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 g/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.KEYWORDS TP-271, fluorocycline, tularemia, Francisella tularensis F rancisella tularensis, the causative agent of tularemia, is a small aerobic nonmotile Gram-negative coccobacillus capable of causing the zoonotic disease tularemia, naturally spread among mammals by ticks, flies, and mosquitoes (1, 2). Humans can become infected with F. tularensis by insect bites, handling infectious animal materials, direct contact with or ingestion of contaminated water, food, or soil, and inhalation of infective aerosols. Inhalation of as few as 10 organisms can cause disease, making F. tularensis subsp. tularensis (type A subspecies) one of the most infectious pathogenic bacteria known and a likely agent for a bioterrorist attack (3). Accordingly, this pathogen is categorized as a priority category A (tier 1) threat agent by the Centers for Disease Control and Prevention (CDC) because of the high likelihood that F. tularensis will be used as a bioweapon (2).Inhalation of F. tularensis bacteria causes pneumonia, respiratory failure, shock, and a high incidence of mortality (2, 4). Aerosol dispersion of F. tularensis is predicted to be

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

“…These B. anthracis isolates exhibited MIC values similar to the MIC for the challenge strain, supporting the suggestion that TP-271 did not select for resistance in B. anthracis during the course of treatment in this study. The levels of TP-271 exposure in infected mice at 24 h and 48 h were similar and comparable to the levels of exposure obtained with similar doses in uninfected mice (data not shown) and in prior efficacy studies (23), indicating that B. anthracis infection did not significantly affect the pharmacokinetics of TP-271 in mice ( Table 2). The pharmacokinetics of doxycycline have been reported previously, and the dose of 40 mg/kg administered twice daily was predicted to be efficacious on the basis of successful outcomes in prior infection models (23,24).…”

“…The values of the pharmacokinetic parameters for TP-271 (Table 3) correlated with the levels of TP-271 exposure in uninfected animals (data not shown) and what was observed in prior efficacy studies (23). After a 14-day administration of TP-271 by intravenous infusion, the mean maximum concentration (C max ) increased from 0.358 g/ml (day 1) to 0.813 g/ml (day 14), a 2.3-fold accumulation.…”

“…Previous work showed that TP-271 was efficacious in mouse models of pneumonia in which the mice were challenged with tetracycline-resistant community-acquired bacterial respiratory pathogens (18). In addition to the proof-of-concept efficacy against inhalational anthrax presented here, TP-271 was previously shown to be efficacious in a mouse model of plague (26) and mouse and NHP models of tularemia (23); this supports the potential for the use of TP-271 as a broad-spectrum medical countermeasure if results in mouse and NHP models translate to efficacy against human disease.…”

“…AUC 0 -24 increased from 1.37 to 2.50 g • h/ml (day 21), a 1.8-fold accumulation. Minimal to modest accumulation has been reported for TP-271 in prior studies (23).…”

“…Antibiotics for susceptibility testing were prepared in sterile deionized water and stored frozen at ՅϪ65°C. Dose formulations were prepared as described previously (23).…”