Eravacycline (TP-434)

Eravacycline is a potent and broad-spectrum antibacterial agent.

Eravacycline is potent antibiotic against A. baumannii, including isolates that are resistant to sulbactam, imipenem/meropenem, levofloxacin, and amikacin/tobramycin. Eravacycline shows greater activity than the comparators of the tetracycline class, levofloxacin, amikacin, tobramycin, and colistin. The eravacycline MIC50/90 values are 0.5/1 mg/L[1]. Eravacycline shows inhibitory effects on six E. coli with MICs ranging from 0.125 to 0.25 mg/L[2]. Eravacycline dihydrochloride is a synthetic antibiotic, with inhibits bacterial protein synthesis through binding to the 30S ribosomal subunit. Eravacycline displays broad spectrum activity against gram-negative bacteria in the panel except P. aeruginosa, as well as excellent activity against major gram-positive pathogens, including methicillin-resistant S. aureus. Eravacycline also displays potent ribosomal inhibition[3]. Eravacycline shows potent broad-spectrum activity against 90% of the isolates (MIC90) in each panel at concentrations ranging from ≤0.008 to 2 μg/mL for all species panels except those of Pseudomonas aeruginosa and Burkholderia cenocepacia (MIC90 values of 32 μg/mL for both organisms). Eravacycline is active against multidrug-resistant bacteria, including those expressing extended-spectrum β-lactamases and mechanisms conferring resistance to other classes of antibiotics, including carbapenem resistance[4].

Mice are treated with two-fold increasing doses (range 3.125 to 50 mg/kg) of eravacycline every 12 hours. The mean fAUC/MIC magnitude associated with net stasis and 1-log kill endpoint are 27.97±8.29 and 32.60±10.85, respectively[2]. Eravacycline is active in multiple murine models of infection against clinically important Gram-positive and Gram-negative pathogens. Eravacycline is efficacious in mouse septicemia models, demonstrating 50% protective dose values of ≤1 mg/kg of body weight once a day (q.d.) against Staphylococcus aureus, including tetracycline-resistant isolates of methicillin-resistant S. aureus (MRSA), and Streptococcus pyogenes. The PD50 values against Escherichia coli isolates are 1.2 to 4.4 mg/kg q.d[5].

Reference

[1]. Seifert H, et al. In-vitro activity of the novel fluorocycline eravacycline against carbapenem non-susceptible Acinetobacter baumannii. Int J Antimicrob Agents. 2017 Jul 10. [2]. Zhao M, et al. In Vivo Pharmacodynamic Target Assessment of Eravacycline against Escherichia coli in a Murine Thigh Infection Model. Antimicrob Agents Chemother. 2017 Jun 27;61(7). [3]. Xiao XY, et al. Fluorocyclines. 1. 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: a potent, broad spectrum antibacterial agent. J Med Chem. 2012 Jan 26;55(2):597-605. [4]. Sutcliffe JA, et al. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob Agents Chemother. 2013 Nov;57(11):5548-58. [5]. Grossman TH, et al. Eravacycline (TP-434) is efficacious in animal models of infection. Antimicrob Agents Chemother. 2015 May;59(5):2567-71.

Eravacycline (TP-434)是一种新型四环素(TET)抗生素。TP-434在体外对各种革兰氏阳性、革兰氏阴性的好氧和厌氧病原体具有活性，包括那些表现出TET特异性获得性耐药机制的病原体^[1]。Eravacycline通过与30S核糖体亚基结合抑制蛋白质合成^[2]。Eravacycline可用于治疗成人并发腹腔内感染(cIAIs)^[3-4]。

Eravacycline (TP-434) (0.03 to 4 μg/ml; 24h)对尿路致病性大肠杆菌菌株形成的生物膜有明显的抑菌作用^[5]。Eravacycline (0-8 μg/ml)在体外对临床脓肿分枝杆菌分离株具有抗菌活性^[6]。

Eravacycline (TP-434) (3-12mg/kg)在感染四环素耐药肺炎链球菌和MRSA分离株后2和12 h经尾静脉注射小鼠后对感染小鼠有明显的治疗作用, 对于MRSA SA191肺部感染，与未治疗组相比，10mg /kg静脉滴注Eravacycline可使CFU降低2.4 log10^[7]。