Since November 2016, Pakistan has been plagued by an outbreak of extremely resistant typhoid fever. What is so special with this outbreak, and are there broader lessons to be learned from it?
A report from the WHO describes an ongoing outbreak of typhoid fever in the Sindh province of Pakistan that has been ongoing since November 2016. It was first discovered in the Hyderabad district, but has since spread to Karachi. A total of 8188 cases have been reported, of which 5274 are extremely drug resistant (XDR) and therefore difficult to treat. 69% of all cases have this far been identified in Karachi. Six related cases have been discovered abroad: one case in the UK and five cases in the USA. Four of these had visited or resided in the affected areas in Pakistan.
The bacterium that causes XDR thypoid fever
The bacterium has been identified as Salmonella enterica serovar Typhi, haplotype H58 which is a common cause of MDR typhoid fever across Asia and Africa, including the outbreak in Malawi. Unlike the more prevalent varieties of the bacterium, the strain causing the current outbreak has acquired an extended spectrum betalactamase (CTX-M-15) causing resistance to third-generation cephalosporins, as well as a mutation that causes resistance to fluoroquinolones like ciprofloxacin. The H58 haplotype has also been known to harbor resistance to azithromycin on occasion.
Actions to limit the spread and control the outbreak
In order to limit the spread and control the outbreak, Pakistani authorities have taken multiple actions:
- Awareness campaigns on hygiene and safe water.
- Water purification and sanitation activities.
- Vaccination of 124 000 children against Salmonella Typhi.
- Sensitization of clinicians on rational use of antibiotics against typhoid fever.
- Establishment of a national task force and updated surveillance.
What is typhoid fever?
Typhoid fever is caused by the bacterium Salmonella Typhi. The infection is generally food-borne, which means that people become exposed to the bacteria through contaminated food or water. The incubation period is up to two weeks, after which the bacteria can be found in the patients’ blood. Diagnosis may be difficult as the symptom are difficult to distinguish from other febrile illnesses:
- Stepwise increase to high fever.
- Muscle pain.
- Spotty red rash on the trunk.
- Diarrhea usually ensues during the second week.
Without effective antibiotic treatment, the case fatality rate is up to 20%, and many who survive suffer serious complications. With antibiotic treatment, the fatality rate is 1-4%, with the highest rates found in children below 4 years. In higher income countries with good sanitation facilities, typhoid fever is very rare. As an example, 722 cases of typhoid fever were reported in in the EU, and 82% of these cases were related to travel, mainly outside the EU/EEA.
For drug-sensitive isolates, ciprofloxacin is often the first choice of treatment, albeit e.g. amoxicillin and co-trimoxazole are also used for oral therapy. If intravenous therapy is used, cephalosporin antibiotics are often used. For multi-drug resistant cases, azithromycin is often the only available and affordable drug for oral therapy. In the current outbreak, the only treatment options are azithromycin for oral therapy and carbapenems for intravenous therapy.
Azithromycin is an antibiotic in the class macrolides, discovered in 1980. It can be used to treat enteric infections such as salmonella and cholera, community acquired pneumonia, upper respiratory tract infections, uncomplicated skin infections, gonorrhea, chlamydia. The WHO Essential Medicines List includes azithromycin as a key access antibiotic. Due to the risk of resistance development, it is often not recommended for pneumococcal diseases – studies have shown a clear correlation between the use of azithromycin and rates of resistance.
Studies have also been made in Africa, where azithromycin has been administered to whole populations of children. These interventions have reduced mortality among some of these populations, but concerns have been raised regarding the long-term effects on development and spread of resistance against such an important antibiotic.
As typhoid mainly spreads through food and water contaminated with human feces, the first measure is to decontaminate these by boiling or cooking. All persons who prepare food for others, should always wash their hands before and after handling foods.
There are also three types of vaccines available to prevent Salmonella Typhi infections. They are up to 80% effective giving 2-3 years’ protection, except for the newest live attenuated vaccine that gives 7 years’ protection. However, as the degree of protection is lower than for many other vaccines, vaccination is not solely sufficient to control typhoid fever.
In order to manage typhoid sustainably, the transmission pathways need to be severed. This includes ensuring access to clean and safe drinking water on one hand, but also safe management of human waste. Depending on region in the world and country, access to these may vary largely. In some parts of the world open defecation is still a common practice, latrines are not properly managed and poorly treated, or even untreated. Waste is commonly released into waterways which are also used for irrigation, washing and even drinking water supply.
Need for further action in typhoid-endemic areas
In typhoid-endemic areas, actions to improve preventive measures to reduce spread of the bacterium are desperately needed. Vaccination campaigns are also of crucial importance, albeit not sufficiently effective without other complementary measures.
Access to effective antibiotics, in this case azithromycin and carbapenems, and their rational use will be instrumental to treat the already infected patients. Given that the bacterium is able to spread to the UK and USA, it is conceivable that it would spread also to other parts of the world. Therefore an eradication campaign in Pakistan could be warranted.
A worrying circumstance is also the potential of Salmonella Typhi H58 to acquire resistance to azithromycin. Should this occur with this particular strain, it would become practically untreatable in many low-income countries. This highlights the need for judicious use of azithromycin not only in Pakistan, but also in other countries where typhoid fever is endemic. If, for example, mass administration would render this strain of Salmonella Typhi resistant also to azithromycin, typhoid fever would become practically untreatable.
ASM Journals: Emergence of an Extensively Drug-Resistant Salmonella enterica Serovar Typhi Clone Harboring a Promiscuous Plasmid Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins.