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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).
Clin Infect Dis. 2015 May 15; 60(10):1462-71.CI

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+Show Affiliations

Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.Cubist Pharmaceuticals, Lexington, Massachusetts.Cubist Pharmaceuticals, Lexington, Massachusetts.Cubist Pharmaceuticals, Lexington, Massachusetts.Cubist Pharmaceuticals, Lexington, Massachusetts.Cubist Pharmaceuticals, Lexington, Massachusetts.Cubist Pharmaceuticals, Lexington, Massachusetts.Cubist Pharmaceuticals, Lexington, Massachusetts.Cubist Pharmaceuticals, Lexington, Massachusetts.Departments of Surgery and Medicine, Weill Cornell Medical College, New York, New York.Department of General, Visceral and Thoracic Surgery, Academic Hospital of Medical University Hannover, Peine, Germany.

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25670823

Citation

Solomkin, Joseph, et al. "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)." Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, vol. 60, no. 10, 2015, pp. 1462-71.
Solomkin J, Hershberger E, Miller B, et al. 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). Clin Infect Dis. 2015;60(10):1462-71.
Solomkin, J., Hershberger, E., Miller, B., Popejoy, M., Friedland, I., Steenbergen, J., Yoon, M., Collins, S., Yuan, G., Barie, P. S., & Eckmann, C. (2015). 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). Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, 60(10), 1462-71. https://doi.org/10.1093/cid/civ097
Solomkin J, et al. 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). Clin Infect Dis. 2015 May 15;60(10):1462-71. PubMed PMID: 25670823.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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). AU - Solomkin,Joseph, AU - Hershberger,Ellie, AU - Miller,Benjamin, AU - Popejoy,Myra, AU - Friedland,Ian, AU - Steenbergen,Judith, AU - Yoon,Minjung, AU - Collins,Sylva, AU - Yuan,Guojun, AU - Barie,Philip S, AU - Eckmann,Christian, Y1 - 2015/02/10/ PY - 2014/10/02/received PY - 2015/02/01/accepted PY - 2015/2/12/entrez PY - 2015/2/12/pubmed PY - 2016/1/21/medline KW - Enterobacteriaceae KW - ceftolozane/tazobactam KW - complicated intra-abdominal infection KW - gram-negative bacteria KW - multidrug resistance SP - 1462 EP - 71 JF - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America JO - Clin Infect Dis VL - 60 IS - 10 N2 - 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. SN - 1537-6591 UR - https://www.unboundmedicine.com/medline/citation/25670823/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__ L2 - https://academic.oup.com/cid/article-lookup/doi/10.1093/cid/civ097 DB - PRIME DP - Unbound Medicine ER -