The β-Lactams Strike Back: Ceftazidime-Avibactam.
The β-Lactams Strike Back: Ceftazidime-Avibactam.
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DOI：
10.1002/phar.1622
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发表时间：
2015-08
期刊：
影响因子：
4.1
通讯作者：
Rybak MJ
中科院分区：
文献类型：
--
作者：
Zasowski EJ;Rybak JM;Rybak MJ
革兰氏阴性耐药性已经达到了一个关键点，出现了对大多数或所有可用抗生素具有耐药性的病原体。头孢他啶-阿维巴坦是一种新批准的药物，将头孢他啶与一种新型β-内酰胺酶抑制剂联合使用，对多重耐药革兰氏阴性菌具有活性。相对于现有的β-内酰胺酶抑制剂（包括超广谱β-内酰胺酶、AmpC酶和肺炎克雷伯菌碳青霉烯酶（KPC）），阿维巴坦对A类和C类β-内酰胺酶的抑制效力增加，抑制谱扩大。阿维巴坦扩大了头孢他啶的活性谱，包括许多头孢他啶和碳青霉烯耐药肠杆菌科和铜绿假单胞菌。早期临床数据表明，头孢他啶-阿维巴坦在复杂性尿路感染（cUTI）和复杂性腹腔内感染（cIAI）患者中有效且耐受性良好。在一项cUTI患者的II期试验中，头孢他啶-阿维巴坦与亚胺培南-西司他丁的临床和微生物学成功率相似（分别为70.5%和71.4%）。同样，在cIAI患者的II期研究中，接受头孢他啶-阿维巴坦联合甲硝唑治疗的患者与接受美罗培南治疗的患者的缓解率相似（临床成功率分别为91.2%和93.4%）。根据现有的体外、体内和II期试验数据，以及头孢他啶耐药、革兰氏阴性cUTI和cIAI的初步III期试验结果，美国食品药品监督管理局批准头孢他啶-阿维巴坦与甲硝唑联合治疗有限或无替代治疗选择的成人患者的cUTI（包括肾盂肾炎）和cIAI。根据药效学分析和可用的临床数据，选择批准剂量头孢他啶2 g-阿维巴坦0. 5 g，每8小时输注2小时。该剂量正在cUTI、cIAI和院内或呼吸机相关肺炎患者中进行进一步研究。目前的大量证据表明，头孢他啶-阿维巴坦是一种很有前途的治疗药物，有可能满足迫切的未满足的医疗需求。需要有关高耐药性革兰氏阴性感染的进一步数据，特别是由产KPC的肠杆菌科引起的感染。随着其引入临床使用，谨慎的管理和合理使用对于保持头孢他啶-阿维巴坦的潜在效用至关重要。
Gram-negative resistance has reached a crucial point, with emergence of pathogens resistant to most or all available antibiotics. Ceftazidime-avibactam is a newly approved agent combining ceftazidime and a novel β-lactamase inhibitor with activity against multidrug-resistant gram-negative bacteria. Avibactam has increased potency and expanded spectrum of inhibition of class A and C β-lactamases relative to available β-lactamase inhibitors, including extended-spectrum β-lactamase, AmpC, and Klebsiella pneumoniae carbapenemase (KPC) enzymes. Avibactam expands ceftazidime's spectrum of activity to include many ceftazidime- and carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa. Early clinical data indicate that ceftazidime-avibactam is effective and well tolerated in patients with complicated urinary tract infections (cUTI) and complicated intraabdominal infections (cIAI). In a phase II trial of patients with cUTI, ceftazidime-avibactam produced similar rates of clinical and microbiologic success compared with imipenem-cilastatin (70.5% and 71.4% microbiologic success rates, respectively). Likewise, patients receiving ceftazidime-avibactam plus metronidazole in a phase II study of patients with cIAI had similar response rates to those receiving meropenem (91.2% and 93.4% clinical success rates, respectively). Based on available in vitro, in vivo, and phase II trial data, as well as preliminary phase III trial results in ceftazidime-resistant, gram-negative cUTI and cIAI, ceftazidime-avibactam received United States Food and Drug Administration approval for treatment of cUTI, including pyelonephritis, and cIAI, in combination with metronidazole, in adult patients with limited or no alternative treatment options. The approved dosage, ceftazidime 2 g–avibactam 0.5 g administered as a 2-hour infusion every 8 hours, was selected based on pharmacodynamic analysis and available clinical data. This dosage is under further investigation in patients with cUTI, cIAI, and nosocomial or ventilator-associated pneumonia. The current body of evidence suggests that ceftazidime-avibactam is a promising addition to our therapeutic armamentarium with potential to answer an urgent unmet medical need. Further data in highly resistant gram-negative infections, particularly those caused by KPC-producing Enterobacteriaceae, are needed. As it is introduced into clinical use, careful stewardship and rational use are essential to preserve ceftazidime-avibactam's potential utility.