title: Combinatorial Pharmacodynamics of Ceftolozane-Tazobactam against Genotypically Defined β-Lactamase-Producing Escherichia coli: Insights into the Pharmacokinetics/Pharmacodynamics of β-Lactam-β-Lactamase Inhibitor Combinations.
abstract: Despite a dearth of new agents currently being developed to combat multidrug-resistant Gram-negative pathogens, the combination of ceftolozane and tazobactam was recently approved by the Food and Drug Administration to treat complicated intra-abdominal and urinary tract infections. To characterize the activity of the combination product, time-kill studies were conducted against 4 strains ofEscherichia colithat differed in the type of β-lactamase they expressed. The four investigational strains included 2805 (no β-lactamase), 2890 (AmpC β-lactamase), 2842 (CMY-10 β-lactamase), and 2807 (CTX-M-15 β-lactamase), with MICs to ceftolozane of 0.25, 4, 8, and >128 mg/liter with no tazobactam, and MICs of 0.25, 1, 4, and 8 mg/liter with 4 mg/liter tazobactam, respectively. All four strains were exposed to a 6 by 5 array of ceftolozane (0, 1, 4, 16, 64, and 256 mg/liter) and tazobactam (0, 1, 4, 16, and 64 mg/liter) over 48 h using starting inocula of 10(6)and 10(8)CFU/ml. While ceftolozane-tazobactam achieved bactericidal activity against all 4 strains, the concentrations of ceftolozane and tazobactam required for a ≥3-log reduction varied between the two starting inocula and the 4 strains. At both inocula, the Hill plots (R(2)> 0.882) of ceftolozane revealed significantly higher 50% effective concentrations (EC50s) at tazobactam concentrations of ≤4 mg/liter than those at concentrations of ≥16 mg/liter (P< 0.01). Moreover, the EC50s at 10(8)CFU/ml were 2.81 to 66.5 times greater than the EC50s at 10(6)CFU/ml (median, 10.7-fold increase;P= 0.002). These promising results indicate that ceftolozane-tazobactam achieves bactericidal activity against a wide range of β-lactamase-producingE. colistrains.
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, Buffalo, New York, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Soon
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, Buffalo, New York, USA School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Lenhard
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, Buffalo, New York, USA School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
authors.forename: Zackery P
authors.initials: ZP
authors.lastname: Bulman
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, Buffalo, New York, USA School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Holden
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, Buffalo, New York, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Kelchlin
authors.affiliation: Merck & Co., Lexington, Massachusetts, USA.
authors.forename: Judith N
authors.initials: JN
authors.lastname: Steenbergen
authors.affiliation: Merck & Co., Lexington, Massachusetts, USA.
authors.forename: Lawrence V
authors.initials: LV
authors.lastname: Friedrich
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, Buffalo, New York, USA School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, Buffalo, New York, USA School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA btsuji@buffalo.edu.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Tsuji
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D015870:Gene Expression; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000078142:Tazobactam; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002511:Cephalosporins; C000594038:ceftolozane, tazobactam drug combination; D010397:Penicillanic Acid; C473109:beta-lactamase CTX-M-15; C048795:AmpC beta-lactamases; C491822:CMY-10 beta-lactamase; D001618:beta-Lactamases; D000078142:Tazobactam