Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI).

Abstract

BACKGROUND:

Treatment of complicated urinary-tract infections is challenging due to rising antimicrobial resistance. We assessed the efficacy and safety of ceftolozane-tazobactam, a novel antibacterial with Gram-negative activity, in the treatment of patients with complicated lower-urinary-tract infections or pyelonephritis.

METHODS:

ASPECT-cUTI was a randomised, double-blind, double-dummy, non-inferiority trial done in 209 centres in 25 countries. Between July, 2011, and September, 2013, hospital inpatients aged 18 years or older who had pyuria and a diagnosis of a complicated lower-urinary-tract infection or pyelonephritis were randomly assigned in a 1:1 ratio to receive intravenous 1·5 g ceftolozane-tazobactam every 8 h or intravenous high-dose (750 mg) levofloxacin once daily for 7 days. The randomisation schedule was computer generated in blocks of four and stratified by study site. The next allocation was obtained by the study site pharmacist via an interactive voice-response system. The primary endpoint was a composite of microbiological eradication and clinical cure 5-9 days after treatment in the microbiological modified intention-to-treat (MITT) population, with a non-inferiority margin of 10%. This study is registered with ClinicalTrials.gov, numbers NCT01345929 and NCT01345955.

FINDINGS:

Of 1083 patients enrolled, 800 (73·9%), of whom 656 (82·0%) had pyelonephritis, were included in the microbiological MITT population. Ceftolozane-tazobactam was non-inferior to levofloxacin for composite cure (306 [76·9%] of 398 vs 275 [68·4%] of 402, 95% CI 2·3-14·6) and, as the lower bound of the two-sided 95% CI around the treatment difference was positive and greater than zero, superiority was indicated. Adverse event profiles were similar in the two treatment groups and were mainly non-serious.

INTERPRETATION:

Treatment with ceftolozane-tazobactam led to better responses than high-dose levofloxacin in patients with complicated lower-urinary-tract infections or pyelonephritis.

FUNDING:

Cubist Pharmaceuticals.

• Authors: Florian M Wagenlehner, Obiamiwe Umeh, Judith Steenbergen, Guojun Yuan, Rabih O Darouiche
• Journal: Lancet (London, England) (Lancet) Vol. 385 Issue 9981 Pg. 1949-56 (May 16 2015) ISSN: 1474-547X [Electronic] England
• PMID: 25931244 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Infective Agents, Urinary
• Cephalosporins
• ceftolozane, tazobactam drug combination
• Levofloxacin
• Penicillanic Acid
• Tazobactam

Topics

• Adult
• Aged
• Anti-Infective Agents, Urinary (administration & dosage, adverse effects)
• Cephalosporins (administration & dosage, adverse effects)
• Double-Blind Method
• Drug Administration Schedule
• Female
• Gram-Negative Bacterial Infections (drug therapy)
• Gram-Positive Bacterial Infections (drug therapy)
• Humans
• Infusions, Intravenous
• Levofloxacin (administration & dosage, adverse effects)
• Male
• Middle Aged
• Penicillanic Acid (administration & dosage, adverse effects, analogs & derivatives)
• Pyelonephritis (drug therapy)
• Tazobactam
• Treatment Outcome
• Urinary Tract Infections (drug therapy)
• Young Adult