Biomarkers Predicting Tissue Pharmacokinetics of Antimicrobials in Sepsis: A Review

Abstract

The pathophysiology of sepsis alters drug pharmacokinetics, resulting in inadequate drug exposure and target-site concentration. Suboptimal exposure leads to treatment failure and the development of antimicrobial resistance. Therefore, we seek to optimize antimicrobial therapy in sepsis by selecting the right drug and the correct dosage. A prerequisite for achieving this goal is characterization and understanding of the mechanisms of pharmacokinetic alterations. However, most infections take place not in blood but in different body compartments. Since tissue pharmacokinetic assessment is not feasible in daily practice, we need to tailor antibiotic treatment according to the specific patient's pathophysiological processes. The complex pathophysiology of sepsis and the ineffectiveness of current targeted therapies suggest that treatments guided by biomarkers predicting target-site concentration could provide a new therapeutic strategy. Inflammation, endothelial and coagulation activation markers, and blood flow parameters might be indicators of impaired tissue distribution. Moreover, hepatic and renal dysfunction biomarkers can predict not only drug metabolism and clearance but also drug distribution. Identification of the right biomarkers can direct drug dosing and provide timely feedback on its effectiveness. Therefore, this might decrease antibiotic resistance and the mortality of critically ill patients. This article fills the literature gap by characterizing patient biomarkers that might be used to predict unbound plasma-to-tissue drug distribution in critically ill patients. Although all biomarkers must be clinically evaluated with the ultimate goal of combining them in a clinically feasible scoring system, we support the concept that the appropriate biomarkers could be used to direct targeted antibiotic dosing.

Predictive Performance of Physiologically Based Pharmacokinetic Modelling of Beta-Lactam Antibiotic Concentrations in Adipose, Bone, and Muscle Tissues

“…This approach was chosen as current PBPK models of perfusion-limited tissues are limited in their functionality to distinguish between healthy and sick tissue. For example, while there are reports that septic shock impacts tissue penetration (Joukhadar et al, 2001), important tissue alterations associated with sepsis such as capillary leakage and microcirculation abnormalities cannot be modelled in current PBPK models (Ibarra et al, 2020;Sanz Codina and Zeitlinger, 2022). Tissue perfusion, expressed as the tissue blood flow over volume ratio, can be changed however and the effect of varying this parameter on target attainment was evaluated.…”

Population Pharmacokinetics of Temocillin Administered by Continuous Infusion in Patients with Septic Shock Associated with Intra-Abdominal Infection and Ascitic Fluid Effusion

“…It might be explained by the variability and instability of the patient’s pathophysiological and biochemical characteristics over time [ 44 , 45 ]. For example, in patients with sepsis or septic shock, blood flow parameters are altered, which can lead to altered tissue distribution or impaired kidney function [ 46 ]. Importantly, fluctuations in albumin/protein levels may also influence the proportion of the drug bound to proteins, as well-documented for highly protein-bound β-lactams [ 31 , 47 , 48 ].…”

Association of Procalcitonin with the Patient’s Infection Characteristics and Prognosis after Hematopoietic Stem Cell Transplantation

“…Combined measurement of PCT with Alb is expected to be a valuable tool to assess prognosis in elderly people at risk of bacterial infection [ 16 ]. High D-dimer levels have been associated with 28-day mortality in patients with infection or sepsis [ 17 ]. High serum IL-8 and D-dimer levels can be useful markers to identify patients with chemotherapy-induced neutropenia [ 18 ].…”