The paediatric cystic fibrosis lung: understanding the evolving microbiome, antimicrobial resistance and novel approaches to treatment

Oakley, Juliette 2022. The paediatric cystic fibrosis lung: understanding the evolving microbiome, antimicrobial resistance and novel approaches to treatment. MD Thesis, Cardiff University. Item availability restricted.

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Abstract

CF pulmonary disease is characterised by recurrent and persistent bacterial infections, which eventually lead to premature death. Given mounting concerns regarding antimicrobial resistance, novel surveillance methodology and therapeutics are needed to enable effective treatment of CF lung infections. Current sampling techniques for studying the paediatric CF lung microbiome are invasive and time-consuming. This thesis used paediatric induced sputum (IS) samples from the CF Sputum Induction Trial (Ronchetti et al. 2018a) to study microbial diversity and the effects of clinical treatment. The dataset represents the largest study to date using exclusively paediatric IS samples. Results demonstrated clear correlations between clinical features and diversity measures, mirroring previous literature obtained from more invasive techniques and supporting the use of IS as a routine surveillance method. OligoG CF-5/20 is a novel anti-biofilm therapy currently undergoing clinical trials. To understand its mechanism of action and potential clinical effects, this work used Fourier transform infrared spectroscopy to analyse a small set of CF sputum samples from the CF SpIT trial and explore the interaction of OligoG CF-5/20 with respiratory mucin. Results demonstrated interaction at key mucin structures including glycan moieties and the peptide backbone, providing a potential mechanism of action to explain the modification of CF sputum. Reflecting the intended clinical use of OligoG CF-5/20 as a prolonged treatment for patients, an evolutionary model was utilised to study the effects of OligoG CF-5/20 treatment on P. aeruginosa. Phenotypic and genotypic characterisation of P. aeruginosa exposed to 2% OligoG CF-5/20 showed a reduction in colonies with multidrug resistant-associated phenotypes. Exposure to 2% OligoG CF-5/20 and azithromycin improved bacterial susceptibility to other classes of antibiotics. These studies provide an insight into the role of culture-independent methods for airway sampling and the development of a novel therapy to treat multi-drug resistant bacteria in children with CF. iv

Item Type:	Thesis (MD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	4 November 2022
Last Modified:	04 Nov 2022 11:06
URI:	https://orca.cardiff.ac.uk/id/eprint/153976

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