Pharmacological Basis of β-Lactamase Inhibitor Therapeutics: Tazobactam in Combination with Ceftolozane
Authors: VanScoy Brian , Mendes Rodrigo E. , McCauley Jennifer , Bhavnani Sujata M. , Bulik Catharine C. , Okusanya Olanrewaju O. , Forrest Alan , Jones Ronald N. , Friedrich Lawrence V. , Steenbergen Judith N. , Ambrose Paul G. 
Published: September 2013

ABSTRACT

We recently investigated the pharmacokinetics-pharmacodynamics (PK-PD) of tazobactam in combination with ceftolozane against an isogenic CTX-M-15-producing
Escherichia coli
triplet set, genetically engineered to transcribe different levels of
bla
CTX-M-15
. The percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold) was identified as the PK-PD exposure measure that was most closely associated with efficacy. Moreover, the tazobactam concentration was dependent upon the enzyme transcription level. Given that the aforementioned strains were genetically engineered to transcribe a single β-lactamase enzyme and that clinical isolates typically produce multiple β-lactamase enzymes with various transcription levels, it is likely that the tazobactam threshold concentration is isolate/enzyme dependent. Our first objective was to characterize the relationship between the tazobactam %Time>threshold in combination with ceftolozane and efficacy using clinical isolates in an
in vitro
PK-PD infection model. Our second objective was to identify a translational relationship that would allow for the comodeling across clinical isolates. The initial challenge panel included four well-characterized β-lactamase-producing
E. coli
strains with variable enzyme expression and other resistance determinants. As evidenced by
r
2
values of ranging from 0.90 to 0.99 for each clinical isolate, the observed data were well described by fitted functions describing the relationship between the tazobactam %Time>threshold and change in log
10
CFU from baseline; however, the data from the four isolates did not comodel well. The threshold concentration identified for each isolate ranged from 0.5 to 4 mg/liter. We identified an enabling translational relationship for the tazobactam threshold that allowed comodeling of all four clinical isolates, which was the product of the individual isolate's ceftolozane-tazobactam MIC value and 0.5. As evidenced by an
r
2
value of 0.90, the transformed data were well described by a fitted function describing the relationship between tazobactam %Time>threshold and change in log
10
CFU from baseline. Due to these findings, the challenge panel was expanded to include three well-characterized β-lactamase-producing
Klebsiella pneumoniae
strains with variable enzyme expression and other resistance determinants. The translational relationship for the tazobactam threshold that allowed for the comodeling of the four
E. coli
isolates performed well for the expanded data set (seven isolates in total; four
E. coli
and three
K. pneumoniae
), as evidenced by an
r
2
value of 0.84. This simple translational relationship is especially useful as it is directly linked to
in vitro
susceptibility test results, which are used to guide the clinician's choice of drug and dosing regimen.