title: Does moderate renal impairment affect clinical outcomes in complicated intra-abdominal and complicated urinary tract infections? Analysis of two randomized controlled trials with ceftolozane/tazobactam.
abstract: For reasons not well understood, antibacterials can yield lower cure rates in renally impaired patients. We explored this subject for the novel antibacterial ceftolozane/tazobactam.
  
  
  
  ASPECT-complicated intra-abdominal infections (cIAIs) and ASPECT-complicated urinary tract infections (cUTIs) were randomized, double-blinded clinical trials. Analyses in moderate [creatinine clearance (CL CR ) 30-50 mL/min] and mild/no (CL CR  > 50 mL/min) renal impairment (RI) patients were pre-specified as exploratory endpoints in the statistical analysis plans. We also explored variables potentially impacting outcomes in these subgroups. Clinicaltrials.gov NCT01445665/NCT01445678 and NCT01345929/NCT01345955.
  
  
  
  At baseline, 4.5% (36/806) of cIAI patients and 7.3% (58/795) of cUTI patients had moderate RI. Moderate RI patients were older, had more comorbid conditions and had higher APACHE-II scores. In the cIAI microbiological intent-to-treat population, response rates were 48% and 69% in moderate RI patients receiving ceftolozane/tazobactam and meropenem, respectively; among moderate RI cIAI patients considered treatment failures, indeterminate responses were more frequent with ceftolozane/tazobactam (39%; 9/23) than meropenem (8%; 1/13). In the cUTI microbiological modified intent-to-treat population, response rates were 81% and 78% in moderate RI patients receiving ceftolozane/tazobactam and levofloxacin, respectively. In both studies, response rates in moderate RI patients were similar between treatment arms in microbiologically evaluable populations, which excluded indeterminate responses due to missing data/protocol deviations (cIAI: 72.7% ceftolozane/tazobactam versus 71.4% meropenem; cUTI: 87% ceftolozane/tazobactam versus 80% levofloxacin).
  
  
  
  Regardless of treatment, clinical cure rates in cIAI and cUTI were lower in moderate versus mild/no RI patients. In moderate RI cIAI patients, numerical differences in response rates between treatments were attributable to imbalances in the numerical patients deemed indeterminate.
authors.affiliation: Merck Research Laboratories, Merck & Co, Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Ravina
authors.initials: R
authors.lastname: Kullar
authors.affiliation: Department of Urology, Pediatric Urology and Andrology, Justus Liebig University Gießen, Rudolf-Buchheim Str. 7, 35392 Gießen, Germany.
authors.forename: Florian M
authors.initials: FM
authors.lastname: Wagenlehner
authors.affiliation: Merck Research Laboratories, Merck & Co, Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Myra W
authors.initials: MW
authors.lastname: Popejoy
authors.affiliation: Merck Research Laboratories, Merck & Co, Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Long
authors.affiliation: Merck Research Laboratories, Merck & Co, Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Yu
authors.affiliation: David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Ave, Los Angeles, CA 90095, USA.|R. M. Alden Research Laboratory, 6133 Bristol Pkway #175, Santa Monica, CA 90230, USA.
authors.forename: Ellie J C
authors.initials: EJ
authors.lastname: Goldstein
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002511:Cephalosporins / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D059413:Intraabdominal Infections / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051437:Renal Insufficiency / Q000150:complications*; D000078142:Tazobactam; D016896:Treatment Outcome; D014552:Urinary Tract Infections / Q000150:complications / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C519491:ceftolozane; D010397:Penicillanic Acid; D000078142:Tazobactam