Date of Award

2022

Degree Name

Master of Medicine/Master of Surgery

Schools and Centres

Medicine

First Supervisor

Dr Indy Sandaradura

Second Supervisor

Dr Craig Smith

Abstract

Children with cystic fibrosis (CF) are predisposed to recurrent pulmonary exacerbations throughout their lifetime. This is characterised by an acute worsening of respiratory symptoms in the setting of bacterial infection and results in significant morbidity and mortality. Appropriate antimicrobial therapy is fundamental to management, in particular aminoglycoside antibiotics. Tobramycin is the preferred aminoglycoside of choice, usually administered intravenously for 7 to 14 days.

Tobramycin dosing can be challenging in patients with CF. This is due to the underlying pharmacokinetic derangements (e.g., volume of distribution, organ function) frequently observed in this population. Accordingly, the use of standard dosing (based on age or mg/kg) often results in fluctuating systemic concentrations, impacting safety and treatment efficacy. To optimise therapy, ‘precision dosing’ has become increasingly favoured.

Precision dosing is the concept of dose individualisation to ensure drug concentrations are within therapeutic range. In clinical practice, the two most popular precision dosing strategies used to ascertain drug exposure and calculate the optimal dose are log linear regression (LLR) and Bayesian forecasting (BF). At present, a comparative evaluation of LLR and BF has not been systematically performed and it remains unclear whether one approach offers a meaningful advantage over the other in clinical practice. In this thesis I endeavoured to assess this shortcoming in the literature.

Chapter 1 is an overview of key concepts underlying tobramycin dosing, concentration monitoring and target attainment and outlines existing literature evaluating LLR and BF. Chapter 2 describes a quasi-experimental intervention study conducted to 6 evaluate clinical and performance outcomes amongst children with CF for whom tobramycin therapy was guided by either LLR or BF at a tertiary children’s hospital. In Chapter 3, I discuss the implications of my study findings as well directions for future research.

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