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

Abstract

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.

Keywords: ceftazidime-avibactam plus metronidazole; complicated intra-abdominal infection; meropenem; noninferiority; phase 3.

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Patient flow. The detailed reasons for exclusion from each population are summarized in Supplementary Table 1 of the Supplementary appendix. Patients who discontinued the study include those stopped study treatment before receiving the minimum 5 days of treatment for any reason or whose treatment was stopped at any time and for any reason before the complicated intra-abdominal infection was considered resolved or cured, with a nonstudy antibiotic required to complete treatment. Abbreviations: CE, clinically evaluable; MITT, modified intention-to-treat; mMITT, microbiologically MITT.

Figure 2.

Difference in clinical cure rates at test-of-cure (TOC) visit by renal function. Dark gray line represents −12.5% noninferiority margin required by the European Medicines Agency for the overall primary populations. Subgroups were not required to meet this noninferiority margin. Confidence intervals (CIs) were calculated using Miettinen and Nurminen method without adjustments. Renal function was based on CrCl reported by the site using the Cockcroft-Gault method [16] and based on local laboratory data. Patients with a baseline CrCl