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Antimicrob Agents Chemother. 2016 Mar 25;60(4):1967-73. doi: 10.1128/AAC.02635-15. Print 2016 Apr.

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.

Author information

1
Laboratory for Antimicrobial Pharmacodynamics, New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, Buffalo, New York, USA.
2
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.
3
Merck & Co., Lexington, Massachusetts, USA.
4
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.

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.

PMID:
26729494
PMCID:
PMC4808171
DOI:
10.1128/AAC.02635-15
[Indexed for MEDLINE]
Free PMC Article

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