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

Abstract and Introduction


In February 2018, a typhoid fever outbreak caused by Salmonella enterica serotype Typhi (Typhi), resistant to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, fluoroquinolones, and third-generation cephalosporins, was reported in Pakistan. During November 2016–September 2017, 339 cases of this extensively drug-resistant (XDR) Typhi strain were reported in Pakistan, mostly in Karachi and Hyderabad; one travel-associated case was also reported from the United Kingdom.[1] More cases have been detected in Karachi and Hyderabad as surveillance efforts have been strengthened, with recent reports increasing the number of cases to 5,372.[2] In the United States, in response to the reports from Pakistan, enhanced surveillance identified 29 patients with typhoid fever who had traveled to or from Pakistan during 2016–2018, including five with XDR Typhi. Travelers to areas with endemic disease, such as South Asia, should be vaccinated against typhoid fever before traveling and follow safe food and water practices. 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.

Typhoid fever is a systemic febrile illness that requires prompt antibiotic treatment.* Worldwide, approximately 12–27 million cases of typhoid fever occur annually.[3] In the United States, approximately 350 culture-confirmed cases are reported to CDC each year. Most U.S. patients report having traveled internationally within the preceding 30 days. Over the past several decades, the emergence of Typhi that is multidrug resistant (MDR) to historically used first-line antibiotics, such as chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole, led to the use of fluoroquinolones (e.g., ciprofloxacin) as the first-line treatment.[4] However, since the early 2000s, increasing fluoroquinolone nonsusceptibility (intermediate or full resistance to ciprofloxacin), especially in South Asia, has led to the use of third-generation cephalosporins (e.g., ceftriaxone) as a recommended first-line treatment.

Local and state health departments report culture-confirmed Typhi to CDC's National Typhoid and Paratyphoid Fever Surveillance (NTPFS) system.[5] Information is collected on travel history in the 30 days preceding illness. Public health laboratories in 54 state and local health departments forward all Typhi isolates to CDC's National Antimicrobial Resistance Monitoring System (NARMS) in batched shipments for antimicrobial susceptibility testing.[6] The NARMS laboratory uses broth microdilution to determine the minimum inhibitory concentration (MIC) for 14 antimicrobial agents. Resistance is defined by MIC breakpoints established by the Clinical and Laboratory Standards Institute (CLSI) where available.[7] Typhi isolates are categorized as fluoroquinolone nonsusceptible if their MICs are classified as intermediate (MIC ≥0.12–0.5 μg/mL) or resistant (MIC ≥1.0 μg/mL) to ciprofloxacin. Typhi isolates are defined as MDR if they are resistant to chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole, and as XDR if they are MDR, nonsusceptible to fluoroquinolones, and resistant to third-generation cephalosporins. In March 2018, CDC enhanced surveillance for typhoid fever by asking state and local health departments to interview every patient with typhoid fever about travel to or from Pakistan and to expedite submission of Typhi isolates from these patients to CDC. Surveillance data from NARMS and NTPFS from 2006–2015 were compared with data from 2016–2018 and reviewed for XDR cases among persons who traveled to Pakistan.

During 2006–2015, a total of 3,538 patients with culture-confirmed typhoid fever were reported to NTPFS (median = 338 patients annually), including 244 (7%) who traveled to only Pakistan in the 30 days before onset (median = 23 patients annually) (Table 1). During 2006–2015, NARMS tested 3,598 Typhi isolates. Among these, 2,350 (65%) were fluoroquinolone nonsusceptible, 418 (12%) were MDR, and none had resistance to ceftriaxone. Fluoroquinolone nonsusceptibility increased from 55% (177 of 323 isolates) in 2006 to 66% (221 of 336) in 2015. Information on international travel was available for 2,242 (62%) patients with isolates tested by NARMS; 169 (8%) traveled to only Pakistan. Of 169 isolates from travelers to Pakistan, 133 (79%) were fluoroquinolone nonsusceptible and 85 (50%) were MDR (Table 1). During 2016–2018, 29 patients with typhoid fever reported travel to or from Pakistan and had isolates tested for antimicrobial susceptibility; among these, five patients had XDR Typhi (Table 2). All patients with XDR Typhi who had traveled to or from Pakistan were children aged 4–12 years and traveled to or from Pakistan during late 2017 through mid-2018.