Tetraphase Pharmaceuticals, Inc., Watertown, Massachusetts, USA
Battelle, Columbus, Ohio, USA.
Antimicrob Agents Chemother. 2017 Jul 25;61(8). doi: 10.1128/AAC.00448-17. Print 2017 Aug.
TP-271 is a novel, fully synthetic fluorocycline in development for complicated bacterial respiratory infections. TP-271 was active against a panel of 29 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)/mouse of 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 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 .
TP-271 是一种新型的全合成氟环素，正在开发用于治疗复杂的细菌性呼吸道感染。TP-271 对 29 株分离株的活性研究显示，MIC50 和 MIC90 分别为 0.25 和 0.5μg/ml。在吸入性土拉菌病的小鼠模型中，动物通过气溶胶暴露于 SCHU S4 的 91 至 283 个 50%致死剂量（LD）/只。在挑战后 24 小时开始，每日一次腹腔内给予 3、6、12 和 18mg/kg 体重/天的 TP-271 治疗 21 天，分别有 80%、100%、100%和 100%的动物存活。在挑战后 72 小时开始治疗时，3、6、12 和 18mg/kg/天的 TP-271 组分别有 89%、100%、100%和 100%的动物存活。用载体对照治疗的动物无一存活。用 TP-271 治疗的幸存动物在治疗后 14 天内几乎没有复发。在吸入性土拉菌病的非人灵长类动物模型中，食蟹猴平均暴露于 1144CFU 的 SCHU S4。在出现发热后 6 小时内，开始每日一次静脉输注 1 或 3mg/kg 的 TP-271 或载体对照，持续 21 天。所有用 TP-271 治疗的动物均存活至研究结束，最后一次治疗后 14 天内无复发，而没有用载体对照治疗的动物均死亡。TP-271 在这些研究中的治疗提供的保护和低复发率支持继续研究 TP-271 用于气溶胶暴露的情况。
