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.

CLINICAL TRIALS REGISTRATION:

NCT01445665 and NCT01445678.

• Authors: Joseph Solomkin, Ellie Hershberger, Benjamin Miller, Myra Popejoy, Ian Friedland, Judith Steenbergen, Minjung Yoon, Sylva Collins, Guojun Yuan, Philip S Barie, Christian Eckmann
• Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (Clin Infect Dis) Vol. 60 Issue 10 Pg. 1462-71 (May 15 2015) ISSN: 1537-6591 [Electronic] United States
• PMID: 25670823 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Chemical References

• Anti-Bacterial Agents
• Cephalosporins
• ceftolozane, tazobactam drug combination
• Metronidazole
• Penicillanic Acid
• Tazobactam

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Anti-Bacterial Agents (administration & dosage)
• Bacterial Infections (drug therapy, microbiology)
• Cephalosporins (administration & dosage)
• Double-Blind Method
• Drug Resistance, Multiple, Bacterial
• Drug Therapy, Combination (methods)
• Female
• Humans
• Intraabdominal Infections (drug therapy, microbiology)
• Male
• Metronidazole (administration & dosage)
• Middle Aged
• Penicillanic Acid (administration & dosage, analogs & derivatives)
• Prospective Studies
• Tazobactam
• Treatment Outcome
• Young Adult