Translating innovative pharmacokinetic sampling techniques into improved antibiotic dosing regimens in critically ill patients

Abstract

Antibiotic resistance is a significant and immediate global health concern. An increasing prevalence of multi-drug resistant bacteria is steadily decreasing the number of antibiotics that can be used, and few new antibiotics are available for effective treatment of multi-drug resistant infections. Effective dosing of antibiotics can have a two-fold effect by firstly improving patient outcomes and secondly suppressing the emergence of antibiotic resistance. In critically ill patients there are significant pathophysiological changes that can complicate antibiotic dosing and knowledge of the pharmacokinetic (dose-concentration relationship) and pharmacodynamic (concentration-effect relationship) properties of antibiotics are essential to ensure effective treatment.In an era of increasing antibiotic resistance, there is substantial interest in the optimal use of previously forgotten antibiotics like fosfomycin for the treatment of infections caused by multi-drug resistant bacteria. Given that resistance commonly arises in critically ill patients, a detailed understanding of antibiotic pharmacokinetics in these patients can lead to development of optimised dosing regimens that maximise bacterial killing and suppress the emergence of resistance of these antibiotics. However, pharmacokinetic studies are often expensive to perform and are resourceheavy. Innovative approaches to collecting, storing and transporting clinical samples, including microsampling techniques, could reduce some of these costs. The use of microsampling techniques in pharmacokinetic studies is likely to lead to simpler, less expensive, less invasive sample collection for more informative pharmacokinetic studies in critically ill patients that can then translate to more effective antibiotic dosing.The principal aims of this Thesis are to investigate how innovative microsampling techniques can be translated into pharmacokinetic studies. Additionally, this Thesis aims to describe optimised dosing regimens for fosfomycin through the conduct of a pharmacokinetic study in critically ill patients. 3This Thesis describes a quantitative bioanalytical validation performed using novel volumetric absorptive microsampling (VAMS) devices for sampling fosfomycin in whole blood. The use of the VAMS devices provided acceptable validation results for lower limit of quantification (LLOQ), linearity, and inter-and intra-day precision and accuracy, and matrix effects. However, the results from recovery and stability testing using VAMS devices for the quantitative bioanalysis of fosfomycin suggest challenges remain for the analysis of fosfomycin in whole blood.The microsampling investigations also describe a validated process for quantitatively measuring fosfomycin in blood samples using a dried plasma spot (DPS) sampling technique. The results of the DPS samples from a clinical pharmacokinetic study were found to correlate with the 'goldstandard' of plasma sampling. The translation of this technique into pharmacokinetic studies can reduce the resource burden du...