Optimizing Antimicrobial Drug Dosing in Critically Ill Patients

Abstract

A fundamental step in the successful management of sepsis and septic shock is early empiric antimicrobial therapy. However, for this to be effective, several decisions must be addressed simultaneously: (1) antimicrobial choices should be adequate, covering the most probable pathogens; (2) they should be administered in the appropriate dose, (3) by the correct route, and (4) using the correct mode of administration to achieve successful concentration at the infection site. In critically ill patients, antimicrobial dosing is a common challenge and a frequent source of errors, since these patients present deranged pharmacokinetics, namely increased volume of distribution and altered drug clearance, which either increased or decreased. Moreover, the clinical condition of these patients changes markedly over time, either improving or deteriorating. The consequent impact on drug pharmacokinetics further complicates the selection of correct drug schedules and dosing during the course of therapy. In recent years, the knowledge of pharmacokinetics and pharmacodynamics, drug dosing, therapeutic drug monitoring, and antimicrobial resistance in the critically ill patients has greatly improved, fostering strategies to optimize therapeutic efficacy and to reduce toxicity and adverse events. Nonetheless, delivering adequate and appropriate antimicrobial therapy is still a challenge, since pathogen resistance continues to rise, and new therapeutic agents remain scarce. We aim to review the available literature to assess the challenges, impact, and tools to optimize individualization of antimicrobial dosing to maximize exposure and effectiveness in critically ill patients.

Pharmacokinetic assessment of vancomycin in critically ill patients and nephrotoxicity prediction using individualized pharmacokinetic parameters

“…Most of the published papers on vancomycin pharmacokinetic and TDM studies are retrospective and observational ( Póvoa et al, 2021 ). In this study, we designed a prospective interventional study of vancomycin pharmacokinetic assessments in critically ill patients and dose adjustments were done for all participants based on Eqs 5 , 6 and individualized pharmacokinetic parameters.…”

Population Pharmacokinetic Modeling and Dose Optimization of Vancomycin in Chinese Patients with Augmented Renal Clearance

“…Several pathophysiological changes might be related to PK modifications in ICU patients [24]. Intravenous fluid loading, hypoalbuminemia and endothelial damage may increase capillary permeability and contribute to interstitial space expansion in the critically ill, especially in cases of sepsis and septic shock [25]. Hydrophilic drugs, characterized by a distribution limited to the extracellular space, are significantly affected [24].A recent study suggested that an increased volume of distribution (Vd) may be due to sepsis-induced third space losses [26].…”

“…A larger Vd of hydrophilic drugs has been reported in ICU patients, but the clinical relevance is questionable. An aminoglycoside is supposed to have lower concentrations in patients with higher Vd and therefore needs an augmented dose [24,25]. An increased dosing is also necessary for β-lactam antibiotics to prevent visible growth of a microorganism [27,28].…”

A Predictive Model Based on Inflammatory and Coagulation Indicators for Sepsis-Induced Acute Kidney Injury

“…In early empiric antimicrobial therapy during sepsis, a great deal of progress has been made in the fields of pharmacokinetics and pharmacodynamics, drug dosing, therapeutic drug monitoring, and antimicrobial resistance. 43 (2) The study cohort was made up of a variety of sepsis patients from a tertiary comprehensive hospital, therefore there was a possibility that selection bias influenced the results. (3) Our study lacked verification of external validity, the adaptive scope of the model in this study needed to be further verified.…”