Mazuski John E, Gasink Leanne B, Armstrong Jon, Broadhurst Helen, Stone Greg G, Rank Douglas, Llorens Lily, Newell Paul, Pachl Jan
Washington University School of Medicine, St Louis, Missouri.
AstraZeneca, Wilmington, Delaware.
Clin Infect Dis. 2016 Jun 1;62(11):1380-1389. doi: 10.1093/cid/ciw133. Epub 2016 Mar 8.
When combined with ceftazidime, the novel non-β-lactam β-lactamase inhibitor avibactam provides a carbapenem alternative against multidrug-resistant infections. Efficacy and safety of ceftazidime-avibactam plus metronidazole were compared with meropenem in 1066 men and women with complicated intra-abdominal infections from 2 identical, randomized, double-blind phase 3 studies (NCT01499290 and NCT01500239).
The primary end point was clinical cure at test-of-cure visit 28-35 days after randomization, assessed by noninferiority of ceftazidime-avibactam plus metronidazole to meropenem in the microbiologically modified intention-to-treat (mMITT) population (in accordance with US Food and Drug Administration guidance), and the modified intention-to-treat and clinically evaluable populations (European Medicines Agency guidance). Noninferiority was considered met if the lower limit of the 95% confidence interval for between-group difference was greater than the prespecified noninferiority margin of -12.5%.
Ceftazidime-avibactam plus metronidazole was noninferior to meropenem across all primary analysis populations. Clinical cure rates with ceftazidime-avibactam plus metronidazole and meropenem, respectively, were as follows: mMITT population, 81.6% and 85.1% (between-group difference, -3.5%; 95% confidence interval -8.64 to 1.58); modified intention-to-treat, 82.5% and 84.9% (-2.4%; -6.90 to 2.10); and clinically evaluable, 91.7% and 92.5% (-0.8%; -4.61 to 2.89). The clinical cure rate with ceftazidime-avibactam plus metronidazole for ceftazidime-resistant infections was comparable to that with meropenem (mMITT population, 83.0% and 85.9%, respectively) and similar to the regimen's own efficacy against ceftazidime-susceptible infections (82.0%). Adverse events were similar between groups.
Ceftazidime-avibactam plus metronidazole was noninferior to meropenem in the treatment of complicated intra-abdominal infections. Efficacy was similar against infections caused by ceftazidime-susceptible and ceftazidime-resistant pathogens. The safety profile of ceftazidime-avibactam plus metronidazole was consistent with that previously observed with ceftazidime alone.
NCT01499290 and NCT01500239.
新型非β-内酰胺类β-内酰胺酶抑制剂阿维巴坦与头孢他啶联合使用时，可作为碳青霉烯类药物的替代品，用于治疗多重耐药感染。在两项相同的随机、双盲3期研究（NCT01499290和NCT01500239）中，对1066例患有复杂性腹腔内感染的男性和女性患者，比较了头孢他啶-阿维巴坦联合甲硝唑与美罗培南的疗效和安全性。
主要终点为随机分组后28 - 35天的治愈访视时的临床治愈情况，通过在微生物学改良意向性治疗（mMITT）人群中（根据美国食品药品监督管理局指南）以及改良意向性治疗和临床可评估人群中（欧洲药品管理局指南），评估头孢他啶-阿维巴坦联合甲硝唑不劣于美罗培南。如果组间差异的95%置信区间下限大于预先设定的非劣效性界值-12.5%，则认为非劣效性成立。
在所有主要分析人群中，头孢他啶-阿维巴坦联合甲硝唑不劣于美罗培南。头孢他啶-阿维巴坦联合甲硝唑和美罗培南的临床治愈率分别如下：mMITT人群中，分别为81.6%和85.1%（组间差异为-3.5%；95%置信区间为-8.64至1.58）；改良意向性治疗人群中，分别为82.5%和84.9%（-2.4%；-6.90至2.10）；临床可评估人群中，分别为91.7%和92.5%（-0.8%；-4.61至2.89）。头孢他啶-阿维巴坦联合甲硝唑治疗对头孢他啶耐药感染的临床治愈率与美罗培南相当（mMITT人群中分别为83.0%和85.9%），且与该方案对头孢他啶敏感感染的疗效相似（82.0%）。两组间不良事件相似。
在治疗复杂性腹腔内感染方面，头孢他啶-阿维巴坦联合甲硝唑不劣于美罗培南。对头孢他啶敏感和耐药病原体引起的感染，疗效相似。头孢他啶-阿维巴坦联合甲硝唑的安全性与之前单独使用头孢他啶时观察到的一致。
NCT01499290和NCT01500239。
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