Recently, the US Centers for Disease Control and Prevention (CDC) issued a Level 2 travel alert for Pakistan as the result of an ongoing outbreak of extensively drug resistant (XDR) typhoid fever. The alert encourages enhanced precautions for travelers, including getting vaccinated against typhoid and practicing safe eating and drinking habits. The incidence of individual cases of drug-resistant infections more broadly have risen in recent years, but sustained transmission, like we are seeing in Pakistan, is considerably more rare.

Typhoid Fever

Typhoid fever is an potentially deadly illness caused by Salmonella typhi that is typically transmitted through contaminated water and food. Symptoms of typhoid fever include high fever, headaches, and vomiting. Typhoid fever was previously so formidable that it had a case fatality rate (CFR) of approximately 15%. Only after the introduction of chloramphenicol as a treatment in 1948 did the CFR dropped to less than 1%. However, typhoid fever has continued to persist, relatively under the radar, in low- and middle-income countries with poor sanitation, water quality, and public health infrastructure. The WHO currently estimates 21 million cases of typhoid fever and 222,000 deaths annually worldwide.

Pakistan is one of many countries where typhoid fever is endemic. A recent study of the early stages of this outbreak notes that each of the 4 water treatment plants in Hyderabad district were “non-functional and [were] supplying contaminated water to the residents.” This article describes how the outbreak has worsened since November 2016, around the time that health officials identified additional resistance characteristics.

Antimicrobial Resistance

Antimicrobial resistance (AMR) occurs when microorganisms mutate such that are less susceptible to the drugs that are meant to combat them. Several factors can contribute to these mutations, including the over-prescription and improper use of antimicrobials—antibiotics being, far and away, the biggest problem. Generally, 3 progressive categories have been used to describe the level of resistance bacteria have acquired: multidrug-resistant (MDR); extensively drug-resistant (XDR), and pan-drug resistant (PDR), which means that a pathogen is resistant to every single available drug.

Typhoid Fever in Pakistan

Since November 2016, the Pakistani province of Sindh has been facing an outbreak of XDR typhoid fever. Official numbers are difficult to come by, but one recent report indicates that more than 2000 cases have been identified. According to another report, 80% of the cases are in children under the age of 10, and the US CDC travel alert states that several victims were travelers that have returned to the US and UK.

Only four cases of XDR typhoid fever been previously recorded, and all have been isolated cases with no subsequent transmission. This outbreak is novel because it is the first documented case of continued transmission of XDR typhoid fever.

Health officials began noticing an increase in the proportion of typhoid fever cases resistant to ceftriaxone, an antibiotic usually reserved to treat MDR typhoid fever, in November 2016. The bacterium is resistant to 5 kinds of antibiotics, which by convention, classifies it as extremely drug-resistant. Genetic analysis indicates that the bacterium acquired the drug resistance in Pakistan, as opposed to the importation of a strain with pre-existing resistance. The only effective oral antibiotic is azithromycin, and the remaining alternatives are all intravenous (IV) antibiotics. The IV products are far more costly and considerably more difficult to administer, particularly on the large scale necessary to combat an outbreak of this size.

In response to this outbreak, Pakistan will incorporate typhoid vaccine into its childhood immunization program. Pakistan hopes to receive support from GAVI to acquire a new, conjugate typhoid vaccine that has been shown to be more effective than previous vaccines and safe for children as young as 6 months—previous versions of the vaccine are only safe for children aged 2 years and older. Because the bacterium currently circulating in Pakistan has acquired such extensive resistance, vaccination is likely the best way to control the outbreak. Health officials may not be able to effectively treat cases—which would decrease or stop their shedding of the bacteria and, therefore, reduce transmission—but they can potentially prevent new cases through immunization.

Conclusion

Public health authorities around the world have warned for years of the looming threat posed by antimicrobial resistance. And while there have been a number of isolated cases and limited outbreaks of drug-resistant pathogens, the world has largely managed to avoid large-scale drug-resistant disease burden in humans, most notably in developed countries. Pakistan’s outbreak of XDR typhoid fever should serve as a reminder of the urgency of the battle against antimicrobial resistance and of the steps that must be taken to protect the public from the potentially catastrophic outcomes of increased drug resistance.

Effective and resilient infrastructure outside of the health system is vital to controlling and preventing these types of health threats. For example, improved sanitation and water treatment could potentially limit the rate of transmission in Pakistan. And as noted above, the bacterium appears to have developed drug resistance characteristics in Pakistan, so had the outbreak been quickly brought under control, it is possible that the extensive drug resistance may not have emerged. Additionally, the inclusion of typhoid vaccine in routine immunization programs could provide a mechanism to prevent these outbreaks from occurring in the first place, denying the bacterium an opportunity to develop resistance. Finally, the limited options for combating pathogens that have acquired high levels of resistance is troubling. Fewer and fewer antibiotics have reached the market in recent years (for a myriad of reasons), and the demand for new kinds of treatment options will continue to rise as resistance becomes more prevalent. Ultimately, prevention is more effective than treatment, and further effort is needed across the board to mitigate the risk of pathogens further developing drug resistance.

 

Photo courtesy of CDC/James Archer.

Outbreak Observatory aims to collect information on challenges and solutions associated with outbreak response and share it broadly to allow others to learn from these experiences in order to improve global outbreak response capabilities.