title: 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: 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.
authors.affiliation: Washington University School of Medicine, St Louis, Missouri.
authors.forename: John E
authors.initials: JE
authors.lastname: Mazuski
authors.affiliation: AstraZeneca, Wilmington, Delaware.
authors.forename: Leanne B
authors.initials: LB
authors.lastname: Gasink
authors.affiliation: AstraZeneca, Alderley Park, United Kingdom.
authors.forename: Jon
authors.initials: J
authors.lastname: Armstrong
authors.affiliation: AstraZeneca, Alderley Park, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Broadhurst
authors.affiliation: AstraZeneca, Waltham, Massachusetts.
authors.forename: Greg G
authors.initials: GG
authors.lastname: Stone
authors.affiliation: Actavis,Oakland, California.
authors.forename: Douglas
authors.initials: D
authors.lastname: Rank
authors.affiliation: Actavis,Oakland, California.
authors.forename: Lily
authors.initials: L
authors.lastname: Llorens
authors.affiliation: AstraZeneca, Alderley Park, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Newell
authors.affiliation: The Charles University, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Pachl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D002442:Ceftazidime / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004338:Drug Combinations; D005260:Female; D006801:Humans; D059413:Intraabdominal Infections / Q000188:drug therapy* / Q000453:epidemiology; D008297:Male; D000077731:Meropenem; D008795:Metronidazole / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008875:Middle Aged; D013845:Thienamycins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D004338:Drug Combinations; D013845:Thienamycins; C000595613:avibactam, ceftazidime drug combination; D008795:Metronidazole; D002442:Ceftazidime; D000077731:Meropenem
keywords: ceftazidime-avibactam plus metronidazole; complicated intra-abdominal infection; meropenem; noninferiority; phase 3