The effects of major burn related pathophysiological changes on the pharmacokinetics and pharmacodynamics of drug use: An appraisal utilizing antibiotics

Abstract

Patients suffering major burn injury represent a unique population of critically ill patients. Widespread skin and tissue damage causes release of systemic inflammatory mediators that promote endothelial leak, extravascular fluid shifts, and cardiovascular derangement. This phase is characterized by relative intra-vascular hypovolaemia and poor peripheral perfusion. Large volume intravenous fluid resuscitation is generally required. The patients' clinical course is then typically complicated by ongoing inflammation, protein catabolism, and marked haemodynamic perturbation. At all times, drug distribution, metabolism, and elimination are grossly distorted. For hydrophilic agents, changes in volume of distribution and clearance are marked, resulting in potentially sub-optimal drug exposure. In the case of antibiotics, this may then promote treatment failure, or the development of bacterial drug resistance. As such, empirical dose selection and pharmaceutical development must consider these features, with the application of strategies that attempt to counter the unique pharmacokinetic changes encountered in this setting.

Bacteriology and Antibiotic Prescription Patterns in a Malawian Tertiary Hospital Burns Unit

“…Post-burn hypermetabolism and systemic inflammatory response syndrome (SIRS) also result in increased in capillary leakage, hypoprotenaemia, decreased protein binding and augmented renal clearance which results in altered pharmacokinetics and pharmacodynamics of drugs including antibiotics. 25,35,36 The effects of these changes are more pronounced with hydrophilic drugs(e.g. Beta-lactams, Aminoglycosides, glycopeptides and lipopeptides) which account for 79.6% of antibiotic prescriptions in this study and are often augmented by administration of intravenous fluids or inotropes.…”

“…Beta-lactams, Aminoglycosides, glycopeptides and lipopeptides) which account for 79.6% of antibiotic prescriptions in this study and are often augmented by administration of intravenous fluids or inotropes. 35,36 Since standard dose calculations are based on relatively healthy populations, these changes are likely to result in suboptimal dosing of antibiotics thus compromising therapeutic outcomes and further contributing towards antibiotic resistance. 35,36…”

“…37 Procalcitonin, Pro-B-type natriuretic peptide and hemodynamic changes (systemic vascular resistance index and stroke volume index) have been proposed as potential biomarkers which meet most of the aforementioned criteria. 30,32,35 To the best of our knowledge, the validity of these biomarkers in an African population is not yet published and there is need to make the biomarkers cost effective for use in low and middle income countries where the incidence of burns and burns-related sepsis is greatest. 3–5 We postulate that validation and adoption of biomarkers in our setting has the potential of curbing the magnitude of inappropriate antibiotic prescriptions and thus AMR.…”

Understanding the impact of pathophysiological alterations during critical illness on drug pharmacokinetics

“…Adequate loading doses may be necessary during initiation of therapy. Various dosing strategies such as use of continuous infusion and weight-based dosing have been used to provide more therapeutic drug dosing in this population [16,17].…”

Expression profile and bioinformatics analysis of circular RNA in intestinal mucosal injury and repair after severe burns

“…A burn is a serious trauma that results in pathophysiological changes such as stress, hypoxia, local ischemia, reperfusion injury, immune responses, inflammation, infection, etc. (Barrett et al, 2019; Deitch et al, 2004; Udy et al, 2018). During burns and trauma, the intestinal mucosal barrier can be seriously damaged (Rathor et al, 2014).…”