Trend of Emerging XDR Salmonella Typhi Infections Persists in Pakistan Outbreak

Over the past several decades, the emergence of typhoid cases that are resistant to historically used antibiotics has led to the use of fluoroquinolones as the first-line treatment. However, since the early 2000s, increasing nonsusceptibility to fluoroquinolones has led to the recommendation of third-generation cephalosporins as first-line treatment.

In February 2018, an extensively drug-resistant (XDR) typhoid fever outbreak caused by Salmonella enterica serotype Typhi (typhi) was reported in Pakistan. Typhi isolates are defined as multidrug-resistant if they are resistant to chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole. Cases are considered XDR if they are multidrug-resistant and also nonsusceptible to fluoroquinolones and resistant to third-generation cephalosporins.

Between November 2016 and September 2017, 339 cases of this XDR Typhi strain were reported in Pakistan, mostly in Karachi and Hyderabad; one travel-associated case was also reported in the United Kingdom.

To determine the burden of the outbreak, health officials in Pakistan increased surveillance efforts and found that approximately 5372 cases of the XDR Typhi strain occurred during this time period.

In response to the increased case counts from Pakistan, the US Centers for Disease Control and Prevention (CDC) in the United States enhanced surveillance in March 2018 by requesting that state and local health departments interview every patient with typhoid fever about travel to or from Pakistan to expedite the investigation. The findings of the surveillance are published in the Morbidity and Mortality Weekly Report.

Typhoid surveillance is typically completed through analyzing culture-confirmed Typhi cases submitted by local and state health departments to the CDC’s National Typhoid and Paratyphoid Fever Surveillance system (NTPFS).

The enhanced surveillance identified 5 cases of XDR Typhi detected in the United States following travel to or from Pakistan. All 5 individuals were children between the ages of 4 and 12 who had traveled to or from Pakistan during late 2017 through mid-2018.

To investigate the overall the trends of resistant typhoid infections, a team of health officials examined surveillance data submitted to NTPFS and the National Antimicrobial Resistance Monitoring System (NARMS) from 2006 through 2015 and compared the information to the data from 2016 through 2018.

The investigators found that a total of 3538 individuals in the United States had culture-confirmed typhoid fever cases reported between 2006 and 2015. For individuals with available information, a total of 169 isolates were collected from travelers to Pakistan, 133 (79%) of which were fluoroquinolone nonsusceptible and 85 (50%) of which were classified as multidrug-resistant.

Between 2016 and 2018, 29 individuals with typhoid fever reported having traveled to or from Pakistan; 5 cases were confirmed to be XDR Typhi.

As a result of these findings, the investigators stated that clinicians caring for patients with suspected typhoid fever should obtain a travel history, blood and stool cultures, and initiate antimicrobial susceptibility testing.

Trends indicate that most typhoid fever infections diagnosed in the United States are fluoroquinolone nonsusceptible and, therefore, health care providers should not use fluoroquinolones as empiric therapy, especially in travelers returning from South Asia. Empiric therapy use has been associated with treatment failure or delayed clinical response.

Instead, the investigators advised using azithromycin to treat patients with suspected uncomplicated typhoid fever who had traveled to or from Pakistan. Those with a travel history to and from Pakistan with severe cases of typhoid fever may be treated with carbapenems. The authors also advised that treatment regimens can be adjusted when culture and sensitivity results are available.

“Clinicians should be aware that most typhoid fever infections in the United States are fluoroquinolone nonsusceptible and that the XDR Typhi outbreak strain associated with travel to Pakistan is only susceptible to azithromycin and carbapenems,” the team wrote in their report.

To prevent and treat further travel-associated cases of typhoid fever, the report authors advocate for enhanced surveillance and use of alternative empiric treatment when clinical suspicion is elevated.

Additionally, travelers to areas with endemic typhoid disease, including South Asia, should be vaccinated against typhoid fever prior to traveling and should follow safe food and water practices.