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

Lancet. 2015 May 16;385(9981):1949-56. doi: 10.1016/S0140-6736(14)62220-0. Epub 2015 Apr 27.

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.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anti-Infective Agents, Urinary / administration & dosage*
  • Anti-Infective Agents, Urinary / adverse effects
  • Cephalosporins / administration & dosage*
  • Cephalosporins / 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*
  • Levofloxacin / adverse effects
  • Male
  • Middle Aged
  • Penicillanic Acid / administration & dosage
  • Penicillanic Acid / adverse effects
  • Penicillanic Acid / analogs & derivatives*
  • Pyelonephritis / drug therapy
  • Tazobactam
  • Treatment Outcome
  • Urinary Tract Infections / drug therapy*
  • Young Adult

Substances

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

Associated data

  • ClinicalTrials.gov/NCT01345929
  • ClinicalTrials.gov/NCT01345955