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


RESULTS
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.


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


BACKGROUND
Cubist Pharmaceuticals.
Clinic for Urology, Paediatric Urology and Andrology, Justus-Liebig University, Giessen, Germany. Electronic address: florian.wagenlehner@chiru.med.uni-giessen.de.
Florian M
FM
Wagenlehner
Cubist Pharmaceuticals, Lexington, MA, USA.
Obiamiwe
O
Umeh
Cubist Pharmaceuticals, Lexington, MA, USA.
Judith
J
Steenbergen
Cubist Pharmaceuticals, Lexington, MA, USA.
Guojun
G
Yuan
Michael E DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, USA.
Rabih O
RO
Darouiche
D000328:Adult; D000368:Aged; D000892:Anti-Infective Agents, Urinary / Q000008:administration & dosage* / Q000009:adverse effects; D002511:Cephalosporins / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D007262:Infusions, Intravenous; D064704:Levofloxacin / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D011704:Pyelonephritis / Q000188:drug therapy; D000078142:Tazobactam; D016896:Treatment Outcome; D014552:Urinary Tract Infections / Q000188:drug therapy*; D055815:Young Adult
D000892:Anti-Infective Agents, Urinary; D002511:Cephalosporins; C000594038:ceftolozane, tazobactam drug combination; D064704:Levofloxacin; D010397:Penicillanic Acid; D000078142:Tazobactam