Investigating mid-infrared absorption spectroscopy as a method for improving dosing and adherence in paediatric pharmacotherapy.

Abstract

Uncertain adherence and suboptimal dosing strategies in paediatric antimicrobial pharmacotherapy presents a challenge that requires further evaluation in the face of rising worldwide antimicrobial resistance. Objective measurements of paediatric adherence and dosing data through blood antimicrobial levels is often limited in children by the invasive nature of the current methods available. This thesis had two components (1) to describe current paediatric adherence to antimicrobials in the community through a questionnaire study (2) to investigate mid-infrared absorption spectroscopy (MAS) as a minimally invasive method for measuring antimicrobial levels in blood, for dosing and adherence data, in the community or at the point-of-care.For the questionnaire component, 304 participants were recruited from January 2020 to April 2022 with a break of 7 months during the start of the COVID-19 pandemic. 194 were recruited prior to the pandemic and 110 afterwards. The age range of children was 0-16 years with the majority (93.4%) aged 0-9 years. Parent/carer-reported total adherence to an antimicrobial course was 67.1%. The most commonly encountered difficulties were taste (n=137), timings (n=62) and volume (n=18); taste was the difficulty most significantly associated with non-adherence (p<0.001). Adherence increased during the course of the COVID-19 pandemic (Pre = 60.3%, post = 79.1%, p <0.001).For the spectroscopy component, developmental work describing the optimum cleaning methods and the spectra of commonly used interferents was performed. The measurement noise of whole blood, serum and water were described which showed that more complex fluids (blood and serum) have higher measurement noise when compared with water, although water still showed some measurement noise. Time also impacted the measurement noise of whole blood with changes in spectral absorption over 10 minutes. The lower limit of detection (LLOD) for all the drugs of interest were outside the range of clinical interest (amoxicillin = 1026 mg/L, tobramycin 479 mg/L, gentamicin = 700 mg/L, rifampicin = 1701 mg/L). Methods to improve MAS sensitivity through chemical extraction, indirect measurement via protein-drug interaction and drying were investigated but none of the methods improved sensitivity.In summary, the questionnaire component showed that in children prescribed oral antimicrobials, guidelines should consider the likely adherence to a given antimicrobial. The variable adherence, in the context of lack of robust paediatric dosing data, highlights the need to investigate methods, such as MAS, which can objectively measure children’s antimicrobial levels in the community in a minimally invasive manner. MAS has been investigated as a possible method for providing accurate and minimally invasive antimicrobial levels. At present it does not possess the sensitivity required but useful data from this thesis have been generated to inform and guide future technological development (waveguides and microfluidic technology) to improve MAS sensitivity so that it could be used as an accurate, rapid and minimally invasive method for measuring drug levels in blood and improving paediatric pharmacotherapy.

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Identifiers

ORCID for Saul Faust: orcid.org/0000-0003-3410-7642

ORCID for Dave Rowe: orcid.org/0000-0002-1167-150X

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