A pharmacokinetic/pharmacodynamic and clinical outcome evaluation of beta-lactam antibiotic therapeutic drug monitoring in critically ill patients

Abstract

Disease-processes experienced by critically ill patients commonly cause unique pharmacokinetic (PK) changes, that may result in drug concentrations that are either sub-therapeutic or toxic when dosing is based on PK data obtained from non-critically ill patients. Ensuring therapeutic dosing of beta-lactam antibiotics in critically ill patient is of increasing concern, given the difficult-to-predict PK in this population, frequent use of this antibiotic class in treating severe infections and the importance of optimal antibiotic therapy for reducing mortality rates. Therapeutic drug monitoring (TDM), a strategy frequently used in dosing drugs with complex PK, has demonstrated potential clinical advantages for improving dosing of beta-lactams in the critically ill. However, the practice of beta-lactam TDM and dose optimisation is still limited by a number of factors. Large-scale data on the adequacy of current dosing regimens and optimal PK/pharmacodynamic (PK/PD) targets associated with maximal clinical outcome is still limited. In particular, currently available data on beta-lactam TDM have not adequately quantified the potentially profound impact of hypoalbuminaemia, common among the critically ill, on the PK of the pharmacologically active unbound concentration of beta-lactams.This Thesis aims to describe the application of a beta-lactam TDM-guided dosing program in critically ill patients, with the utilization of directly-measured unbound drug concentration data. Specifically, this work will first characterise the impact of altered protein binding in critically ill patients on the accuracy of commonly used methods for calculation of unbound beta-lactam concentrations (from measured total concentrations). Secondly, this work will describe the achievement of PK/PD targets in relation to directly-measured unbound beta-lactam concentrations in critically ill patients receiving empiric dosed and TDM-guided beta-lactam antibiotic treatments. Finally, the association of beta-lactam concentrations with clinical outcome in critically ill patients with blood stream infections will also be characterised.This Thesis comprises of seven chapters. Chapter one introduces relevant PK/PD and beta-lactam dosing concepts for this Thesis.Chapter two includes a published review article that systemically analyses the current literature at the time on the risk of inadequate drug exposure in critically ill patients and discusses the role of TDM for different class of antibiotics in this setting. This chapter specifically addresses available evidence relating to practices of antibiotic TDM, and the practical aspects of applying TDM to potentially improve outcomes from severe infections in the critically ill.Chapter three is an original research article that reports findings of a multicentre survey on the various approaches used for beta-lactam TDM in intensive care units (ICUs) worldwide.Chapter four is an original research article that describes findings of a single-centre prospective study on unbound beta-lactam concentrations in the critically ill determined by two assays. The aim of this study was to compare the measured unbound concentrations with the unbound concentrations conventionally predicted from published protein binding values for seven beta-lactam antibiotics commonly used in the critically ill. Chapter five describes findings of a single-centre prospective study on attainment of predefined PK/PD targets in critically ill patients who received empirically dosed and TDM-guide (using direct-measured unbound drug concentrations) beta-lactam antibiotics. Furthermore, the study also aimed to describe patient and treatment factors associated with attainment of target concentrations.Chapter six describes findings of association between beta-lactam exposures, using PK/PD indices, and clinical outcomes from a retrospective analysis of prospective studies database. Furthermore, the study also aimed to describe patient and treatment factors associated with patient outcome.Chapter seven includes an overall discussion and summary of the findings of this Thesis, and explores on potential future research in this area.