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In Vitro and In Vivo Characterization of Tebipenem, an Orally Active Carbapenem, against Biothreat Pathogens
Antimicrobial Agents and Chemotherapy ( IF 4.1 ) Pub Date : 2021-04-19 , DOI: 10.1128/aac.02385-20
Nicholas P Clayton 1 , Akash Jain 2 , Stephanie A Halasohoris 3 , Lisa M Pysz 3 , Sanae Lembirik 3 , Steven D Zumbrun 3 , Christopher D Kane 3 , Michael J Hackett 4 , Denise Pfefferle 4 , M Autumn Smiley 4 , Michael S Anderson 4 , Henry Heine 5 , Gabriel T Meister 4 , Michael J Pucci 2
Affiliation  

Bacillus anthracis and Yersinia pestis, the causative pathogens for anthrax and plague, respectively, along with Burkholderia mallei and Burkholderia pseudomallei are potential bioterrorism threats. Tebipenem pivoxil hydrobromide (TBP HBr) (formerly SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacterales. We evaluated the in vitro activity and in vivo efficacy of tebipenem against biothreat pathogens. Tebipenem was active in vitro against 30-strain diversity sets of B. anthracis, Y. pestis, B. mallei, and B. pseudomallei with MIC values of 0.001 to 0.008 μg/ml for B. anthracis, ≤0.0005 to 0.03 μg/ml for Y. pestis, 0.25 to 1 μg/ml for B. mallei, and 1 to 4 μg/ml for B. pseudomallei. In a B. anthracis murine model, all control animals died within 52 h postchallenge. The survival rates in the groups treated with tebipenem were 75% and 73% when dosed at 12 h and 24 h postchallenge, respectively. The survival rates in the positive-control groups treated with ciprofloxacin were 75% when dosed at 12 h and 25% when dosed at 24 h postchallenge. Survival rates were significantly (P = 0.0009) higher in tebipenem groups treated at 12 h and 24 h postchallenge and in the ciprofloxacin group at 12 h postchallenge than in the vehicle control group. For Y. pestis, survival rates for all animals in the tebipenem and ciprofloxacin groups were significantly (P < 0.0001) higher than for the vehicle control group. These results support the further development of tebipenem for treating biothreat pathogens.

中文翻译:


替比培南(一种口服活性碳青霉烯)针对生物威胁病原体的体外和体内表征



炭疽芽孢杆菌鼠疫耶尔森氏菌分别是炭疽和鼠疫的致病病原体,与鼻疽伯克霍尔德氏菌类鼻疽伯克霍尔德氏菌一起是潜在的生物恐怖主义威胁。氢溴酸替比培南匹酯 (TBP HBr)(以前称为 SPR994)是替比培南的口服前药,替比培南是一种碳青霉烯类药物,具有对抗多重耐药 (MDR) 革兰氏阴性病原体的活性,包括喹诺酮耐药和产生广谱 β-内酰胺酶的肠杆菌。我们评估了替比培南对抗生物威胁病原体的体外活性和体内功效。替比培南在体外炭疽杆菌鼠疫杆菌鼻疽杆菌类鼻疽杆菌的 30 个菌株多样性组具有活性,炭疽杆菌的MIC 值为 0.001 至 0.008 μg/ml,≤0.0005 至 0.03 μg/ml对于鼠疫耶尔森氏菌,对于鼻疽伯克氏菌为 0.25 至 1 μg/ml,对于伪鼻疽伯克氏菌为 1 至 4 μg/ml。在炭疽芽孢杆菌小鼠模型中,所有对照动物在攻击后 52 小时内死亡。攻击后 12 小时和 24 小时给药时,替比培南治疗组的存活率分别为 75% 和 73%。使用环丙沙星治疗的阳性对照组的存活率在攻击后 12 小时给药时为 75%,在攻击后 24 小时给药时为 25%。攻击后 12 小时和 24 小时治疗的替比培南组以及攻击后 12 小时的环丙沙星组的存活率显着高于载体对照组( P = 0.0009)。对于Y。 鼠疫杆菌中,替比培南和环丙沙星组中所有动物的存活率均显着高于载体对照组 ( P < 0.0001)。这些结果支持进一步开发替比培南治疗生物威胁病原体。
更新日期:2021-04-19
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