Abstract
Background: Although aminoglycosides are often used as treatment for Gram-negative infections, optimal dosing regimens remain unclear, especially in ICU patients. This is due to a large between- and within-subject variability in the aminoglycoside pharmacokinetics in this population. Objective: This review provides comprehensive data on the pharmacokinetics of aminoglycosides in patients hospitalized in the ICU by summarizing all published PopPK models in ICU patients for amikacin, gentamicin, and tobramycin. The objective was to determine the presence of a consensus on the structural model used, significant covariates included, and therapeutic targets considered during dosing regimen simulations. Method: A literature search was conducted in the Medline/PubMed database, using the terms: ‘amikacin’, ‘gentamicin’, ‘tobramycin’, ‘pharmacokinetic(s)’, ‘nonlinear mixed effect’, ‘population’, ‘intensive care’, and ‘critically ill’. Results: Nineteen articles were retained where amikacin, gentamicin, and tobramycin pharmacokinetics were described in six, 11, and five models, respectively. A two-compartment model was used to describe amikacin and tobramycin pharmacokinetics, whereas a one-compartment model majorly described gentamicin pharmacokinetics. The most recurrent significant covariates were renal clearance and bodyweight. Across all aminoglycosides, mean interindividual variability in clearance and volume of distribution were 41.6% and 22.0%, respectively. A common consensus for an optimal dosing regimen for each aminoglycoside was not reached. Conclusions: This review showed models developed for amikacin, from 2015 until now, and for gentamicin and tobramycin from the past decades. Despite the growing challenges of external evaluation, the latter should be more considered during model development. Further research including new covariates, additional simulated dosing regimens, and external validation should be considered to better understand aminoglycoside pharmacokinetics in ICU patients.
Highlights
Aminoglycosides are a class of antibiotics used as treatment for Gram-negative infections in patients hospitalized in intensive care units (ICUs)
A literature search was conducted in the Medline/PubMed database, from its inception until March 2020, using the following terms: AND [(pharmacokinetics/or renal elimination/) OR (pharmacokinetic* OR ((pharmaco OR drug) ADJ kinetic*) OR area under curve? OR area under the curve (AUC) OR (renal ADJ)) OR (((nonlinear OR non-linear) ADJ mixed effect model*) OR NONMEM OR WinNonMix OR P-PHARM OR NLMIXED OR ADAPT)] AND (EXP population/OR population groups/OR) AND [critical care/OR intensive care or EXP intensive care units/OR critical illness/OR ((intensive OR critical) ADJ care?) OR ICU OR ((respiratory OR coronary) ADJ care unit?) OR (critical* ADJ)]
Peak and AUC pharmacodynamic targets could not be reached simultaneously in more than 45% of the ICU patient population
Summary
Aminoglycosides are a class of antibiotics used as treatment for Gram-negative infections in patients hospitalized in intensive care units (ICUs). Considering the narrow therapeutic index of aminoglycosides with potential nephrotoxicity and ototoxicity, therapeutic drug monitoring (TDM) has been used to achieve these targets while minimizing toxicity by individualizing treatments [9] This practice is especially crucial in ICU patients that suffer from septic shock where the survival rate is increased with the timely administration of an appropriate antibiotic [10]. Aminoglycosides are often used as treatment for Gram-negative infections, optimal dosing regimens remain unclear, especially in ICU patients. This is due to a large between- and within-subject variability in the aminoglycoside pharmacokinetics in this population. Further research including new covariates, additional simulated dosing regimens, and external validation should be considered to better understand aminoglycoside pharmacokinetics in ICU patients
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