Pharmacokinetics-pharmacodynamics of tazobactam in combination with ceftolozane in an in vitro infection model

Abstract

Despite β-lactamase inhibitors being available for clinical use for nearly 30 years, a paucity of data exists describing the pharmacokinetic-pharmacodynamic (PK-PD) determinants of efficacy for these agents. Herein, we describe dose fractionation studies designed to determine the exposure measure most predictive of tazobactam efficacy in combination with ceftolozane and the magnitude of this measure necessary for efficacy in a PK-PD in vitro infection model. The challenge organism panel was comprised of an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of bla(CTX-M-15). These recombinant strains exhibited ceftolozane MIC values of 4, 16, and 64 μg/ml representing low, moderate, and high levels of CTX-M-15, respectively. Different bla(CTX-M-15) transcription levels were confirmed by relative quantitative real-time PCR (qRT-PCR) and β-lactamase hydrolytic assays. The exposure measure associated with efficacy was the percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold), regardless of enzyme expression (r(2) = 0.938). The threshold concentrations identified were 0.05 μg/ml for low and moderate and 0.25 μg/ml for the high-β-lactamase expression strain constructs. The magnitudes of %Time>threshold for tazobactam associated with net bacterial stasis and a 1- and 2-log10 CFU reduction in bacteria at 24 h were approximately 35, 50, and 70%, respectively. These data provide an initial target tazobactam concentration-time profile and a paradigm to optimize tazobactam dosing when combined with ceftolozane.

Fig 1

Relationships between the observed and targeted ceftolozane (A) and tazobactam (B) concentrations or regimens studied. The drug concentrations are given in micrograms per milliliter.

Fig 2

Dose fractionation study results for the low- (A), medium- (B) and high-level (C) CTX-M-15-producing E. coli. The effect of each active regimen is shown relative to the no-treatment controls. CXA-101, ceftolozane; Tazo, tazobactam; Q8h, every 8 h.

Fig 3

Relationships between three tazobactam exposure measures, AUC, C_max, and %Time>threshold, and the change in log₁₀ CFU of isogenic CTX-M-15-producing E. coli after 24 h of therapy in a PK-PD in vitro infection model. The color of the symbols represent the different dose fractionation schedules, while the shape of the symbol represents the level of β-lactamase production. C_max is shown in micrograms per milliliter. ¹, the threshold concentration was 0.05 μg/ml for the low- and moderate-β-lactamase genetic constructs and 0.25 μg/ml for the high-β-lactamase genetic construct.

Fig 4

Relationships between tazobactam %Time>threshold and the change in log₁₀ CFU of low-, medium- and high-level CTX-M-15-producing E. coli after 24 h of therapy in a PK-PD in vitro infection model. The threshold concentrations are given in micrograms per milliliter.