title: A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia.
abstract: Ceftazidime/avibactam comprises the broad-spectrum cephalosporin ceftazidime and the non-β-lactam β-lactamase inhibitor avibactam. This phase 3, randomised, double-blind study (NCT01726023) assessed the efficacy and safety of ceftazidime/avibactam plus metronidazole compared with meropenem in patients with complicated intra-abdominal infection (cIAI) in Asian countries. Subjects aged 18-90 years and hospitalised with cIAI requiring surgical intervention were randomised 1:1 to receive every 8 h either: ceftazidime/avibactam (2000/500 mg, 2-h infusion) followed by metronidazole (500 mg, 60-min infusion); or meropenem (1000 mg, 30-min infusion). Non-inferiority of ceftazidime/avibactam plus metronidazole to meropenem was concluded if the lower limit of the 95% confidence interval (CI) for the between-group difference in clinical cure rate was greater than -12.5% at the test-of-cure (TOC) visit (28-35 days after randomisation) in the clinically evaluable (CE) population. Safety was also evaluated. Of 441 subjects randomised, 432 received at least one dose of study medication (ceftazidime/avibactam plus metronidazole, n = 215; meropenem, n = 217). In the CE population at the TOC visit, non-inferiority of ceftazidime/avibactam plus metronidazole to meropenem was demonstrated, with clinical cure reported for 93.8% (166/177) and 94.0% (173/184) of subjects, respectively (between-group difference, -0.2, 95% CI -5.53 to 4.97). The clinical cure rate with ceftazidime/avibactam plus metronidazole was comparable in subjects with ceftazidime-non-susceptible and ceftazidime-susceptible isolates (95.7% vs. 92.1%, respectively). Adverse events were similar between the study groups. Ceftazidime/avibactam plus metronidazole was non-inferior to meropenem in the treatment of cIAIs in Asian populations and was effective against ceftazidime-non-susceptible pathogens. No new safety concerns were identified.
authors.affiliation: Zhongshan Hospital affiliated to Fudan University, Shanghai, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Qin
authors.affiliation: Viet-Duc Hospital, Hanoi, Viet Nam.
authors.forename: Binh Giang
authors.initials: BG
authors.lastname: Tran
authors.affiliation: Korea University Anam Hospital, Seoul, Republic of Korea.
authors.forename: Min Ja
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Fuzhou General Hospital of Nanjing Military Region, Fuzhou, China.
authors.forename: Lie
authors.initials: L
authors.lastname: Wang
authors.affiliation: Gia Dinh People Hospital, Ho Chi Minh, Viet Nam.
authors.forename: Dung Anh
authors.initials: DA
authors.lastname: Nguyen
authors.affiliation: Affiliated Hospital of Guilin Medical University, Guangxi, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Global Medicines Development, AstraZeneca, 199 Liangjing Road, Zhangjiang Hi-tech Park, Shanghai 201203, China. Electronic address: jie.song2@astrazeneca.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Song
authors.affiliation: Statistical Services Unit, University of Sheffield, Sheffield, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Laud
authors.affiliation: AstraZeneca, Waltham, MA, USA.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Stone
authors.affiliation: AstraZeneca, Wilmington, DE, USA.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Chow
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001208:Asia; D053961:Azabicyclo Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D002442:Ceftazidime / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006760:Hospitalization; D006801:Humans; D059413:Intraabdominal Infections / Q000188:drug therapy* / Q000382:microbiology; D008297:Male; D000077731:Meropenem; D008795:Metronidazole / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D013845:Thienamycins / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult; D065093:beta-Lactamase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D004338:Drug Combinations; D013845:Thienamycins; C000595613:avibactam, ceftazidime drug combination; D065093:beta-Lactamase Inhibitors; D008795:Metronidazole; D002442:Ceftazidime; D000077731:Meropenem
keywords: Asia; Ceftazidime/avibactam; Complicated intra-abdominal infection; Efficacy; Phase 3; Safety