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

J Antimicrob Chemother. 2017 Jan;72(1):268-272. doi: 10.1093/jac/dkw374. Epub 2016 Oct 5.

Abstract

Objectives: 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).

Methods: 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.

Results: 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.

Conclusions: Randomized trial data demonstrated high clinical cure rates with ceftolozane/tazobactam treatment of cIAI and cUTI caused by ESBL-ENT.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial

MeSH terms

  • Administration, Intravenous
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anti-Infective Agents, Urinary / administration & dosage*
  • Cephalosporins / administration & dosage*
  • Double-Blind Method
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology
  • Escherichia coli / genetics
  • Escherichia coli Infections / drug therapy*
  • Female
  • Genotype
  • Humans
  • Intraabdominal Infections / drug therapy*
  • Klebsiella Infections / drug therapy*
  • Klebsiella pneumoniae / drug effects
  • Klebsiella pneumoniae / enzymology
  • Klebsiella pneumoniae / genetics
  • Levofloxacin / administration & dosage
  • Male
  • Meropenem
  • Metronidazole / administration & dosage
  • Middle Aged
  • Penicillanic Acid / administration & dosage
  • Penicillanic Acid / analogs & derivatives*
  • Tazobactam
  • Thienamycins / administration & dosage
  • Treatment Outcome
  • Urinary Tract Infections / drug therapy*
  • Young Adult
  • beta-Lactamase Inhibitors / administration & dosage*
  • beta-Lactamases / genetics
  • beta-Lactamases / metabolism

Substances

  • Anti-Infective Agents, Urinary
  • Cephalosporins
  • Thienamycins
  • beta-Lactamase Inhibitors
  • ceftolozane, tazobactam drug combination
  • Metronidazole
  • Levofloxacin
  • Penicillanic Acid
  • beta-Lactamases
  • Meropenem
  • Tazobactam