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Title: Clinical issues and molecular characterisation of Salmonella typhi isolates from South East Asia
Author: Dolecek, Christiane
ISNI:       0000 0004 2712 7140
Awarding Body: London School of Hygiene & Tropical Medicine
Current Institution: London School of Hygiene and Tropical Medicine (University of London)
Date of Award: 2011
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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.
Supervisor: Wren, B. W. ; Dougan, Gordon Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral