The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Francisella tularensis SCHU S4 Infection in BALB/c Mice and Cynomolgus Macaques

Abstract

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 (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.

Keywords: Francisella tularensis; TP-271; fluorocycline; tularemia.

FIG 1

Efficacy of TP-271 in a postexposure prophylaxis (PEP) model of inhalational tularemia in mice. Antibiotic and vehicle control dosing initiated at 24 h postinfection. Survival plots for the 21-day dosing phase (A) and the 14-day posttreatment phase (B) are shown. The following dose groups were used: black line, 3 mg/kg/day TP-271; blue line, 6 mg/kg/day TP-271; burgundy line, 12 mg/kg/day TP-271; yellow line, 18 mg/kg/day TP-271; green line, 80 mg/kg/day doxycycline; red line, vehicle control. Lines at 100% survival are drawn staggered for visibility.

FIG 2

Efficacy of TP-271 in a treatment (Tx) model of inhalational tularemia in mice. Antibiotic and vehicle control dosing were initiated at 72 h postinfection. Survival plots for the 21-day dosing phase (A) and the 14-day posttreatment phase (B) are shown. The following dose groups were used: black line, 3 mg/kg/day TP-271; blue line, 6 mg/kg/day TP-271; burgundy line, 12 mg/kg/day TP-271; yellow line, 18 mg/kg/day TP-271; green line, 80 mg/kg/day doxycycline; red line, vehicle control. Lines at 100% survival are drawn staggered for visibility.

FIG 3

Efficacy of TP-271 in a treatment (Tx) model of inhalational tularemia in NHPs. TP-271 and vehicle control dosing initiated within 6 h of the onset of a confirmed fever as described in Materials and Methods. The following dose groups were used: black line, 3 mg/kg/day TP-271; blue line, 1 mg/kg/day TP-271; red line, vehicle control. Lines at 100% survival are drawn staggered for visibility.