The Microbiologist listened as the Emergency Department (ED) Consultant expanded on the story with where exactly the patient had been in India, what she had been doing there and what pre-travel vaccinations she had had. It was a great presentation and showed that the Consultant had clearly been listening to the teaching on fever in a returning traveller that the Microbiologist had given the week before!
“Okay, she’s been to the North of India, we’d better cover for XDR typhoid as well as meningitis and other potential causes of sepsis. The best thing to do is start IV Meropenem 2g TDS, and if it’s not meningitis then we can reduce the dose to 1g later” replied the Microbiologist.
“Isn’t IV Ceftriaxone the normal first line for typhoid?” asked the ED Consultant.
“It is” replied the Microbiologist, “unless you have the XDR typhoid which is currently causing mayhem in Pakistan next to India, XDR is Ceftriaxone resistant and so you need Meropenem instead.”
“Crikey!” exclaimed the ED Consultant, “long gone are the days when I could treat this with Ampicillin…I’m sure Typhoid Mary would have accepted Ampicillin!”
“We all feel a little old these days, I find it’s more about the mileage not so much the years…!” said the Microbiologist.
Typhoid fever is a systemic bacterial infection caused by Salmonella typhi; it is similar to other types of enteric fever caused by Salmonella paratyphi A, B and C.
Typhoid occurs all over the World, especially in developing countries where access to clean water to drink and safe disposal of sewerage and good sanitation are limited. It has been estimated that there are about 27 million cases of typhoid every year. Humans are the only known hosts for S. typhi and so to get typhoid you have to have eaten someone else’s poo! The mortality of typhoid without treatment is 40%.
How does typhoid fever present?
Typhoid usually starts with a non-specific prodrome of fever, headache and malaise. Typhoid can be split into mild and severe:
- Mild – fever, headache and malaise which resolves spontaneously in 60-90% of patients
- Severe – anorexia, bradycardia, splenomegaly, cough, rash (rose spots on trunk in 25% of fair skinned people) progressing to sepsis, encephalopathy, bowel perforation, peritonitis, intestinal haemorrhage, hepatitis and death
Up to 20% of patients who have had typhoid will have relapsing infections as S. typhi can colonise the biliary tree and “re-infect” the patient from there. Remember last week’s blog about the historical case of Typhoid Mary, an amazingly well research outbreak and a rather tragic tale before the era of antibiotics!
How is typhoid fever diagnosed?
Typhoid fever is usually diagnosed by growing S. typhi from blood, urine or faeces. S. typhi grows easily on most agar plates; it is in the same family of Enterobacterales as Escherichia coli and Klebsiella spp.
It’s important to remember that S. typhi (and S. paratyphi) is a Biological Safety Level 3 bacterium which should be processed in a category 3 laboratory facility. Please ensure the request form alerts the laboratory to the potential diagnosis and danger.
There have been typhoid vaccines available for a long time for use in travellers to countries where enteric fever is endemic but there are a number of drawbacks to these:
- Oral Ty21a vaccine – is a live vaccine which cannot be used in immunosuppressed people or in those on antibiotics (the antibiotic kills the vaccine strain of bacteria making it ineffective), it is a large capsule too big to be swallowed by children under 2 years old and provides no long-term immunity therefore boosters are required every 2-5 years
- Injectable Vi polysaccharide vaccine – but it is not immunogenic in young children
The new typhoid vaccine
A new polysaccharide vaccine has recently hit the news following a successful clinical trial in Nepal. In this study 10,000 children were vaccinated against typhoid. The vaccine was shown to reduce the incidence of typhoid by 81.6%; there was only 1 severe adverse event related to the vaccine (high fever requiring hospital admission) in the 6 months post vaccination.
What does this mean in real terms? The mortality of typhoid without treatment is 40% therefore in a country like Nepal where medical care isn’t easily available, for every 400 cases per 100,000 it could be expected that 160 children would die every year. The study showed that with the vaccine this would be reduced to 32 deaths, or looking at this the other way the vaccine would save 128 lives per 100,000 population per year.
In reality there are 150,000 deaths Worldwide per year from typhoid, so preventing 80% of cases with universal vaccination could potentially save 120,000 lives… it’s maybe a “pipe dream” as getting vaccines into arms in developing countries for global good doesn’t seem to be high priority in the modern “me first - Covid-19 era” but those are the statistics.
The Pakistan outbreak
At the moment most outbreaks of typhoid cases are treatable and thwarted with antibiotics however there are outbreaks of antibiotic-resistant typhoid occurring with increasing frequency. In Pakistan there has been an on-going outbreak of extensively-resistant (XDR) S. typhi which started in 2016 in Hyderabad and then spread throughout the Sindh District. As of August 2019 there had been 10,365 cases, with further cases in travellers returning from Pakistan to the UK, USA and Australia, amongst others.
What is XDR S. typhi?
XDR S. typhi is resistant to the normal first and second line treatments of typhoid (Chloramphenicol, Ampicillin, Co-trimoxazole, fluoroquinolones such as Ciprofloxacin) as well as the cephalosporins Cefotaxime, Ceftriaxone and Cefepime. This means that unless resistance is suspected patients will not receive adequate treatment and may come to harm before the resistance is “detected”, in most countries IV Ceftriaxone is the first line treatment for severe typhoid fever.
How should XDR typhoid fever be treated?
The treatment for XDR typhoid fever depends on how sick the patient is:
- Mild – PO Azithromycin
- Severe – IV Meropenem
At the end of the day Salmonella typhi is an Enterobacterales, like Escherichia coli or Klebsiella pneumoniae, both already have increasing rates of carbapenem resistance which could easily transfer into Salmonella spp. We are rapidly approaching a time when we may have no options for treating typhoid fever. It’s a scary thought!
Typhoid fever rant!
So the new typhoid vaccine is a great tool in the fight against typhoid, as it is antibiotic resistance independent, however it doesn’t correct the underlying problem. Typhoid fever occurs in countries where people are without access to safe drinking water, good sanitation and safe disposal of sewerage. If clean water and sanitation were available the vaccine wouldn’t be needed at all! Plus, other waterborne infections such as paratyphoid fever, cholera and viral gastroenteritis would also be prevented.
I my opinion access to safe drinking water and good sanitation should be an equal right for everyone in the World. I know this sounds a lot simpler to say than to achieve but I really believe this. I have been fortunate enough to travel to some amazing countries, meet fantastic people and see tremendous sites, but every time I go to a developing country I am struck about the continuing need for the basics: safe drinking water and sanitation.
I get really irritated when I see people wasting water in the UK by not turning off taps after they have washed their hands (at least they were washing their hands!!). Or when I hear about people leave taps dripping, keep the water running when they clean their teeth or allow water to flow while they soap up in the shower. Editor Chief in Charge is even worse! She has had a passion about access to clean water for many years, especially since she helped on a voluntary project after University in Kenya digging a 30ft stone well (yet no water…so kept digging deeper) for a village who had to otherwise walk 6 hours to get water carrying water back in bottles on their heads, a journey repeated, by women, every single day!!
So, the patient had blood, urine and stool cultures sent, all of which were labelled “Suspected Typhoid - high risk” and were processed in the Biological Safety Level 3 facility. The patient was started in IV Meropenem and their clinical condition started to stabilise. The next day S. typhi was grown from all 3 samples but fortunately the bacterium was shown to be sensitive to fluoroquinolones, so the patient was changed to oral Ciprofloxacin. They were discharged home a day later and made a full recovery… but they explained to the ward Doctor that they were thinking of going to Cornwall for the next holiday… safer… unless you have read the blog “is it safe to swim in the sea!!!”