Typhoid fever is a life-threating systemic infection caused by Salmonella enterica sub-species enterica serovars Typhi (S. Typhi) and Paratyphi A (S. Paratyphi A). While the disease is mainly travel-associated in developed countries, it still causes significant burden in the poorest areas in developing countries where safe water and adequate sanitation and food hygiene remain limited. Typhoid management largely relies on antimicrobial therapy; however, antimicrobial resistance (AMR) in these causative pathogens has become a global threat, compromising the effectiveness of the treatment therapy and signifying the burden of this disease. Understanding the epidemiology of typhoid fever in different endemic settings as well as the impact of AMR on the disease outcome is crucial for disease control and management.
First, this thesis utilized whole genome sequences of S. Typhi combined with clinical data from a randomized controlled trial to investigate the impact of AMR and bacterial genotype on the disease outcome. A novel subclade of ciprofloxacin-resistant H58 S. Typhi associated with increased treatment failure was identified and these organisms were likely widespread in Indian subcontinent. Subsequently, this study combined bacterial genomics with conventional epidemiological tools to reveal the population structure and spatiotemporal dynamics of S. Paratyphi A isolates in Nepal. The Nepalese S. Paratyphi A population was highly dynamic with evidences of regular inter-country transmission, clonal expansion and replacement of distinct genotypes during the study period. A number of localized spatiotemporal clusters of S. Paratyphi A cases were also identified. A molecular epidemiological investigation was also performed to provide insights into the AMR, epidemiological features and population structure and dynamics of S. Typhi in rural areas of Siem Reap, Cambodia. A substantial burden of pediatric typhoid fever was revealed and communes with high-risk of infection were identified. Multidrug resistant H58 S. Typhi with reduced susceptibility to fluoroquinolones was dominant in this setting. This study also investigated the phylogenetic relationship between acute and carriage S. Typhi isolates in Nepal and deciphered the genetic characteristics associated with carriage isolates. My study suggested that typhoid carriage was likely not an important source of new infections in endemic area
