Sharma Roopali, Park Tae Eun, Moy Stanley
Long Island University, The Health Science Center at Brooklyn (SUNY), Brooklyn, New York.
Fairleigh Dickinson University, School of Pharmacy, Florham Park, New Jersey.
Clin Ther. 2016 Mar;38(3):431-44. doi: 10.1016/j.clinthera.2016.01.018. Epub 2016 Mar 2.
Multidrug-resistant gram-negative bacterial infections have emerged as a major threat in hospitalized patients. Treatment options are often inadequate and, as a result, these infections are associated with high mortality. A cephalosporin and a novel synthetic non-β-lactam, β-lactamase inhibitor, ceftazidime-avibactam, is approved for the treatment of serious infections caused by resistant gram-negative bacteria. This article reviews the spectrum of activity, clinical pharmacology, pharmacodynamic and pharmacokinetic properties, clinical efficacy and tolerability, and dosing and administration of ceftazidime-avibactam.
Searches of MEDLINE and International Pharmaceutical Abstracts from 1980 to September 2015 were conducted by using the search terms ceftazidime, avibactam, and ceftazidime-avibactam. Abstracts from Infectious Disease Week (2014-2015), the Interscience Conference on Antimicrobial Agents and Chemotherapy (2014-2015), and the European Congress of Clinical Microbiology and Infectious Diseases were also searched.
Ceftazidime, a third-generation cephalosporin, when combined with avibactam has a significant improvement in its activity against β-lactamase-producing gram-negative pathogens, including extended-spectrum β-lactamases, AmpC β-lactamases, Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Data from 2 Phase II and 1 Phase III clinical trial are available. In the Phase II trial of patients with complicated intra-abdominal infections, ceftazidime-avibactam produced clinical cure rates comparable to meropenem (91.2% vs 93.4%). Similarly, patients receiving ceftazidime-avibactam in a Phase II study of complicated urinary tract infections had clinical and microbiologic response rates similar to those receiving imipenem-cilastatin (70.4% and 71.4% microbiologic success rates, respectively). A Phase III trial compared ceftazidime-avibactam to best available therapy for the treatment of ceftazidime-resistant organisms. Clinical response and microbiological response for ceftazidime-avibactam versus best available therapy was comparable (90.9% and 91.2% clinical response, respectively); (81.8% and 63.5% microbiological response, respectively).
Currently, ceftazidime-avibactam is approved for the indications of complicated intra-abdominal infections (with metronidazole) and complicated urinary tract infections. Clinical trials published to date on this antimicrobial agent have shown its excellent safety and tolerability. This new combination agent has a role, but its use should be limited to patients without other treatment options in the empiric and documented treatment of multidrug-resistant gram-negative organisms. Further investigation is needed in patients with carbapenemase-producing Enterobacteriaceae and multidrug-resistant P aeruginosa who have bacteremia or nosocomial or ventilator-associated pneumonia. It is imperative that ceftazidime-avibactam be used in a responsible manner so that its effectiveness can be retained.
多重耐药革兰阴性菌感染已成为住院患者面临的主要威胁。治疗选择往往不足，因此，这些感染与高死亡率相关。一种头孢菌素与一种新型合成非β-内酰胺类β-内酰胺酶抑制剂头孢他啶-阿维巴坦已被批准用于治疗由耐药革兰阴性菌引起的严重感染。本文综述了头孢他啶-阿维巴坦的抗菌谱、临床药理学、药效学和药代动力学特性、临床疗效和耐受性以及给药剂量和方式。
使用搜索词头孢他啶、阿维巴坦和头孢他啶-阿维巴坦对1980年至2015年9月的MEDLINE和国际药学文摘进行检索。还检索了传染病周（2014 - 2015年）、抗菌药物和化疗跨学科会议（2014 - 2015年）以及欧洲临床微生物学和传染病大会的摘要。
第三代头孢菌素头孢他啶与阿维巴坦联合使用时，对产β-内酰胺酶的革兰阴性病原体的活性有显著提高，包括超广谱β-内酰胺酶、AmpCβ-内酰胺酶、产肺炎克雷伯菌碳青霉烯酶的肠杆菌科细菌以及多重耐药铜绿假单胞菌。有2项II期和1项III期临床试验的数据。在复杂性腹腔内感染患者的II期试验中，头孢他啶-阿维巴坦的临床治愈率与美罗培南相当（91.2%对93.4%）。同样，在复杂性尿路感染的II期研究中，接受头孢他啶-阿维巴坦治疗的患者的临床和微生物学反应率与接受亚胺培南-西司他丁治疗的患者相似（微生物学成功率分别为70.4%和71.4%）。一项III期试验将头孢他啶-阿维巴坦与治疗头孢他啶耐药菌的最佳可用疗法进行了比较。头孢他啶-阿维巴坦与最佳可用疗法的临床反应和微生物学反应相当（临床反应分别为90.9%和91.2%）；（微生物学反应分别为81.8%和63.5%）。
目前，头孢他啶-阿维巴坦已被批准用于复杂性腹腔内感染（与甲硝唑联合）和复杂性尿路感染的适应症。迄今为止发表的关于这种抗菌药物的临床试验表明了其出色的安全性和耐受性。这种新的联合药物有一定作用，但其使用应限于在多重耐药革兰阴性菌的经验性和确诊治疗中没有其他治疗选择的患者。对于产碳青霉烯酶的肠杆菌科细菌和多重耐药铜绿假单胞菌引起菌血症或医院获得性或呼吸机相关性肺炎的患者，需要进一步研究。必须以负责任的方式使用头孢他啶-阿维巴坦，以便保留其有效性。
