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(2023)ThesisCurrent healthcare infection surveillance rarely monitors the distribution of antimicrobial resistance (AMR) in bacteria beyond clinical settings in Australia and overseas. This results in a significant gap in our ability to fully understand and manage the spread of AMR in the general community. This thesis explores whether wastewater-based monitoring could reveal geospatial-temporal and demographic trends of antibiotic-resistant bacteria in the urban area of Greater Sydney, Australia. Untreated wastewater from 25 wastewater treatment plants sampled between 2017 and 2019 consistently contained extended-spectrum β-lactamases-producing Enterobacteriaceae (ESBL-E) isolates, suggesting its endemicity in the community. Carbapenem-resistant Enterobacteriaceae (CRE), vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA) isolates were occasionally detected. Demographic and healthcare infection-related factors correlated with the ESBL-E load, and demographic variables influenced the VRE load. In contrast, the healthcare infection-related factor mainly drove the CRE load. These findings demonstrate the potential of wastewater-based surveillance to understand the factors driving AMR distribution in the community. The subsequent thesis work covers the genomic characterisation of selected ESBL-E and CRE wastewater isolates to reveal their nature, origin, and underlying resistance mechanisms. Phylogenetic analysis showed that Escherichia coli isolates were related to high-risk human-associated pandemic clones and non-human-associated clones. The Klebsiella pneumoniae and K. variicola isolates were related to globally disseminated and emerging human-associated clones, and some were detected for the first time in Australia. Genomic analysis also indicated novel resistance mechanisms against nitrofurantoin in E. coli, and against piperacillin/tazobactam and ticarcillin/clavulanic acid in Klebsiella isolates. The virulence gene content indicated that some E. coli and Klebsiella isolates were likely associated with infections, while the asymptomatic carriage was suggested for other isolates. These results demonstrate a clear potential for wastewater-based surveillance to monitor the emergence and dissemination of resistance in non-clinical isolates, and in particular, isolates from the community and non-human sources. The findings of this study can complement healthcare infection surveillance to inform management strategies to mitigate the emergence and dissemination of AMR and important human pathogens in the general community.
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(2020)ThesisPseudomonas aeruginosa causes both contact lens and non-contact lens-related keratitis (corneal infection). This opportunistic bacterium naturally has the ability to resist the mechanism of action of many antibiotics which are used for treatment. P. aeruginosa resistance patterns and the mechanism of resistance in isolates from keratitis are not well understood. This thesis described the phenotypic and genotypic patterns of antimicrobial resistance and compared these between ocular isolates of P. aeruginosa from Australia (contact lens) and India (non-contact lens). Changes in the antimicrobial susceptibility between isolates over time were also analysed. Susceptibility to antibiotics, multipurpose disinfecting solutions and disinfectants was analysed for twenty-seven Australian isolates from contact lens-related keratitis and forty non-contact lens-related isolated from India. The whole genomes of fourteen Australian (historical and recent) and twelve Indian isolates were sequenced using Illumina® MiSeq®. Computational analysis of the genomes was performed to analyse their core and pan genomes and these were examined for the presence of acquired resistance genes, virulence genes, gene mutations, and these compared to their phenotypic resistance to antibiotics. Indian isolates possessed large pan genomes with more acquired resistance (30) genes and larger numbers of genetic variations. The Indian isolates contained clones of three sequence types ST308, ST316 and ST491, whereas Australian isolates contained only one sequence type ST233. Isolates with larger gene variations had mutations in the DNA mismatch repair system. Most multi-drug resistant Indian (non-contact lens) isolates were exoU +. Indian isolates had large accessory genes compared to Australian isolates and this increased the pan genome size of the Indian isolates. The number of core genome mutations were larger in the Indian isolates a median of 50006 (IQR=26967-50600) compared to Australian isolates a median of 26317 (IQR=25681-33780). There were differences between isolates from Australia and India with respect to their antibiotic resistance and associated genes. Indian strains had more genetic diversity and were multi-drug resistant. However, there was no evidence of substantial genetic or phenotypic changes within isolates from their respective countries.