title: Efficacy of ceftolozane/tazobactam against urinary tract and intra-abdominal infections caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae: a pooled analysis of Phase 3 clinical trials.
abstract: The increase in infections caused by drug-resistant ESBL-producing Enterobacteriaceae (ESBL-ENT) is a global concern. The characteristics and outcomes of patients infected with ESBL-ENT were examined in a pooled analysis of Phase 3 clinical trials of ceftolozane/tazobactam in patients with complicated urinary tract infections (ASPECT-cUTI) and complicated intra-abdominal infections (ASPECT-cIAI).
  
  
  
  Trials were randomized and double blind. The ASPECT-cUTI regimen was 7 days of either intravenous ceftolozane/tazobactam (1.5 g) every 8 h or levofloxacin (750 mg) once daily. The ASPECT-cIAI regimen was 4-14 days of either intravenous ceftolozane/tazobactam (1.5 g) plus metronidazole (500 mg) or meropenem (1 g) every 8 h. Baseline cultures were obtained in both indications. Enterobacteriaceae were selected for ESBL characterization based on predefined criteria and were verified genotypically. Outcomes were assessed at the test-of-cure visit 5-9 days post-therapy in ASPECT-cUTI and 24-32 days post-randomization in ASPECT-cIAI among microbiologically evaluable (ME) patients.
  
  
  
  Of 2076 patients randomized, 1346 were included in the pooled ME population and 150 of 1346 (11.1%) had ESBL-ENT at baseline. At US FDA/EUCAST breakpoints of ≤2/≤1 mg/L, 81.8%/72.3% of ESBL-ENT (ESBL-Escherichia coli, 95%/88.1%; ESBL-Klebsiella pneumoniae, 56.7%/36.7%) were susceptible to ceftolozane/tazobactam versus 25.3%/24.1% susceptible to levofloxacin and 98.3%/98.3% susceptible to meropenem at CLSI/EUCAST breakpoints. Clinical cure rates for ME patients with ESBL-ENT were 97.4% (76/78) for ceftolozane/tazobactam [ESBL-E. coli, 98.0% (49 of 50); ESBL-K. pneumoniae, 94.4% (17 of 18)], 82.6% (38 of 46) for levofloxacin and 88.5% (23 of 26) for meropenem.
  
  
  
  Randomized trial data demonstrated high clinical cure rates with ceftolozane/tazobactam treatment of cIAI and cUTI caused by ESBL-ENT.
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA myra.popejoy@merck.com.
authors.forename: Myra W
authors.initials: MW
authors.lastname: Popejoy
authors.affiliation: Center for Clinical Research, University of Queensland, Brisbane, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Paterson
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cloutier
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Huntington
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Miller
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Caleb A
authors.initials: CA
authors.lastname: Bliss
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Judith N
authors.initials: JN
authors.lastname: Steenbergen
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Ellie
authors.initials: E
authors.lastname: Hershberger
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Obiamiwe
authors.initials: O
authors.lastname: Umeh
authors.affiliation: Detroit Medical Center and Department of Medicine, Wayne State University, Detroit, MI, USA.
authors.forename: Keith S
authors.initials: KS
authors.lastname: Kaye
mesh_terms: D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000892:Anti-Infective Agents, Urinary / Q000008:administration & dosage*; D002511:Cephalosporins / Q000008:administration & dosage*; D004311:Double-Blind Method; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D004927:Escherichia coli Infections / Q000188:drug therapy*; D005260:Female; D005838:Genotype; D006801:Humans; D059413:Intraabdominal Infections / Q000188:drug therapy*; D007710:Klebsiella Infections / Q000188:drug therapy*; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D064704:Levofloxacin / Q000008:administration & dosage; D008297:Male; D000077731:Meropenem; D008795:Metronidazole / Q000008:administration & dosage; D008875:Middle Aged; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000078142:Tazobactam; D013845:Thienamycins / Q000008:administration & dosage; D016896:Treatment Outcome; D014552:Urinary Tract Infections / Q000188:drug therapy*; D055815:Young Adult; D065093:beta-Lactamase Inhibitors / Q000008:administration & dosage*; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism
chemical_list: D000892:Anti-Infective Agents, Urinary; D002511:Cephalosporins; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; C000594038:ceftolozane, tazobactam drug combination; D008795:Metronidazole; D064704:Levofloxacin; D010397:Penicillanic Acid; D001618:beta-Lactamases; D000077731:Meropenem; D000078142:Tazobactam