Back to Search
Start Over
Pharmacodynamics of Ceftolozane plus Tazobactam Studied in an In Vitro Pharmacokinetic Model of Infection.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2015 Nov 09; Vol. 60 (1), pp. 515-21. Date of Electronic Publication: 2015 Nov 09 (Print Publication: 2016). - Publication Year :
- 2015
-
Abstract
- Ceftolozane plus tazobactam is an antipseudomonal cephalosporin combined with tazobactam, an established beta-lactamase inhibitor, and has in vitro potency against a range of clinically important β-lactamase-producing bacteria, including most extended-spectrum-β-lactamase (ESBL)-positive Enterobacteriaceae. The pharmacodynamics of β-lactam-β-lactamase inhibitor combinations presents a number of theoretical and practical challenges, including modeling different half-lives of the compounds. In this study, we studied the pharmacodynamics of ceftolozane plus tazobactam against Escherichia coli and Pseudomonas aeruginosa using an in vitro pharmacokinetic model of infection. Five strains of E. coli, including three clinical strains plus two CTX-M-15 (one high and one moderate) producers, and five strains of P. aeruginosa, including two with OprD overexpression and AmpC β-lactamases, were employed. Ceftolozane MICs (E. coli, 0.12 to 0.25 mg/liter, and P. aeruginosa, 0.38 to 8 mg/liter) were determined in the presence of 4 mg/liter tazobactam. Dose ranging of ceftolozane (percentage of time in which the free-drug concentration exceeds the MIC [fT>MIC], 0 to 100%) plus tazobactam (human pharmacokinetics) was simulated every 8 hours, with half-lives (t1/2) of 2.5 and 1 h, respectively. Ceftolozane and tazobactam concentrations were confirmed by high-performance liquid chromatography (HPLC). The ceftolozane-plus-tazobactam fT>MIC values at 24 h for a static effect and a 1-log and 2-log drop in initial inoculum for E. coli were 27.8% ± 5.6%, 33.0% ± 5.6%, and 39.6% ± 8.5%, respectively. CTX-M-15 production did not affect the 24-h fT>MIC for E. coli strains. The ceftolozane-plus-tazobactam fT>MIC values for a 24-h static effect and a 1-log and 2-log drop for P. aeruginosa were 24.9% ± 3.0%, 26.6% ± 3.9%, and 31.2% ± 3.6%. Despite a wide range of absolute MICs, the killing remained predictable as long as the MICs were normalized to the corresponding fT>MIC. Emergence of resistance on 4× MIC plates and 8× MIC plates occurred maximally at an fT>MIC of 10 to 30% and increased as time of exposure increased. The fT>MIC for a static effect for ceftolozane plus tazobactam is less than that observed with other cephalosporins against E. coli and P. aeruginosa and is more similar to the fT>MIC reported for carbapenems.<br /> (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Subjects :
- Anti-Bacterial Agents pharmacology
Bacterial Proteins genetics
Bacterial Proteins metabolism
Bioreactors
Cephalosporins pharmacology
Chromatography, High Pressure Liquid
Colony Count, Microbial
Computer Simulation
Escherichia coli enzymology
Escherichia coli genetics
Gene Expression
Half-Life
Infusion Pumps
Microbial Sensitivity Tests
Penicillanic Acid pharmacokinetics
Penicillanic Acid pharmacology
Porins genetics
Porins metabolism
Pseudomonas aeruginosa enzymology
Pseudomonas aeruginosa genetics
Tazobactam
beta-Lactamases genetics
beta-Lactamases metabolism
Anti-Bacterial Agents pharmacokinetics
Cephalosporins pharmacokinetics
Escherichia coli drug effects
Models, Statistical
Penicillanic Acid analogs & derivatives
Pseudomonas aeruginosa drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 60
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 26552975
- Full Text :
- https://doi.org/10.1128/AAC.00727-15