Journal Article

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

Gasink, Leanne B., Stone, Greg G., Broadhurst, Helen, Pachl, Jan, Armstrong, Jon, Llorens, Lily, Rank, Douglas, Newell, Paul, Mazuski, John E.

2016

Overview

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.

• Publisher: Oxford University Press
• Subject: Adolescent / Adult / Aged / Aged, 80 and over / and Commentaries / Anti-Bacterial Agents - administration & dosage / Anti-Bacterial Agents - adverse effects / Anti-Bacterial Agents - therapeutic use / Antibiotics / ARTICLES AND COMMENTARIES / Azabicyclo Compounds - administration & dosage / Azabicyclo Compounds - adverse effects / Azabicyclo Compounds - therapeutic use / Ceftazidime - administration & dosage / Ceftazidime - adverse effects / Ceftazidime - therapeutic use / Clinical trials / Confidence intervals / Female / Humans / Intraabdominal Infections - drug therapy / Intraabdominal Infections - epidemiology / Male / Metronidazole - administration & dosage / Metronidazole - adverse effects / Metronidazole - therapeutic use / Middle Aged / Pathogens / Prescription drugs / Safety / Thienamycins - administration & dosage / Thienamycins - adverse effects / Thienamycins - therapeutic use / Treatment Outcome / Young Adult