Doctors in Canada have been warned about extensively-drug resistant (XDR) typhoid from Pakistan as it surfaced in their first pediatric case in a three-year-old boy who picked it up on a visit to Karachi for a wedding with his family.

The child contracted enteric fever during his visit in the summer of 2018. He was diagnosed after returning to Toronto and blood tests showed Salmonella enterica serovar Typhi. It did not respond to all first-line antibiotics, including ceftriaxone. He was successfully treated with a two-week course when Empiric ceftriaxone was switched to meropenem.

The doctors published their warning in the journal ID Cases on January 15, 2019. “To our knowledge, this is one of the first cases of XDR typhoid in a child outside of Pakistan,” they wrote. “Current empiric antimicrobial choices will result in treatment failure if an XDR strain is encountered, therefore clinicians must adapt their empiric approach for those returning from high risk regions,” they wrote. “Clinicians must be vigilant of future cases.”

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An outbreak of XDR typhoid is currently emerging from Pakistan and several cases have been identified in the UK and US. International travel is increasing, so doctors need to be alert to diseases that are commonly imported from abroad and of how they may be resistant to drugs. Travelers who visit friends and relatives, particularly to the Indian subcontinent, are at the highest risk of contracting enteric fever.

The US CDC recommends vaccination for Typhoid for all travelers to South Asia, especially Pakistan, due to outbreak of extensively drug-resistant Salmonella Typhi. It has also cautioned travelers to take extra care to follow safe food and water guidelines.

In a recent 28-year review of all children with enteric fever who came to Toronto’s Hospital for Sick Children, 89% had visited friends and relatives, and 80% got sick during travel to Pakistan, India or Bangladesh.

Typhoid fever is caused by S. Typhi. The highest number of typhoid cases emerges in low to middle income countries that have poor sanitation and public health infrastructure. Rates are highest in South Asia. An estimated 26m cases of Enteric fever happen worldwide, with an estimated 216,000 deaths each year attributed to Salmonella Typhi.

Doctors treat typhoid with third-generation cephalosporins. In November 2016, a large outbreak of extensively drug-resistant typhoid emerged in Pakistan which is resistant to all first-line antimicrobials drugs, including third-generation cephalosporins.

Related: Superbug typhoid fever rings alarm bells in Sindh

The healthy three-year-old boy became unwell during a holiday to Karachi, in June-July 2018. Before his return to Canada, he developed fever, abdominal pain, diarrhea, and vomiting for two days. A local physician prescribed cefixime and advised the family to follow up at the Emergency Department in Canada.

There were no known contacts from which he could have been infected and he stayed with his maternal grandparents in Karachi throughout the visit. The family only visited relatives and attended a family wedding in the same area. They ate locally prepared food and drank bottled water. The family did not seek pre-travel advice and did not receive the typhoid vaccine, malaria prophylaxis, or other travel related medication.

The child was seen at the emergency department at Toronto’s Hospital for Sick Children soon after returning to Canada and was diagnosed with presumed enteric fever. They started him on ceftriaxone and admitted him to a nearby pediatric unit. Tests showed his infection grew to Salmonella enterica serovar Typhi.

Despite being treated with appropriate antibiotics, the child continued to have daily high grade fevers thirteen days into meropenem treatment albeit less frequent.

Sindh outbreak

Since November 2016, Sindh has seen a large outbreak of XDR S. Typhi, predominantly in Hyderabad and Karachi. As of December 2018, more than 5,000 cases have been reported and all have been resistant to ampicillin, TMP-SMX, ciprofloxacin and ceftriaxone but remain susceptible to azithromycin.

Related: Sindh to launch vaccination campaign against superbug typhoid fever in March

So far in 2018, there have been six Pakistan outbreak-related cases of XDR typhoid in travelers from the UK and US. “The current practice of initiating ceftriaxone in these patients will be ineffective if the infecting strain is XDR,” they wrote. “A potential empiric strategy is the use of meropenem for the septic child or the combination of ceftriaxone and azithromycin for the clinically stable.”

The WHO has recently noted progress in stopping the spread of typhoid with the Vi polysaccharide tetanus-toxoid conjugate vaccine (Typbar-TCV). The WHO recommends large scale TCV vaccination programs in endemic areas, which is effective from six months of age.

The Pakistan Medical Association also issued a health alert cautioning people to only drink boiled water, avoid ice if they don’t know how pure it is, wash their fruits, vegetables and utensils with boiled water and wash their hands before eating and after using the toilet.

They also advised people to avoid eating food from outside. Always visit a qualified doctor, said a health alert issued by the PMA on February 11. It also advised people to avoid self-medication and taking antibiotics prescribed by hakeems or homeopaths.

Background

It was in the 1970s when drug-resistant S. Typhi strains first appeared. By the 1980s and early 1990s doctors were looking at multidrug resistant (MDR) typhoid.

Fluoroquinolones, particularly ciprofloxacin, become first line therapy in the 1990s however, resistance developed shortly thereafter. Due to the emergence of MDR typhoid, most nations are now reliant upon third-generation cephalosporins like ceftriaxone and azilides like azithromycin, as first-line agents. For poorer countries, these antimicrobials have become the only financially feasible options.

Over the last two decades, sporadic cases have been reported of XDR typhoid resistant to ceftriaxone and even azithromycin.

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