Enteric fever is a potentially life-threatening bacterial infection caused by i) Salmonella Typhi, which causes typhoid fever, and ii) Salmonella Paratyphi types A, B and C, which cause paratyphoid fever. It is commonly transmitted via contaminated water and food and is endemic in regions of southeast Asia and sub-Saharan Africa. As an indication of the scale of this global public health threat, there were an estimated 14.3 million cases worldwide in 2017 and ~136,000 associated deaths.

Salmonella is no exception to the trend of increasingly observed antimicrobial resistant (AMR) pathogens. In the past 6 years, an extensively drug resistant (XDR) type of typhoid fever began to spread worldwide; in addition to physical suffering, this places an increased burden on healthcare services and is of great concern due to limited treatment options. Dr Gemma Langridge leads a team at the Quadram Institute (QI) who have been collaborating with the UK Health Security Agency (UKHSA) formerly known as Public Health England the Child Health Research Foundation in Bangladesh, and the Allama Iqbal Medical College & Jinnah Hospital and Government College University in Pakistan, using genome sequencing and analysis to better understand and track cases of enteric fever, including both paratyphoid and typhoid variants, providing an evidence base for clinical management and targeted interventions.

Timeline

1990 to 2018

Outbreaks of typhoid fever increasing in frequency and size and also being observed in non-endemic regions.

1997

Standard treatment for typhoid fever is antibiotics (uncomplicated cases: ciproflaxacin or azithromycin /sever cases: cetriaxone)

1999 to 2000

Salmonella Typhi strains highly resistant to cetriaxone and ciprofloxacin are observed by Dhaka Shishu Hospital, Bangladesh.

Pre 2015

PHE’s standard method of detecting Salmonella Typhi is serotyping, which relies on antibody preparations. In 2014, PHE undertake parallel testing of phenotypic and genotypic methods for identification.

2015

Whole Genome Sequencing (WGS) providing more detailed information is validated with antibiotic phenotype testing for identification and AMR surveillance in Salmonella.

2016

Outbreak of Extensively Drug Resistant (XDR) typhoid fever identified in Sindh province, southern Pakistan

2017

First isolate of ceftriaxone resistant Salmonella Paratyphi A is obtained from a traveller returning to England from Bangladesh. Prompts a Health resistance alert and advisory action from PHE.

2017

From November 2017 to April 2020 XDR Salmonella Typhi consistent with the ongoing outbreak in Pakistan was isolated by PHE from 68 cases of travellers returning to the UK. Cases are increasing and treatment options are decreasing.

2018

PHE developed and implemented a real-time PCR test for the identification and differentiation of typhoidal from non-typhoidal Salmonella enabling same day testing to support case management and public health intervention.

2019

Jinnah Hospital, Lahore observed a dramatic rise in XDR typhoid fever cases (27 cases in 10 weeks).

2019

Quadram Institute researchers generated WGS data for local clinicals in Pakistan confirming an outbreak in Lahore was linked to that in Sindh Province in 2016.

“Increased number of XDR Salmonella Typhi cases in Lahore, Pakistan were creating panic in the medical community but sequencing some of these isolates by Quadram Institute has helped in understanding the origin and management of XDR xases.” Dr Farhan Rasheed, Allama Iqbal Medical College and Jinnah Hospital.

2019

The WGS data is being used to support the case for mass typhoid vaccination being put forward to the Pakistan

2020

Tracking the spread of antibiotic resistant enteric fever infections also assists in outbreak response by health authorities in Pakistan.

2021

In multiple cases the key antibiotic resistance gene responsible for XDR had integrated into Salmonella Typhi genome.

2022

Updated clinical guidelines for management of enteric fever in England are published and include treatment with meropenem and azithromycin for complicated cases from XDR regions.

“This genetic mobility may lead to the maintenance of resistance even in the absence of antibiotic selection pressure. Treatment guidelines may change to reflect this,” Satheesh Nair, UKHSA.

Where next?

Continue sequencing efforts of clinical specimens potentially contaminated waterways and looking for asymptomatic carriers.

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