| 2016年6月29日，英国制药巨头阿斯利康（AstraZeneca）抗生素管线近日在欧盟监管方面传来喜讯。欧盟委员会（EC）已批准新型复方抗生素产品Zavicefta（ceftazidime-avibactam，CAZ-AVI，头孢他啶-阿维巴坦，2g/0.5g，粉剂），用于需要住院治疗的严重革兰氏阴性菌感染患者的治疗。具体适应症为，将Zavicefta用于静脉输注，治疗复杂性腹腔内感染（cIAI）、复杂性尿路感染（cUTI，包括肾盂肾炎）、医院获得性肺炎（HAP，包括呼吸机相关肺炎VAP）成人患者，以及由好氧革兰氏阴性菌所致感染但缺乏治疗选择的成人患者。 Zavicefta（ceftazidime-avibactam，CAZ-AVI，头孢他啶-阿维巴坦）是由一种广谱头孢菌素ceftazidime（头孢他啶）和一种新一代非β-内酰胺类β内酰胺酶抑制剂avibactam（阿维巴坦）组成的复方产品，开发用于治疗广泛的革兰氏阴性菌感染，包括多重耐药铜绿假单胞菌、碳青霉烯类抗生素耐药的革兰氏阴性菌，产ESBL肠杆菌科细菌。ceftazidime（头孢他啶）是第三代头孢菌素，这是一种常用于治疗严重革兰氏阴性菌感染的抗生素产品。Zavicefta产品中所添加的avibactam成分，将保护ceftazidime免于被这些耐药阴性菌所产生的β-内酰胺酶的分解。 当前，日益严峻的抗生素耐药问题已对公众健康构成了严重威胁。在欧洲，每年由抗生素耐药导致的死亡病例高达2.5万例，其中革兰氏阴性菌所致死亡病例占到了三分之二。在面对严重革兰氏阴性菌感染时，当前很多有效的治疗方案很快会失去作用。Zavicefta作为全球抗击耐药菌抗生素弹药库的一个重要补充，将帮助弥补这个缺口，使更多的患者能够从这种新的抗生素产品中受益。 CAZ-AVI由艾尔健（Allergan）和阿斯利康联合开发，艾尔健拥有CAZ-AVI在北美市场的权利，阿斯利康则拥有CAZ-AVI在全球其他地区的权利。 在美国，FDA已于2015年2月批准CAZ-AVI（品牌名Avycaz）用于复杂性腹腔内感染 (cIAI)（联合甲硝唑）及复杂性尿路感染（cUTI）成人患者的治疗。 Zerbaxa药物组成与Avycaz相似，也是由一种新型头孢菌素（ceftolozane）和一种β-内酰胺酶抑制剂（tazobactam，他唑巴坦）组成的复方产品，在美国获批的适应症也是复杂性腹腔内感染（cIAI）和复杂性尿路感染（cUTI）。 New Drugs Online Report for ceftazidime+avibactam Information Generic Name: ceftazidime + avibactam Trade Name: Zavicefta (EU), Avycaz (US) Synonym: CAZ-AVI, NXL104, CAZ104 Entry Type: New formulation Development and Regulatory status UK: Approved (Licensed) EU: Approved (Licensed) US: Approved (Licensed) UK launch Plans: Available only to registered users Actual UK launch date: Comments Jun 16. Approved in EU [16] 29/06/2016 11:28:12 Apr 16: EU positive opinion for treatment of the following infections in adults: Complicated intra-abdominal infection, complicated urinary tract infection, including pyelonephritis, hospital-acquired pneumonia, including ventilator-associated pneumonia, & infections due to aerobic Gram-negative organisms in patients with limited treatment options [15]. 29/04/2016 14:12:35 Jun 15: Filed in the EU via the centralised procedure [13]. 23/07/2015 12:27:11 Feb 15: The licence restricts use to patients with limited or no other alternatives. Actavis holds US rights to Avycaz while AstraZeneca controls the drug in the rest of the world. PIII trials set to complete this year. Actavis will submit late-stage data to the FDA in hopes of expanding the drug´s label, and AstraZeneca will use it to support global approvals [11]. 10/03/2015 12:12:52 Dec 14: EU filing planned Q1 2015 [12]. 10/03/2015 12:12:36 Sept 14: Filed with US FDA for the treatment of patients with Complicated Intra-Abdominal Infections (cIAI), including those caused by multi-drug resistant Gram-negative bacterial pathogens. [9] 08/09/2014 09:26:23 Aug 14: EU filing is now anticipated in Q1 2015 [8] 20/08/2014 18:47:25 Dec 13: EU filing will be in 4Q 2014 [6]. 03/03/2014 17:38:30 AstraZeneca plan for EU filing in 2014 [3]. 02/03/2012 14:50:17 Jan 12: PIII studies started [2]. 16/02/2012 09:15:44 Oct 11: AstraZeneca and Forest plan to enter ceftazidime/avibactam into 5 PIII trials for treating hospitalised patients with serious Gram-negative bacterial infections including complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI and to submit for regulatory approval in 2014 [1]. 20/10/2011 09:46:06 Trial or other data Apr 16: Results of PIII (NCT01644643; REPRISE) trial published in the Lancet Infectious Diseases. In this RCT (n=333), proportions of patients with clinical response at test-of-cure visit, 7–10 days after last infusion of study therapy, were similar with ceftazidime-avibactam or best available therapy (91% each group). An adverse event was reported in 31% and 39%, respectively [14]. 25/04/2016 11:43:55 Aug 14: Positive topline results from RECLAIM-1 and -2, pivotal PIII studies; ceftazidime-avibactam met the objective of statistical non-inferiority compared to meropenem. The primary endpoint was a clinical cure rate 28 to 35 days after randomization (the Test of Cure visit). [7] 20/08/2014 09:23:01 Avibactam, a bicyclo-heterocyclic compound that is the first of a new chemical series of β-lactamase inhibitors, potently inhibits both class A and class C β-lactamases [4]. 24/04/2012 10:41:22 Feb 12: NCT01499290 and NCT01500239: are two similarly designed PIII, randomized, multicentre, double blind, double-dummy studies of ceftazidime avibactam plus metronidazole vs meropenem in the treatment of complicated intra-abdominal infections each in 1106 hospitalized adults. The primary outcome is clinical cure as measured by proportion of patients meeting cure criteria in the microbiological modified intent-to-treat analysis set 28 to 35 days after start of study drug. The studies started Jan 12 and are due to complete Oct 13 [2]. 16/02/2012 09:16:06 In a PII prospective, double-blind RCT in 203 adults hospitalised with cIAI requiring treatment with IV antimicrobial therapy those treated with CAZ-AVI plus metronidazole had a similar clinical response rate (91.2%) to those treated with meropenem (93.4%) [1]. 20/10/2011 09:46:29 Forest has the rights to commercialise CAZ-AVI in North America and AstraZeneca to commercialise CAZ-AVI in the rest of the world [1]. 20/10/2011 09:46:18 References Available only to registered users Category BNF Category: Cephalosporins, carbapenems and other beta-lactams (05.01.02) Pharmacology: Cephalosporin and a beta-lactamase inhibitor Epidemiology: Complicated intra-abdominal infections are often defined as extending beyond the hollow viscus of origin into the peritoneal space with associated abscess formation or peritonitis. They are potentially serious conditions that require an invasive procedure for source control. The overall incidence is difficult to establish & varies with the underlying abdominal disease processes [5]. Indication: Bacterial infections Additional Details: intra-abdominal, complicated and infections due to aerobic Gram-negative organisms in adults with limited treatment options Method(s) of Administration Intravenous Company Information Name: AstraZeneca US Name: Actavis (now Allergan) Further Information Anticipated commissioning route (England) CCG High cost drug list? Awaiting Update Implications Available only to registered users |