Journal Article

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)

Miller, Benjamin, Barie, Philip S., Yuan, Guojun, Eckmann, Christian, Collins, Sylva, Solomkin, Joseph, Popejoy, Myra, Steenbergen, Judith, Yoon, Minjung, Hershberger, Ellie, Friedland, Ian

2015

Overview

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.

• Publisher: Oxford University Press
• Subject: Adolescent / Adult / Aged / Aged, 80 and over / and Commentaries / Anti-Bacterial Agents - administration & dosage / Antibiotics / Antimicrobial agents / ARTICLES AND COMMENTARIES / Bacterial infections / Bacterial Infections - drug therapy / Bacterial Infections - microbiology / Cephalosporins - administration & dosage / Clinical trials / Confidence intervals / Double-Blind Method / Drug resistance / Drug Resistance, Multiple, Bacterial / Drug Therapy, Combination - methods / Female / Humans / Intraabdominal Infections - drug therapy / Intraabdominal Infections - microbiology / Male / Metronidazole - administration & dosage / Middle Aged / Pathogens / Penicillanic Acid - administration & dosage / Penicillanic Acid - analogs & derivatives / Prospective Studies / Treatment Outcome / Young Adult