Enteric fever continues to affect people living in endemic settings substantially causing at least 20 million cases of febrile illnesses every year with 1% mortality. Over the last decade there has been considerable debate surrounding the burden and disease profile of enteric fever in the paediatric population. This is partially due to the similarity of the clinical features of paediatric enteric fever to most other febrile illness seen in endemic settings. The treatment of enteric fever is proving to be a challenge with the emergence of antimicrobial resistant strains, particularly the 4.3.1 genotype (H58 haplotype), which is spreading rapidly. Multi-drug resistant (MDR) enteric fever, defined as infection with typhoidal Salmonellae that exhibit a combined resistance to ampicillin, cotrimoxazole and chloramphenicol emerged in the 1990s and was mediated primarily via the 4.3.1 genotype population through the horizontal acquisition of antimicrobial resistance determinants. Subsequently, fluoroquinolones became the drug of choice and the treatment of enteric fever following which fluoroquinolone resistance emerged, again through the 4.3.1 genotype. However, these antimicrobial trends may not be uniform across endemic regions and an understanding of these differing patterns as well the temporal changes in these trends are important in planning treatment strategies. In the short and medium term work needs to be focused on achieving the greatest benefits from the prudent use of the recently WHO pre-qualified Vi-TT conjugate vaccine candidate. Whilst the long term vision towards eradicating enteric fever needs to focus on better understanding the underlying the biology of this disease through the use of contemporary technologies while simultaneously improving infrastructure for the provision of clean water, adequate sanitation and hygiene. This thesis aims to age-characterise the disease burden of typhoid fever in endemic regions of South and South-East Asia as well as the African continent. Following this, the molecular epidemiology of enteric fever in two endemic settings in the Indian subcontinent is delineated with a keen focus on the 4.3.1 genotype (H58) population as well the phenotypic patterns and molecular determinants of antimicrobial resistance. This thesis finally systematically reviews the global trends of antimicrobial resistance of S. Typhi isolates over time both from a phenotypic and molecular perspective. The key results from this thesis include; the age stratification of disease occurrence in endemic regions which showed a substantial proportion occurs in the youngest age group in both Africa and Asia, the uniform dominance of 4.3.1 genotypes conferring a high degree of fluoroquinolone resistance contrary to earlier suggestions of younger children being more susceptible to a broader range of infecting genotypes, the dissimilarities between the antimicrobial resistance carrying capabilities of lineage I and lineage II strains of the 4.3.1 genotype as well as novel AMR gene arrangements and finally the temporal trends of AMR in S. Typhi which were different between Asia an Africa. The high prevalence of lineage I strains in Africa and South-East Asia in contrast to the high prevalence of lineage II strains in the Indian subcontinent reflect the antimicrobial selection pressures as well the evolutionary characteristics of circulating pathogen populations in these regions. The implications of the data reported in this thesis have implications for treatment and prevention strategies. For the first time in history an opportunity has risen to effectively vaccinate the youngest age group (0-4 years) from typhoid through the Vi-TT conjugate vaccine. As highlighted in this thesis the youngest age group (0-4 years) have a high disease occurrence in endemic areas as seen in a meta-analysis as well as through data from two endemic sites collated and reported in this thesis. The older age groups also suffer greatly from this disease calling for a broad based vaccine strategy. The implications for treatment of enteric fever are however more relevant in the immediate term which suggest that in endemic regions in Asia, fluoroquinolones have little role to play in treatment protocols while fluoroquinolones are still relevant in the African setting. In Asia, reverting back to former first-line antimicrobials might be an option but the possibility of re-emergence of widespread resistance to these currently sensitive antimicrobials is very high exemplifying the ability of S. Typhi to adapt to changing antimicrobial pressures.</p
