Clinical Issues and Molecular Characterisation of Salmonella Typhi Isolates from South East Asia

Due to the spread of antimicrobial drug resistance, typhoid fever has become increasingly difficult to treat. In Vietnam, more than 50% of S. Typhi isolates are multidrug resistant and 90% are quinolone resistant. This thesis examines three aspects of typhoid fever; treatment, genotyping of bacteria and the clinical development of an oral vaccine. We enrolled 358 children and adults with suspected typhoid fever into a randomised controlled trial to compare the efficacy and safety of gatifloxacin (10 mg/kglday) versus azithromycin (20 mg/kglday) for 7 days. In the blood culture confinned group, 145 patients received gatifloxacin and 142 patients received azithromycin. Overall treatment failure occurred in 13/145 (9%) patients in the gatitloxacin group and 13/140 (9.3%) patients in the azithromycin group (HR = 0.93; 95% CI 0.43 - 2.0; p = 0.854). We found a statistically significant relationship between drug exposure to gatifloxacin and clinical response. In patients with AUCo-24: MIC ratios of greater than 92.7, 93.5% of patients had a favourable response; whilst in patients with AUC 0-24: MIC ratios equal or less than 92.7, only 75% had a favorable response (OR = 4.81; 95% CI 1.23-18.9; P = 0.02). We investigated the genetic variability and relationship between the S. Typhi trial isolates by using a novel SNP genotyping array. The majority of isolates (98%) belonged to the H58 haplotype, a quinolone resistant haplotype that has expanded globally. Within this group three main subgroups could be distinguished. We conducted a randomised placebo controlled trial to detennine the safety and immunogenicity of a novel oral typhoid vaccine (MO IZH09) with two independently-attenuating deletions (Ty2 aroC- ssa V -) in healthy 5 to 14 year old children in Vietnam. One hundred and fifty-one children were enrolled and followed up for 28 days. Twenty-six percent of MOIZH09 subjects and 22% of placebo subjects experienced an adverse event. There were no serious adverse events and no bacteraemia. Ninety-seven percent of the subjects showed a positive immune response. MOIZH09 was immunogenic and had an appropriate safety and reactogenicity profile in children in an area with endemic typhoid fever.