Affiliation:
1. Albany College of Pharmacy and Health Sciences, Albany, New York, USA
2. Institute for Clinical Pharmacodynamics, Latham, New York, USA
3. JMI Laboratories, North Liberty, Iowa, USA
4. Merck & Co, Inc., Kenilworth, New Jersey, USA
5. University of Oxford, Oxford, United Kingdom
Abstract
ABSTRACT
We have previously demonstrated the pharmacokinetic-pharmacodynamic (PK-PD) index best associated with the efficacy of tazobactam when used in combination with ceftolozane to be the percentage of the dosing interval during which tazobactam concentrations remained above a threshold value (%time>threshold). Using an
in vitro
infection model and the same isogenic CTX-M-15-producing
Escherichia coli
triplet set genetically engineered to transcribe different levels of
bla
CTX-M-15
, herein we describe dose fractionation studies designed to evaluate the PK-PD index associated with tazobactam efficacy, when given in combination with piperacillin, and the impact of the presence of a different β-lactam agent, or different
bla
CTX-M-15
transcription levels, on the magnitude of the tazobactam PK-PD index necessary for efficacy. The recombinant strains demonstrated piperacillin MIC values of 128, >256, and >256 μg/ml for the low-, moderate-, and high-level CTX-M-15-producing
E. coli
strains, respectively. The MIC value for piperacillin in the presence of 4 μg/ml of tazobactam was 2 μg/ml for all three strains. The PK-PD index associated with tazobactam efficacy was confirmed to be %time>threshold, regardless of β-lactamase transcription (
r
2
= 0.839). The tazobactam concentration thresholds, however, changed with the CTX-M-15 transcription level and were 0.25, 0.5, and 2 μg/ml for the low-, moderate-, and high-level CTX-M-15-producing strains, respectively (
r
2
= 0.921, 0.773, and 0.875, respectively). The %time>threshold values for tazobactam necessary for net bacterial stasis and a 1- and 2-log
10
-unit CFU/ml decrease from baseline at 24 h were 44.9, 62.9, and 84.9%, respectively. In addition to verifying our previous study results, these results also demonstrated that the magnitude of bacterial-cell killing associated with a β-lactam–β-lactamase inhibitor combination is dependent on the amount of β-lactamase produced. These data provide important information for the development of β-lactam–β-lactamase inhibitor combination agents.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology