Vol.71 No.6 November 2023

Pharmacokinetic/pharmacodynamic simulations of tazobactam/ceftolozane for antimicrobial resistance in Enterobacterales

Toshiharu Urakami¹⁾, Yohei Hamada¹⁾, Yusuke Oka¹⁾, Megumi Oho²⁾, Shintaro Sumi³⁾ and Yosuke Aoki^{1, 4)}

¹⁾Division of Infectious Disease and Hospital Epidemiology, Saga University Hospital, 5-1-1 Nabeshima, Saga City, Saga, Japan
²⁾Department of Clinical Laboratory, Saga University Hospital
³⁾Department of Pharmacy, Saga University Hospital
⁴⁾Department of International Medicine, Faculty of Medicine, Saga University

Abstract

Tazobactam/ceftolozane (TAZ/CTLZ), a combination of ceftolozane, a cephalosporin antibiotic, and tazobactam, a β-lactamase inhibitor, is active against various β-lactamase-producing Enterobacterales and multidrug-resistant Pseudomonas aeruginosa; However, there are no reports yet on pharmacokinetic/pharmacodynamic (PK/PD) analysis of the antibiotic combination against antimicrobial-resistant Enterobacterales in Japanese adult patients. We conducted PK/PD simulations of TAZ/CTLZ against extended-spectrum β-lactamase (ESBL) and/or AmpC β-lactamase-producing Enterobacterales, and carbapenem-resistant Enterobacterales (CRE) on the basis of Monte Carlo simulations performed for 5,000 subjects. Based on the PK parameters in Japanese adult patients and the antimicrobial susceptibility distribution at Saga University Hospital, the simulations predicted the probabilities of attaining the PK/PD target (duration for which free CTLZ concentrations are above the minimum inhibitory concentration for the pathogens greater than 32.2%). The dosing regimen was TAZ/CTLZ 1.5 g (0.5/1.0 g) administered q8h by 1-hour infusion, and the PK model was a 1-compartment model. The probabilities of target attainment of TAZ/CTLZ at MIC 2 μg/mL (the susceptibility break point in CLSI M100-Ed33) and 16 μg/mL were 98.9% and 84.9%, respectively. TAZ/CTLZ provided sufficient cumulative fraction of response (≥90%) for ESBL and/or AmpC β-lactamase-producing Enterobacterales, and CRE.
These results indicate that TAZ/CTLZ is an appropriate empiric treatment for infections caused by presumed antimicrobial-resistant Enterobacterales in Japanese patients.

Key word

tazobactam/ceftolozane, pharmacokinetics/pharmacodynamics, extended-spectrum β-lactamase, AmpC β-lactamase, carbapenem-resistant Enterobacterales

Received

July 21, 2023

Accepted

August 18, 2023

Jpn. J. Chemother. 71 (6): 564-570, 2023