHU S4. Following 21 days of once-daily intraperitoneal dosing of 3, 6, 12 and 18 mg/kg/day TP-271, initiating at 24 hours post-challenge, survival was 80%, 100%, 100%, and 100%, respectively. When treatment was initiated at 72 hours post-challenge, 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 post-treatment. In a non-human primate model of inhalational tularemia, cynomolgus macaques received an average aerosol exposure of 1144 colony forming units 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 hours of confirmed fever. All animals treated with TP-271 survived to the end of the study, with no relapse during 14 days post-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.

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