PK/PD Target Attainment With Ceftolozane/Tazobactam Using Monte Carlo Simulation in Patients With Various Degrees of Renal Function, Including Augmented Renal Clearance and End-Stage Renal Disease

Abstract

Introduction: Ceftolozane/tazobactam is an antibacterial agent with potent in vitro activity against Gram-negative pathogens, including many extended-spectrum β-lactamase-producing Enterobacteriaceae and drug-resistant Pseudomonas aeruginosa. Because ceftolozane/tazobactam is primarily excreted renally, appropriate dose adjustments are needed for patients with renal impairment. Monte Carlo simulations were used to determine the probability of pharmacokinetic/pharmacodynamic target attainment for patients with varying degrees of renal function, including augmented renal clearance (ARC) and end-stage renal disease (ESRD) with hemodialysis.

Methods: Monte Carlo simulations were conducted for 1000 patients with ARC and normal renal function, mild renal impairment, moderate renal impairment, or severe renal impairment, and for 5000 patients with ESRD. Simulated dosing regimens were based on approved doses for each renal function category. Attainment targets for ceftolozane were 24.8% (bacteriostasis), 32.2% (1-log kill; bactericidal), and 40% (2-log kill) fT > minimum inhibitory concentration (MIC). The target for tazobactam was to achieve a 20% fT > minimum effective concentration (MEC) at an MEC of 1 mg/L, which was derived from a neutropenic mouse thigh infection model and was confirmed by efficacy data from clinical studies for complicated intraabdominal infections and complicated urinary tract infections.

Results: In patients with ARC or normal renal function, ≥91% achieved bactericidal activity (32.2% fT > MIC) up to an MIC of 4 mg/L with a 1000-mg ceftolozane dose. In patients with renal impairment (mild, moderate, severe, ESRD), ≥93% achieved bactericidal activity up to an MIC of 8 mg/L. In patients of all renal function categories, the approved dosing regimens of tazobactam achieved ≥91% target attainment against a target of 20% fT > MEC.

Conclusions: At the approved dosing regimens for ceftolozane/tazobactam, ≥91% of patients in all renal function categories, including ARC (up to 200 mL/min) and ESRD, reached target attainment for bactericidal activity at MICs that correspond to susceptibility breakpoints for Enterobacteriaceae and P. aeruginosa.

Keywords: Antibacterial; Ceftolozane/tazobactam; Complicated intraabdominal infection; Complicated urinary tract infection; ESRD; Gram-negative pathogens; Monte Carlo simulation; Renal impairment; Target attainment.

Fig. 1

Typical tazobactam concentration–time profile (after a 1-h infusion of 90 mg tazobactam in patients with cIAI and normal renal function), showing consistency across different target/threshold settings: 20% fT > MEC of 1 mg/L is equivalent to 50% fT > threshold of 0.25 mg/L and 80% fT > threshold of 0.05 mg/L. The targets are achieved in 50% of patients at a dose of 90 mg and can be achieved in ≥97% patients at the approved dose of 500 mg (covering variability). cIAI intraabdominal infection, fT  > MEC free-drug time above MEC, MEC minimum effective concentration

Fig. 2

Simulated ceftolozane PK/PD target attainment [32.2% fT > MIC target (1-log kill)] at steady state by renal function group across MIC values following administration of the approved dose regimens. Histograms show MIC distributions for 2015 surveillance isolates [; data on file]. a P. aeruginosa [MIC₉₀, 1 mg/L (United States), 16 mg/L (European Union)]. b Enterobacteriaceae [MIC₉₀, 1 mg/L (United States), 2 mg/L (European Union)]. CrCl creatinine clearance, ESRD end-stage renal disease, HD hemodialysis, MIC minimum inhibitory concentration, PD pharmacodynamics, PK pharmacokinetics

Fig. 3

Simulated tazobactam PK/PD target attainment (20% fT > MEC) at steady state by renal function group across MEC values following administration of the approved dose regimens. CrCl creatinine clearance, ESRD end-stage renal disease, fT > MEC free-drug time above MEC, HD hemodialysis, MEC minimum effective concentration, PD pharmacodynamics, PK pharmacokinetics