Affiliation:
1. Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol, and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, United Kingdom
Abstract
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 (
t
1/2
) 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
f
T
>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.
Funder
Cubist Pharmaceuticals, Inc.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
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