Genomic Dissection of Travel-Associated Extended-Spectrum-Beta-Lactamase-Producing Salmonella enterica Serovar Typhi Isolates Originating from the Philippines: a One-Off Occurrence or a Threat to Effective Treatment of Typhoid Fever?

Abstract

f One unreported case of extended-spectrum-beta-lactamase (ESBL)-producing Salmonella enterica serovar Typhi was identified, whole-genome sequence typed, among other analyses, and compared to other available genomes of S. Typhi. The reported strain was similar to a previously published strain harboring bla SHV-12 from the Philippines and likely part of an undetected outbreak, the first of ESBL-producing S. Typhi. The occurrence of extended-spectrum-beta-lactamase (ESBL)-producing Salmonella enterica serovar Typhi is an alarming development which may significantly complicate the treatment of typhoid fever. To date, ESBL-producing S. enterica serovar Typhi has only been reported from Bangladesh, Egypt, India, Iran, Iraq, Pakistan, and the Philippines (1). A subset of strains (from India, Iraq, and the Philippines) has been independently confirmed, and an assortment of ESBL genes (bla , bla , and bla CMY-2 ) have been identified and sequenced.The purpose of the present study was to identify potentially unreported cases of typhoid fever caused by ESBL-producing S. Typhi at a global level, to confirm ESBL production phenotypically, and to identify the responsible ESBL genes. Furthermore, we wanted to investigate the genetic relatedness to other available ESBL-producing S. Typhi isolates using whole-genome sequence typing (WGST) and a variety of molecular and genomic studies and to test the hypothesis that impaired restriction modification (RM) systems could be a factor for the development of ESBL resistance.On 4 May 2012, an electronic message requesting information about any confirmed or suspected ESBL-producing S. Typhi isolates was sent to the members of the World Health Organization (WHO) Global Foodborne Infections Network (GFN). Of 1,062 recipients, 3 members (0.28%) responded. We believe that the low response rate reflects a true low prevalence as the members frequently receive and respond to messages.One strain (strain 1107-3567) confirmed as an ESBL-producing S. Typhi strain was submitted by The Norwegian Institute of Public Health. The Norwegian patient in question and a previously published case from the Netherlands (strain TY5359) (2) had travel histories to the Philippines in late 2007 that were almost identical. The Norwegian patient had gastroenteritis, whereas the Dutch patient was admitted to a hospital with typhoid fever caused by an ESBL-producing S. Typhi containing the bla gene. The Dutch patient was treated successfully with ciprofloxacin; the treatment of the Norwegian patient was unknown.The isolates were sequenced using the MiSeq platform (Illumina, Inc., San Diego, CA) (see Methods in the supplemental material). The raw reads were assembled using the Assembler pipeline (version 1.0) available from the Center for Genomic Epidemiology (CGE) (http://cge.cbs.dtu.dk/services/all.php) and submitted to the European Nucleotide Archive (http://www.ebi .ac.uk/ena/data/view/PRJEB6961) (accession no. ERS525820 and ERS525821). A complete list of genomic sequence data is available in Table S1A in the s...

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“…typhi in the Philippines suggests there may be an unrecognised outbreak of ESBL S . typhi there . In Nigeria, plasmid‐mediated CTX‐M1 has recently been reported in 9/25 blood culture isolates of S .…”

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