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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.
Clin Infect Dis. 2016 06 01; 62(11):1380-1389.CI

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.

Authors+Show Affiliations

Washington University School of Medicine, St Louis, Missouri.AstraZeneca, Wilmington, Delaware.AstraZeneca, Alderley Park, United Kingdom.AstraZeneca, Alderley Park, United Kingdom.AstraZeneca, Waltham, Massachusetts.Actavis,Oakland, California.Actavis,Oakland, California.AstraZeneca, Alderley Park, United Kingdom.The Charles University, Prague, Czech Republic.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

26962078

Citation

Mazuski, John E., et al. "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." Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, vol. 62, no. 11, 2016, pp. 1380-1389.
Mazuski JE, Gasink LB, Armstrong J, et al. 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. Clin Infect Dis. 2016;62(11):1380-1389.
Mazuski, J. E., Gasink, L. B., Armstrong, J., Broadhurst, H., Stone, G. G., Rank, D., Llorens, L., Newell, P., & Pachl, J. (2016). 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. Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, 62(11), 1380-1389. https://doi.org/10.1093/cid/ciw133
Mazuski JE, et al. 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. Clin Infect Dis. 2016 06 1;62(11):1380-1389. PubMed PMID: 26962078.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Mazuski,John E, AU - Gasink,Leanne B, AU - Armstrong,Jon, AU - Broadhurst,Helen, AU - Stone,Greg G, AU - Rank,Douglas, AU - Llorens,Lily, AU - Newell,Paul, AU - Pachl,Jan, Y1 - 2016/03/08/ PY - 2015/11/26/received PY - 2016/02/26/accepted PY - 2016/3/11/entrez PY - 2016/3/11/pubmed PY - 2017/10/28/medline KW - ceftazidime-avibactam plus metronidazole KW - complicated intra-abdominal infection KW - meropenem KW - noninferiority KW - phase 3 SP - 1380 EP - 1389 JF - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America JO - Clin Infect Dis VL - 62 IS - 11 N2 - 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. SN - 1537-6591 UR - https://www.unboundmedicine.com/medline/citation/26962078/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_ L2 - https://academic.oup.com/cid/article-lookup/doi/10.1093/cid/ciw133 DB - PRIME DP - Unbound Medicine ER -