title: Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI).
abstract: BACKGROUND
  Increasing antimicrobial resistance among pathogens causing complicated intra-abdominal infections (cIAIs) supports the development of new antimicrobials. Ceftolozane/tazobactam, a novel antimicrobial therapy, is active against multidrug-resistant Pseudomonas aeruginosa and most extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae.
  
  
  METHODS
  ASPECT-cIAI (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-abdominal Infections) was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either ceftolozane/tazobactam (1.5 g) plus metronidazole (500 mg) every 8 hours or meropenem (1 g) every 8 hours intravenously for 4-14 days. The prospectively defined objectives were to demonstrate statistical noninferiority in clinical cure rates at the test-of-cure visit (24-32 days from start of therapy) in the microbiological intent-to-treat (primary) and microbiologically evaluable (secondary) populations using a noninferiority margin of 10%. Microbiological outcomes and safety were also evaluated.
  
  
  RESULTS
  Ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in the primary (83.0% [323/389] vs 87.3% [364/417]; weighted difference, -4.2%; 95% confidence interval [CI], -8.91 to .54) and secondary (94.2% [259/275] vs 94.7% [304/321]; weighted difference, -1.0%; 95% CI, -4.52 to 2.59) endpoints, meeting the prespecified noninferiority margin. In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 95.8% (23/24) and 88.5% (23/26) in the ceftolozane/tazobactam plus metronidazole and meropenem groups, respectively, and 100% (13/13) and 72.7% (8/11) in patients with CTX-M-14/15 ESBLs. The frequency of adverse events (AEs) was similar in both treatment groups (44.0% vs 42.7%); the most common AEs in either group were nausea and diarrhea.
  
  
  CONCLUSIONS
  Treatment with ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in adult patients with cIAI, including infections caused by multidrug-resistant pathogens.
  
  
  BACKGROUND
  NCT01445665 and NCT01445678.
authors: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors: Joseph
authors: J
authors: Solomkin
authors: Cubist Pharmaceuticals, Lexington, Massachusetts.
authors: Ellie
authors: E
authors: Hershberger
authors: Cubist Pharmaceuticals, Lexington, Massachusetts.
authors: Benjamin
authors: B
authors: Miller
authors: Cubist Pharmaceuticals, Lexington, Massachusetts.
authors: Myra
authors: M
authors: Popejoy
authors: Cubist Pharmaceuticals, Lexington, Massachusetts.
authors: Ian
authors: I
authors: Friedland
authors: Cubist Pharmaceuticals, Lexington, Massachusetts.
authors: Judith
authors: J
authors: Steenbergen
authors: Cubist Pharmaceuticals, Lexington, Massachusetts.
authors: Minjung
authors: M
authors: Yoon
authors: Cubist Pharmaceuticals, Lexington, Massachusetts.
authors: Sylva
authors: S
authors: Collins
authors: Cubist Pharmaceuticals, Lexington, Massachusetts.
authors: Guojun
authors: G
authors: Yuan
authors: Departments of Surgery and Medicine, Weill Cornell Medical College, New York, New York.
authors: Philip S
authors: PS
authors: Barie
authors: Department of General, Visceral and Thoracic Surgery, Academic Hospital of Medical University Hannover, Peine, Germany.
authors: Christian
authors: C
authors: Eckmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D001424:Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D002511:Cephalosporins / Q000008:administration & dosage*; D004311:Double-Blind Method; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D059413:Intraabdominal Infections / Q000188:drug therapy* / Q000382:microbiology; D008297:Male; D008795:Metronidazole / Q000008:administration & dosage*; D008875:Middle Aged; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011446:Prospective Studies; D000078142:Tazobactam; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C000594038:ceftolozane, tazobactam drug combination; D008795:Metronidazole; D010397:Penicillanic Acid; D000078142:Tazobactam
keywords: Enterobacteriaceae; ceftolozane/tazobactam; complicated intra-abdominal infection; gram-negative bacteria; multidrug resistance