Emergence of Extensively Drug-Resistant Salmonella Typhi Infections Among Travelers to or From Pakistan — United States, 2016–2018

Kevin Chatham-Stephens, MD; Felicita Medalla, MD; Michael Hughes, MPH; Grace D. Appiah, MD; Rachael D. Aubert, PhD; Hayat Caidi, PhD; Kristina M. Angelo, DO; Allison T. Walker, PhD; Noël Hatley, MPH; Sofia Masani, MSN; June Nash; John Belko, MD; Edward T. Ryan, MD; Eric Mintz, MD; Cindy R. Friedman, MD


Morbidity and Mortality Weekly Report. 2019;68(1):11-13. 

In This Article


A large typhoid fever outbreak in Pakistan has resulted in 5,372 XDR Typhi cases reported during 2016–2018, and five travel-related cases in the United States. Approximately 250,000 trips to Pakistan were taken from the United States in 2017 (modeled data from OAG, Inc., https://www.oag.com); travelers to Pakistan might be at risk for acquiring XDR Typhi and having limited treatment options. Spread of the XDR Typhi strain to neighboring countries, such as India, might occur; approximately 2.4 million trips from the United States to India were taken in 2017 (modeled data from OAG, Inc.), and returning travelers from India typically account for 57%–69% of typhoid fever cases reported to CDC.[5,8]

Providers caring for patients with suspected typhoid fever should obtain a travel history, blood and stool cultures, and antimicrobial susceptibility testing. Serologic tests have several limitations and do not yield a bacterial isolate that can be used for antimicrobial susceptibility testing; they should not be used to diagnose typhoid fever. Patients with confirmed typhoid fever should be reported to the local health department. Health departments should notify CDC of typhoid fever cases and send all Typhi isolates to NARMS for antimicrobial susceptibility testing.

Most typhoid fever infections diagnosed in the United States are fluoroquinolone nonsusceptible; therefore, health care providers should not use fluoroquinolones as empiric therapy, especially in returning travelers from South Asia.[8] Fluoroquinolone nonsusceptibility has been associated with treatment failure or delayed clinical response.[4] Typhoid fever relapses involving a similar, but often less severe, illness can occur even with appropriate treatment, typically 1–3 weeks after initial clinical improvement.[4]

The emergence of fluoroquinolone nonsusceptible strains that are resistant to third-generation cephalosporins, such as ceftriaxone, in Pakistan and other countries complicates typhoid fever treatment. The XDR Typhi strain is only susceptible to azithromycin and carbapenems. Azithromycin should be used to treat patients with suspected uncomplicated typhoid fever who have traveled to or from Pakistan. Azithromycin dosing for typhoid fever is higher than the dosage for more routine indications.[9] Patients with suspected severe or complicated typhoid fever (which includes encephalopathy, intestinal perforation, peritonitis, intestinal hemorrhage, or bacteremia with sepsis or shock) and who have traveled to or from Pakistan might need to be treated with a carbapenem.[9] Treatment regimens can be adjusted when culture and sensitivity results are available.

Effective strategies to promote pretravel typhoid vaccination, surveillance with rapid reporting of XDR Typhi cases, and use of alternative empiric treatments when clinical suspicion is high are critical to preventing and treating further travel-associated cases. Two typhoid fever vaccines are available in the United States for travelers: an oral live, attenuated vaccine (Vivotif) and an intramuscular Vi capsular polysaccharide vaccine (Typhim Vi). Both vaccines are moderately effective, protecting 50%–80% of recipients. The oral vaccine can be given to persons aged ≥6 years at least 1 week before travel, and the intramuscular vaccine can be given to persons aged ≥2 years at least 2 weeks before travel.[10]

The findings in this report are subject to at least two limitations. First, surveillance data from NTPFS and NARMS identify only culture-confirmed infections, which represent a fraction of all infections. Second, some Typhi isolates were from patients for whom a case report form with travel information was not sent to NTPFS; thus travel history and resistance data were not available for all confirmed cases of typhoid fever.

Vaccination and safe food and water practices (only drinking water that is disinfected or bottled and washing hands before eating) while traveling provide the best protection from typhoid fever.[10] Travelers should seek medical care if they become ill while traveling abroad or after returning home. Early clinical suspicion for typhoid fever can ensure that cultures are sent to the laboratory and that appropriate antibiotic treatment is started quickly, thereby reducing morbidity and mortality. In the United States, collaboration among health care providers, local and state health departments, and CDC is essential to ensuring that emerging resistance patterns are identified quickly and that patients receive appropriate treatment. Globally, public health partners should work to improve prevention efforts that include vaccination in the face of diminishing therapeutic options.