Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program.
Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program.
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DOI：
10.1093/cid/ciw133
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发表时间：
2016-06-01
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影响因子：
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通讯作者：
Pachl J
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作者：
Mazuski JE;Gasink LB;Armstrong J;Broadhurst H;Stone GG;Rank D;Llorens L;Newell P;Pachl J
在这项随机3期试验中，头孢他啶-阿维巴坦联合甲硝唑在治疗复杂性腹腔内感染方面不劣于美罗培南，对头孢他啶耐药和头孢他啶敏感病原体具有相似的疗效，并且没有观察到新的安全问题。背景。 当与头孢他啶联合使用时，新型非β-内酰胺β-内酰胺酶抑制剂阿维巴坦提供了对抗多重耐药感染的碳青霉烯类替代品。通过 2 项相同、随机、双盲 3 期研究（NCT01499290 和 NCT01500239），对 1066 名患有复杂腹腔内感染的男性和女性，头孢他啶-阿维巴坦加甲硝唑与美罗培南的疗效和安全性进行了比较。方法。 主要终点是随机化后 28-35 天治愈试验访视时的临床治愈，通过微生物改良意向治疗 (mMITT) 人群（根据美国食品和药物管理局指南）以及改良意向治疗和临床可评估人群（欧洲药品管理局指南）中头孢他啶-阿维巴坦加甲硝唑相对于美罗培南的非劣效性进行评估。如果组间差异的 95% 置信区间下限大于预先指定的非劣效界值 -12.5%，则认为满足非劣效性。结果。 在所有初步分析人群中，头孢他啶-阿维巴坦加甲硝唑并不劣于美罗培南。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，81.6%和85.1%（组间差异，-3.5%；95%置信区间-8.64至1.58）；修改后的意向治疗，82.5%和84.9%（-2.4%；-6.90至2.10）；临床可评估，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头孢他啶耐药感染的临床治愈率与美罗培南相当（mMITT人群分别为83.0%和85.9%），并且与该方案本身对头孢他啶敏感感染的疗效（82.0%）相似。各组之间的不良事件相似。结论。 头孢他啶-阿维巴坦联合甲硝唑在治疗复杂性腹腔内感染方面不劣于美罗培南。对头孢他啶敏感和头孢他啶耐药病原体引起的感染的功效相似。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观察到的安全性一致。临床试验注册。 NCT01499290 和 NCT01500239。
In this randomized phase 3 trial, ceftazidime-avibactam plus metronidazole was noninferior to meropenem in treating complicated intra-abdominal infection, with similar efficacy against ceftazidime-resistant and ceftazidime-susceptible pathogens and no new safety concerns observed. Background. 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). Methods. 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%. Results. 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. Conclusions. 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. Clinical Trials Registration. NCT01499290 and NCT01500239.