β-lactam antibiotic pharmacokinetics during continuous venovenous haemofiltration in critically ill patients: continuous infusion versus intermittent bolus administration

Abstract

Sepsis is a pathological syndrome that leads to unique physiological changes in critically ill patients, and can affect antibiotic pharmacokinetics. Acute kidney injury (AKI) is common in critically ill patients. The commencement of renal replacement therapy (RRT) in the management of AKI can further affect antibiotic pharmacokinetics. RRT prescription within intensive care units (ICUs) worldwide is highly variable as it depends on availability, speciality and cost. Thus, antibiotic pharmacokinetic studies in RRT derived from one type of RRT are not readily transferrable to another type of RRT. The major challenge caused by RRT is altered antibiotic clearance by the extracorporeal circuit, which will vary depending on the RRT modality and settings. It follows, that standardisation of antibiotic dosing regimens is not advisable. Clinically, when prescribing antibiotic doses for critically ill patients on RRT, various factors require consideration including; RRT mode and settings, patient characteristics (body size and other organ function), and the likely bacterial pathogen susceptibility. Whilst numerous pharmacokinetic studies have been published on various classes of antibiotics to optimize dosing, continuous infusion (CI) as a method to optimise antibiotic activity, has rarely been studied in these patients. Certainly, there has been much recent interest in this alternative mode of administration for beta-lactam antibiotics (e.g penicillin, cephalosporin, carbapenem antibiotics), as a mechanism to achieve sustained antibiotic concentrations in plasma, as well as optimal pharmacokinetic/pharmacodynamics (PK/PD) indices.This Thesis aims to describe the pharmacokinetics of two commonly used beta-lactam antibiotics in intensive care unit (ICU) setting, namely meropenem and piperacilllin/tazobactam during continuous RRT (CRRT) using ex vivo and clinical pharmacokinetic data. Specifically this work will characterise the pharmacokinetics and the probability of PK/PD attainment of beta-lactam dosing by two methods of antibiotic administration, CI and intermittent bolus (IB) in critically ill patients receiving a common form of CRRT, continuous venovenous haemofiltration (CVVH).This Thesis comprises of nine chapters. Chapter one is an introductory chapter where it provides an overview on the literatures on the Thesis topic. The discussion section in Chapter one outlines a theoretical framework behind the objectives of this Thesis, as well as the specific aims of this Thesis.Chapter two incorporates a published review article that systemically analysed the current literatures on different classes of antibiotic pharmacokinetics in special situations in the ICU iii including patients receiving different types of RRT, burn patients and extracorporeal membrane oxygenation (ECMO). This chapter describes the frequency with which current antibiotic dosing regimens achieve the therapeutic targets or the PK/PD targets and outlines alternative dosing strategies that may optimise antibiotic dosing in these populations....