title: In vitro pharmacodynamic evaluation of ceftolozane/tazobactam against β-lactamase-producing Escherichia coli in a hollow-fibre infection model.
abstract: The proliferation of multidrug-resistant Gram-negative pathogens has been exacerbated by a lack of novel agents in current development by pharmaceutical companies. Ceftolozane/tazobactam was recently approved by the FDA for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. In the present study, the activity of ceftolozane/tazobactam against four isogenic Escherichia coli strains was investigated in a hollow-fibre infection model simulating various clinical dosing regimens. The four investigational E. coli strains included #2805 (no β-lactamase), #2890 (AmpC β-lactamase), #2842 (CMY-10 β-lactamase) and #2807 (CTX-M-15 β-lactamase). Each strain was exposed to regimens simulating 1 g ceftolozane, 2 g ceftolozane, 1 g ceftolozane/0.5 g tazobactam, and 2 g ceftolozane/1 g tazobactam utilising a starting inoculum of ca. 106CFU/mL. Whereas 1 g of ceftolozane eradicated strains #2805 and #2842 without subsequent regrowth, 1 g ceftolozane/0.5 g tazobactam was required to eradicate strain #2890. For strain #2890, ceftolozane monotherapy led to bacterial growth on plates impregnated with 20 mg/L ceftolozane by 24 h, whilst combination treatment with tazobactam completely suppressed the development of ceftolozane resistance. In contrast, none of the regimens, including 2 g ceftolozane/1 g tazobactam, were able to entirely suppress bacterial growth in strain #2807, with bacterial counts exceeding 108CFU/mL by 48 h and ceftolozane-resistant populations being amplified after 24 h. Thus, the combination of ceftolozane and tazobactam achieved bactericidal activity followed by sustained killing over 10 days for three of four isogenic E. coli strains. Ceftolozane/tazobactam is a promising new agent to counter multidrug-resistant Gram-negative bacteria.
authors.affiliation: Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, NY, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Soon
authors.affiliation: Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, NY, USA; School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA; California Northstate University College of Pharmacy, Elk Grove, CA, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Lenhard
authors.affiliation: Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, NY, USA; School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
authors.forename: Zackery P
authors.initials: ZP
authors.lastname: Bulman
authors.affiliation: Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, NY, USA; School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Holden
authors.affiliation: Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, NY, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Kelchlin
authors.affiliation: Merck & Co., Lexington, MA, USA.
authors.forename: Judith N
authors.initials: JN
authors.lastname: Steenbergen
authors.affiliation: Merck & Co., Lexington, MA, USA.
authors.forename: Lawrence V
authors.initials: LV
authors.lastname: Friedrich
authors.affiliation: Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, NY, USA; School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.affiliation: Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, NY, USA; School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA. Electronic address: btsuji@buffalo.edu.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Tsuji
mesh_terms: D000892:Anti-Infective Agents, Urinary / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D002511:Cephalosporins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D006801:Humans; D050296:Microbial Viability / Q000187:drug effects; D044085:Microfluidics / Q000379:methods*; D008954:Models, Biological; D008962:Models, Theoretical; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000078142:Tazobactam; D065093:beta-Lactamase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000892:Anti-Infective Agents, Urinary; D002511:Cephalosporins; D065093:beta-Lactamase Inhibitors; C000594038:ceftolozane, tazobactam drug combination; D010397:Penicillanic Acid; D001618:beta-Lactamases; D000078142:Tazobactam
keywords: AmpC; CMY-10; CTX-M-15; Ceftolozane/tazobactam; Escherichia coli; β-Lactamase