Ceftolozane / tazobactam:一种新型头孢菌素对革兰氏阴性杆菌耐多药/ beta-lactamase抑制剂结合活动。

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Zhanel GG,钟P,亚当·H Zelenitsky年代,Denisuik,瑞士F, Lagace-Wiens公关,鲁宾斯坦E,杜松子酒,Walkty,贺朋的DJ,林奇JP 3日Karlowsky农协

Ceftolozane / tazobactam:一种新型头孢菌素对革兰氏阴性杆菌耐多药/ beta-lactamase抑制剂结合活动。

药。2014年1月,74 (1):31-51。doi: 10.1007 / s40265 - 013 - 0168 - 2。

PubMed ID
24352909 (在PubMed
]
文摘

Ceftolozane与beta-lactamase当前研发的一种新型头孢菌素抑制剂tazobactam治疗复杂的尿路感染(皮肤),复杂腹腔感染(cIAIs),与机械通气相关细菌性肺炎和(VABP)。ceftolozane的化学结构类似于头孢他啶,除了修改侧链的第三位cephem核,它赋予强大的antipseudomonal活动。beta-lactam,它的作用机理是抑制penicillin-binding蛋白质(是)。Ceftolozane显示活动增加对革兰氏阴性杆菌,包括那些港口古典beta-lactamases(例如,TEM-1和SHV-1),但是,类似于其他oxyimino-cephalosporins如头孢他啶和头孢曲松钠,它是被extended-spectrum beta-lactamases (ESBLs)和"。添加tazobactam ceftolozane的活动扩展到包括大多数ESBL生产商以及一些厌氧物种。Ceftolozane区别于其他头孢菌素的有效的活动与铜绿假单胞菌,包括各种耐药表型,如碳青霉烯、哌拉西林/ tazobactam ceftazidime-resistant隔离,以及那些耐多药菌株(MDR)。antipseudomonal活动是由于它能够逃避众多受雇于铜绿假单胞菌的耐药机制,包括射流泵,减少吸收是通过名叫孔和修改。Ceftolozane表明线性药物动力学的影响共同服用tazobactam的;具体地说,它遵循一个two-compartmental模型与线性消除。单剂后,从250到2000毫克,超过1小时静脉输液,ceftolozane显示平均血浆半衰期为2.3 h(范围1.9 - -2.6 h),一个稳态的体积分布范围从13.1到17.6 L,和平均间隙是102.4毫升/分钟。 It demonstrates low plasma protein binding (20 %), is primarily eliminated via urinary excretion (>/=92 %), and may require dose adjustments in patients with a creatinine clearance <50 mL/min. Time-kill experiments and animal infection models have demonstrated that the pharmacokinetic-pharmacodynamic index that is best correlated with ceftolozane's in vivo efficacy is the percentage of time in which free plasma drug concentrations exceed the minimum inhibitory concentration of a given pathogen (%fT >MIC), as expected of beta-lactams. Two phase II clinical trials have been conducted to evaluate ceftolozane +/- tazobactam in the settings of cUTIs and cIAIs. One trial compared ceftolozane 1,000 mg every 8 h (q8h) versus ceftazidime 1,000 mg q8h in the treatment of cUTI, including pyelonephritis, and demonstrated similar microbiologic and clinical outcomes, as well as a similar incidence of adverse effects after 7-10 days of treatment, respectively. A second trial has been conducted comparing ceftolozane/tazobactam 1,000/500 mg and metronidazole 500 mg q8h versus meropenem 1,000 mg q8h in the treatment of cIAI. A number of phase I and phase II studies have reported ceftolozane to possess a good safety and tolerability profile, one that is consistent with that of other cephalosporins. In conclusion, ceftolozane is a new cephalosporin with activity versus MDR organisms including P. aeruginosa. Tazobactam allows the broadening of the spectrum of ceftolozane versus beta-lactamase-producing Gram-negative bacilli including ESBLs. Potential roles for ceftolozane/tazobactam include empiric therapy where infection by a resistant Gram-negative organism (e.g., ESBL) is suspected, or as part of combination therapy (e.g., with metronidazole) where a polymicrobial infection is suspected. In addition, ceftolozane/tazobactam may represent alternative therapy to the third-generation cephalosporins after treatment failure or for documented infections due to Gram-negative bacilli producing ESBLs. Finally, the increased activity of ceftolozane/tazobactam versus P. aeruginosa, including MDR strains, may lead to the treatment of suspected and documented P. aeruginosa infections with this agent. Currently, ceftolozane/tazobactam is being evaluated in three phase III trials for the treatment of cUTI, cIAI, and VABP.

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