Emergence of Resistance to Fluoroquinolones and Third-Generation Cephalosporins in Salmonella Typhi in Lahore, Pakistan

Background Extensively drug-resistant (XDR) Salmonella Typhi has been reported in Sindh province of Pakistan since 2016. The potential for further spread is of serious concern as remaining treatment options are severely limited. We report the phenotypic and genotypic characterisation of 27 XDR S . Typhi isolated from patients attending Jinnah Hospital, Lahore, Pakistan. Methods Isolates were identified by biochemical profiling; antimicrobial susceptibility was determined by a modified Kirby-Bauer method. These findings were confirmed using Illumina whole genome nucleotide sequence data. All sequences were compared to the outbreak strain from southern Pakistan and typed using the S . Typhi genotyping scheme. Findings Twenty-seven XDR S . Typhi isolates were identified from patients at Jinnah Hospital in Lahore between January and April 2019. All isolates were confirmed by sequence analysis to harbour an IncY plasmid and the CTX-M-15 ceftriaxone resistance determinant. All isolates were of the same genotypic background as the outbreak strain from Sindh province. Summary We report the first emergence of XDR S . Typhi in Punjab province of Pakistan confirmed by whole genome sequencing. Funding This work was supported by the BBSRC-funded QIB Institute Strategic Programme “Microbes in the Food Chain” BB/R012504/1 and its constituent projects Microbial Survival in the Food Chain (BBS/E/F/000PR10349) and Research Infrastructure (BBS/E/F/000PR10352), and the BBSRC funded Core Capability Grant (project number BB/CCG1860/1). Research in context Evidence before this study Typhoid fever is endemic in Pakistan, with widespread resistance to first line drugs: ampicillin, co-trimoxazole, and chloramphenicol, and to fluoroquinolones. In 2017 the first report of additional resistance to ceftriaxone was published as XDR typhoid fever from southern Pakistan. Treatment of XDR typhoid fever has been a clinical challenge; options are scarce, and the level of chronic carriage is unknown. Current treatment is dependent upon azithromycin and this represents a major threat for the community as resistance has been reported from Bangladesh. Added value of this study This study is the first genomic report of XDR typhoid fever in a central part of Pakistan, describing the same genetic background as strains responsible for XDR typhoid in Sindh province. We have confirmed that the outbreak strain of XDR S . Typhi is now present in the most populated province and second largest city of Pakistan. Implications of all the available evidence The present study highlights the gravity of the situation - the spread of this strain is of serious concern. The clinical situation remains unchanged since this study was performed; we believe it is imperative that future research focuses upon the biology, transmission and control of this strain.