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While multidrug-resistant (MDR) <jats:italic>Salmonella<\/jats:italic> Typhi (<jats:italic>S<\/jats:italic>. Typhi) has spread globally, fluoroquinolone resistance has mainly affected Asia.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Consecutively, 1038 blood cultures were obtained from patients of all age groups with fever and\/or suspicion of serious systemic infection admitted at Mnazi Mmoja Hospital, Zanzibar in 2015\u20132016. <jats:italic>S<\/jats:italic>. Typhi were analyzed with antimicrobial susceptibility testing and with short read (61 strains) and long read (9 strains) whole genome sequencing, including three <jats:italic>S<\/jats:italic>. Typhi strains isolated in a pilot study 2012\u20132013.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Sixty-three <jats:italic>S<\/jats:italic>. Typhi isolates (98%) were MDR carrying <jats:italic>bla<\/jats:italic><jats:sub>TEM-1B<\/jats:sub>, <jats:italic>sul1<\/jats:italic> and <jats:italic>sul2<\/jats:italic>, <jats:italic>dfrA7<\/jats:italic> and <jats:italic>catA1<\/jats:italic> genes. Low-level ciprofloxacin resistance was detected in 69% (43\/62), with a single gyrase mutation <jats:italic>gyrA<\/jats:italic>-D87G in 41 strains, and a single <jats:italic>gyrA-<\/jats:italic>S83F mutation in the non-MDR strain. All isolates were susceptible to ceftriaxone and azithromycin. All MDR isolates belonged to genotype 4.3.1 lineage I (4.3.1.1), with the antimicrobial resistance determinants located on a composite transposon integrated into the chromosome. Phylogenetically, the MDR subgroup with ciprofloxacin resistance clusters together with two external isolates.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>We report a high rate of MDR and low-level ciprofloxacin resistant <jats:italic>S<\/jats:italic>. Typhi circulating in Zanzibar, belonging to genotype 4.3.1.1, which is widespread in Southeast Asia and African countries and associated with low-level ciprofloxacin resistance. Few therapeutic options are available for treatment of typhoid fever in the study setting. Surveillance of the prevalence, spread and antimicrobial susceptibility of <jats:italic>S<\/jats:italic>. 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