Extensively Drug-Resistant Typhoid Fever in the United States

Abstract

Cases of extensively drug-resistant (XDR) typhoid fever have been reported in the United States among patients who did not travel internationally. Clinicians should consider if and where the patient traveled when selecting empiric treatment for typhoid fever. XDR typhoid fever should be treated with a carbapenem, azithromycin, or both.

Typhoid fever is a systemic illness caused by the bacterium Salmonella enterica serotype Typhi (Typhi). In the era before antimicrobials, typhoid fever could be fatal in up to 10%–30% of cases; mortality drops to 1%–2% with appropriate treatment [1–6]. Most cases (~85%) of typhoid fever diagnosed in the United States are acquired during international travel [1, 7].

In 2016, a large outbreak of extensively drug-resistant (XDR) typhoid fever linked to contaminated water began in Sindh province, Pakistan, and continues today [8]. XDR Typhi strains are resistant to antibiotics used to treat susceptible strains, including ampicillin, ceftriaxone, chloramphenicol, ciprofloxacin, and trimethoprim-sulfamethoxazole [8, 9]. Most isolates from patients linked to the outbreak have been susceptible to azithromycin and carbapenems [8, 10]. XDR Typhi infections among travelers to or from Pakistan have been reported globally [11–14], including in the United States [10, 15]. An unrelated cluster of ceftriaxone-resistant Typhi infections linked to Iraq has been reported in the United States and the United Kingdom [10].

The first reported case of XDR typhoid fever diagnosed in the United States occurred in February 2018 [15]; by August 2019, there were 30 US cases, all among travelers to or from Pakistan [10]. In November 2019, the first case in a person with no history of international travel was diagnosed in an Illinois resident. This report describes the emergence of XDR typhoid fever among US residents with no history of international travel and provides recommendations for management.

METHODS

Typhoid Fever Surveillance

State and local health officials interview case patients using a standardized questionnaire that includes travel history and clinical outcomes and report cases of typhoid and paratyphoid fever to the Centers for Disease Control and Prevention’s (CDC’s) National Typhoid and Paratyphoid Fever Surveillance system (https://www.cdc.gov/typhoid-fever/surveillance.html). The CDC requested additional exposure information for patients who reported no international travel in the 30 days before their illness (usual incubation period 6–30 days) with a culture that yielded XDR Typhi.

Antimicrobial Susceptibility Testing

US public health laboratories are asked to submit all Typhi isolates to the CDC’s National Antimicrobial Resistance Monitoring System (NARMS) laboratory for antimicrobial susceptibility testing (AST) using broth microdilution (Sensititre). Antibiotics tested by the NARMS include ampicillin, azithromycin, ceftriaxone, chloramphenicol, ciprofloxacin, meropenem, and trimethoprim-sulfamethoxazole. Susceptibility was determined using clinical breakpoints established by the Clinical & Laboratory Standards Institute [16]. At the time of this report, AST results were complete for 2018 and preliminary for 2019.

Whole-genome sequencing is performed on a subset of isolates by state health departments subject to available resources. We screened sequences for resistance determinants using a modified workflow based on ResFinder 3.0 (https://bitbucket.org/genomicepidemiology/resfinder/src/master/). Resistance for isolates without AST results was predicted based on the presence of resistance determinants [17].

We defined multidrug resistance (MDR) as resistance to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole, and XDR as MDR with additional resistance to ceftriaxone and resistant or intermediate results for ciprofloxacin. We defined XDR variant as resistance to ceftriaxone and 2 or more additional antibiotic classes in an isolate highly related to XDR isolates from the Pakistan outbreak (0–8 alleles by core genome multilocus sequencing typing [cgMLST]).

RESULTS

Typhoid Fever Surveillance

The CDC identified 76 XDR and XDR variant Typhi infections between February 6, 2018, and March 27, 2021, in US residents. Sixty-seven (88%) reported travel to or from Pakistan, and 9 (12%) denied having traveled internationally in the 30 days before their illness (Figure 1).

Figure 1.

Extensively drug-resistant (XDR)^a and XDR variant^bSalmonella Typhi cases by month of first positive culture and travel history—United States, January 2018–April 2020 (n=76)^c. ^an = 71. Isolates were considered XDR if they were resistant to ampicillin, ceftriaxone, chloramphenicol, and trimethoprim-sulfamethoxazole and were resistant or intermediate to ciprofloxacin. ^bn = 5. Isolates were considered XDR variants if they were highly related to XDR isolates by whole-genome sequencing and were resistant to ceftriaxone and at least 2 additional antibiotic classes. All 5 patients with Typhi isolates that were XDR variants reported travel to Pakistan. ^cResistance was determined by antimicrobial susceptibility testing for 72 isolates and predicted based on whole-genome sequencing for 4 isolates.

Patients who denied recent international travel ranged in age from 1 to 62 (median, 8) years, and 67% were female. Patients identified as Asian (78%), including Bangladeshi, Nepalese, and Pakistani; White (11%); and other (11%). Eight (89%) were hospitalized, and none died. None of the nontravelers reported having close contact with ill persons, and none had contacts in common. Two of 8 patients with follow-up interviews mentioned that someone in their household returned from travel to Pakistan without symptoms of Typhi infection in the year before the patient’s illness began. Times between the return of household contacts and the patients’ illness onsets were between 11 and 12 months.

Most XDR isolates from patients who did not travel were genetically indistinguishable from XDR isolates among travelers to Pakistan (all were within 0–2 alleles by cgMLST of 1 or more isolates from known travelers) (Supplementary Figure A; Supplementary Table A). The XDR isolates from patients who did not travel were also highly related to each other (0–4 alleles by cgMLST).

Antimicrobial Susceptibility Testing

Among 1030 Typhi isolates collected from US patients during 2018–2019, ~80% were resistant (minimum inhibitory concentration [MIC] ≥1 μg/mL) or intermediate (MIC 0.12–0.5 μg/mL) to ciprofloxacin; 11.8% were MDR, and 4.3% were XDR (Supplementary Table B). All were susceptible to azithromycin and meropenem.

DISCUSSION

This report describes the first cases of XDR typhoid fever detected in residents of the United States who did not travel internationally. To our knowledge, these cases represent the first documented instance of XDR typhoid fever acquired outside of Pakistan. No source for any of these infections has been identified. There are no documented cases of secondary transmission, but most cases have occurred among persons of South Asian ethnicity and person-to-person spread remains a possibility. A common source exposure that could account for cases in multiple households (such as an imported food product) has not been identified. Surveillance for XDR typhoid fever is ongoing. On February 12, 2021, the CDC issued a Health Advisory about XDR typhoid fever for clinicians [18].

The symptoms and clinical presentation of typhoid fever may resemble those of other infectious diseases. Common symptoms include fever, headache, constipation or diarrhea, malaise, chills, and myalgia; up to 30% of patients report cough or abdominal pain [1]. Maintaining a high index of suspicion can be critical to making the diagnosis. Public health authorities should conduct in-depth interviews to identify possible sources of infection, perform stool testing of household members who may be carriers, and take measures to prevent secondary transmission. Antibiotics reduce the morbidity and mortality of typhoid fever, but antibiotic choice has been complicated by high rates of resistance to traditional treatment agents. While ciprofloxacin remains the treatment of choice for susceptible Typhi infections [9], most infections diagnosed in the United States are not susceptible to ciprofloxacin. Furthermore, while ceftriaxone resistance was not documented in the United States before 2018 [15], the rapid dissemination of XDR infections worldwide has prompted careful re-consideration of ceftriaxone for empiric treatment. Reduced susceptibility to azithromycin in Typhi has also been reported globally, including in Pakistan, and may be encountered by US clinicians [19–22].

Additional studies are needed to establish optimal treatment regimens and to inform treatment guidelines for patients with XDR typhoid fever. Guidelines developed before the emergence of XDR illness may no longer be appropriate for all patients, prompting the need for updated recommendations. Clinicians should order cultures and AST for all patients with suspected typhoid fever, and antibiotic treatment should be adjusted according to AST results (Table 1). Empiric treatment should be guided by the patient’s travel history; a regimen effective against XDR typhoid fever should be considered for patients who have traveled to Pakistan or Iraq or who did not travel internationally before their illness. Patients with XDR typhoid fever should be treated with a carbapenem (such as meropenem), azithromycin, or both. Case reports have suggested that patients who do not improve on a carbapenem alone may benefit from the addition of a second antibiotic, such as azithromycin [11, 23–26].

Table 1.

Recommendations for the Management of Extensively Drug-Resistant Typhoid Fever in the United States

General management considerations	Obtain a 30-day international travel historya from all patients with suspected or confirmed typhoid fever. Lack of international travel does not rule out a diagnosis of typhoid fever; Typhi can be acquired in the United States. Order blood cultures if typhoid fever is suspected; multiple cultures are usually needed. Bone marrow cultures have the highest sensitivity and may be considered for some patients (eg, those who have already started or completed a course of antimicrobial treatment). Stool, urine, and duodenal cultures may also be helpful. Order antimicrobial susceptibility testing for Typhi isolates and adjust antibiotic treatment accordingly. Vaccination is recommended for people in close contact with a typhoid carrier. Ask the patient if they have additional household members or other close contacts.
Selection of empiric treatment by country of exposureb	Pakistan	Patients are often infected with XDR Typhi. Consider prescribing a carbapenem (particularly if patients have severe or complicated illnessc) or azithromycin for empiric treatment.
	Iraq	Patients often have strains that are resistant or intermediate to ciprofloxacin; some strains are also resistant to ampicillin and ceftriaxone. Consider prescribing a carbapenem (particularly if patients have severe or complicated illnessc) or azithromycin for empiric treatment.
	Other countries	Most patients have strains that are susceptible to ceftriaxone and azithromycin, which remain appropriate empiric treatment options.
	No international travelb	Patients might be infected with XDR Typhi. Consider prescribing a carbapenem (particularly if patients have severe or complicated illnessc) or azithromycin for empiric treatment.
Treatment of known XDR Typhi	Treat patients with XDR Typhi infection with a carbapenem, azithromycin, or bothd. Treat patients with severe or complicated illnessc with a carbapenem, such as meropenem. Patients with uncomplicated illness may be treated with oral azithromycin alone.

Abbreviation: XDR, extensively drug-resistant.

The patient should be asked about any exposures outside of the United States even if these are not strictly travel related (ie, patients may be international citizens traveling to the United States, immigrants, or US citizens who live in border areas and commute). Nontravelers may be asked if they have close contacts such as household members who have recently traveled.

In the 30 days before illness onset.

Severe or complicated typhoid fever can include bacteremia with sepsis or shock, gastrointestinal complications (eg, intestinal perforation, peritonitis, intestinal hemorrhage, hepatitis), and neurologic complications (eg, encephalopathy).

Case reports have suggested that patients who do not improve on a carbapenem alone may benefit from the addition of a second antibiotic, such as azithromycin.

The challenges associated with treating XDR typhoid fever underscore the importance of preventive measures. Persons age >2 years who are traveling to regions where typhoid fever is endemic, who are in close contact with a known typhoid carrier, or who work with Salmonella Typhi in a laboratory setting should be vaccinated. Clinicians should counsel travelers, including those visiting friends and relatives, about safe food and water precautions [1].

The findings in this report are subject to several limitations. First, most public health departments and laboratories have not yet submitted case reports or isolates from 2020 or 2021, so recent XDR cases may be underestimated. Second, travel histories are based on patient self-report and were not independently verified. However, it is noteworthy that all patients with XDR typhoid fever before November 2019 reported travel to Pakistan, whereas 40% of patients in 2020 denied international travel. Third, investigation of contacts and culturing of stools of household members were not possible for all patients. A common source of infection in the United States would be difficult to identify due to the small number of cases, their geographic spread, and limited epidemiologic information. Finally, the recommendations in this report are based on information about antimicrobial resistance in Typhi isolates in the United States as of April 2021; all patients with XDR typhoid fever had traveled to Pakistan or had not traveled internationally before illness began. Resistance can emerge rapidly and may necessitate a change in recommendations.

CONCLUSIONS

Cases of XDR typhoid fever have been reported among US residents, predominantly persons of South Asian ethnicity, who did not travel internationally. Clinicians evaluating patients with possible typhoid fever should consider the patient’s travel history when selecting empiric treatment and remember that patients without a history of international travel may have XDR typhoid fever. Nontravelers should be asked if they have close contacts, such as household members, who have traveled. Patients with known or suspected XDR typhoid fever should be treated with a carbapenem, azithromycin, or both.

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.