An innovative population pharmacokinetic/pharmacodynamic strategy for attaining aggressive joint PK/PD target of continuous infusion ceftazidime/avibactam against KPC- and OXA-48- producing Enterobacterales and preventing resistance development in critically ill patients.

Autor:	Cojutti PG; Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.; Clinical Pharmacology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Pai MP; Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA., Gatti M; Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.; Clinical Pharmacology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Rinaldi M; Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.; Infectious Diseases Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Ambretti S; Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.; Microbiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Viale P; Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.; Infectious Diseases Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Pea F; Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.; Clinical Pharmacology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Jazyk:	angličtina
Zdroj:	The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2024 Nov 04; Vol. 79 (11), pp. 2801-2808.
DOI:	10.1093/jac/dkae290
Abstrakt:	Objectives: Ceftazidime/avibactam is a key antibiotic for carbapenemase-producing Enterobacterales (CPE) Gram-negative infections, but current dosing may be suboptimal to grant activity. This study explores the population pharmacokinetics/pharmacodynamics (PK/PD) of continuous infusion (CI) ceftazidime/avibactam for maximizing treatment efficacy in critically ill patients. Methods: A retrospective analysis of adult patients receiving CI ceftazidime/avibactam and therapeutic drug monitoring (TDM) of both compounds was performed. Population PK/PD modelling identified the most accurate method for estimating ceftazidime/avibactam clearance based on kidney function and Monte Carlo simulations investigated the relationship between various CI dosing regimens and aggressive joint PK/PD target attainment of ceftazidime/avibactam. Results: The European Kidney Function Consortium (EKFC) equation best described kidney function for ceftazidime/avibactam clearance. The findings challenge the current approach of only reducing the ceftazidime/avibactam dose based on kidney function by identifying dose adjustments in patients with augmented kidney function. Our CI ceftazidime/avibactam dosing strategies, adjusted by TDM, showed promise for achieving optimal aggressive joint PK/PD targets and potentially improving clinical/microbiological outcomes against KPC- and OXA-48-producing Enterobacterales. The risk of neurotoxicity associated with these strategies appears acceptable. Conclusions: This study suggests that adjusting ceftazidime/avibactam dosing regimen based solely on eCLcr might be suboptimal for critically ill patients. Higher daily doses delivered by CI and adjusted based on TDM have the potential to improve aggressive joint PK/PD target attainment and potentially clinical/microbiological outcomes. Further investigations are warranted to confirm these findings and establish optimal TDM-guided dosing strategies for ceftazidime/avibactam in clinical practice. (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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