Antimicrobial resistance is a major problem in the treatment of typhoid fever; a systemic human infection caused by Salmonella Typhi (S. Typhi). The co-existence of multidrug resistant and fluoroquinolone resistant S. Typhi isolates is increasingly common. Therefore, it is essential to understand the molecular mechanisms and the epidemiology of antimicrobial resistant S. Typhi in endemic countries such as Viet Nam. A cross section of S. Typhi strains isolated from 8 Asian countries and a Vietnamese S. Typhi collection were investigated for antimicrobial resistance patterns. Molecular approaches were used to identify the mechanisms of (fluoro)quinolone resistance in S. Typhi isolates. Specific phenotypic characteristics of each of the naturally mutations were assessed in S. Typhi isolates that were reconstructed in an isogenic strain. The antimicrobial resistance phenotypes of both wild type and reconstructed mutants were calculated using antimicrobial susceptibility tests and time-kill experiments. To predict the relative fitness of these mutants, the strains were subjected to independent and competitive growth assays. Finally, we developed a molecular epidemiological tool which was used to genotype and identify fluoroquinolone resistant S. Typhi strains circulating in Asia. The findings of this study show that antimicrobial resistant S. Typhi is continuing problem in Asian countries, especially in Viet Nam. Fluoroquinolone resistance in S. Typhi is caused by mutations in specific locations of the gyrA and parC genes. The majority of reconstructed mutants had a selective growth advantage when placed in competition with a non-mutant S. Typhi strain. Strains that had the highest level of fluoroquinolone resistance had a selective disadvantage. We conclude that S. Typhi haplotype H58 with associated nalidixic acid resistance is dominant across Asian countries
