Hinojal Zazo1,2, Aguazul, Yuridia1, José M. Lanao1,2.
(1) Pharmaceutical Sciences Department, University of Salamanca, Salamanca, Spain: (2) Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
Introduction:
Pseudomonas aeruginosa is the most common microorganism involved in many ICU-acquired infections. This bacterium presents a remarkable capacity to develop extensively drug-resistant (XDR) strains, so the use of a correct dosage regimen is pivotal to avoid suboptimal concentrations which favour resistance development and are associated with worse outcomes and higher mortality rates.
Objectives:
The objectives of this study were to perform a pharmacokinetic/pharmacodynamic (PK/PD) evaluation using Monte Carlo simulation of recommended dosage regimens of Ceftazidime/Avibactam (CAZ/AVI) for intensive care unit patients with different degrees of renal function.
Methods:
A semi-mechanistic CAZ/AVI PK/PD model has been developed. The population PK model used was a one-compartment kinetic model with linear elimination and correlation between plasma clearance and renal function [1]. PD model described the bacterial growth and death in response to CAZ/AVI in a P. aeruginosa isolate [2]. In addition, bacterial density-dependent degradation of ceftazidime was considered in the model. This model allows the simulation of steady-state plasma level curves, the evolution of bacterial growth curves and PK/PD efficacy indexes such as the time during which the serum drug concentration remains above the minimum inhibitory concentration (MIC) (T>MIC) and the ratio of the trough serum concentration to MIC (Cmin/MIC). MIC value selected for this strain was 4 mg/mL. The percentage reduction of the bacterial load after one week of treatment and the value of the recommended PK/PD indexes have been taken into account to define the success or failure of the dosage regimens. Simulations were performed in two populations, control and ICU patients, both with specific pharmacokinetic behaviour. Using the proposed PK/PD model, dosing regimens recommended in the drug’s technical sheet were evaluated in patients with different degrees of renal function. Probabilistic analysis was performed using Monte Carlo simulation based on 1000 runs.
Results: In both populations, dosing regimens endorsed for renal function with CLcr higher than 10 mL/min reach the PK/PD index recommended (T>MIC>90% and Cmin/MIC>2) with a PTA>90%. However, dosage regimens recommended for patients with CLcr lower than 10 mL/min failure, especially in ICU patients. In these patients the PTA of reach the recommended PK/PD index is lower than 90% and even the bacterial load increases after one week of treatment Based on that, shortening dosing interval or higher doses have been suggested for these populations, and they have been simulated successfully .
Conclusions:
The likelihood of failure of recommended treatments may be higher in ICU patients with CLcr lower than 10 mL/min, according to the PK/PD model tested. Thus, for these populations, regimens based on shortening dosing intervals or higher doses will be successful. Therefore, the CAZ/AVI dosing strategies could directly influence the efficacy results in ICU patients.
References:
[1] Stein GE, et al. (2019) Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime/Avibactam in Critically Ill Patients. Surg Infect (Larchmt). 20(1):55–61.
[2] Sy SKB, et al. (2018). A mathematical model-based analysis of the time-kill kinetics of ceftazidime/avibactam against Pseudomonas aeruginosa. Antimicrob Chemother. 73(5):1295-1304.
Reference: PAGE 32 (2024) Abstr 11250 [www.page-meeting.org/?abstract=11250]
Poster: Drug/Disease Modelling - Infection