International Travel and the Risk of Extensively Drug-resistant Typhoid: Issues and Potential Solutions Free

(See the Major Article by McAteer et al on pages e4581–9.)

Despite significant progress in our understanding of typhoid fever, its pathogenesis, and risk factors, this disease is still responsible for a significant global burden of disease. Globally, 14.3 million (95% uncertainty interval (UI), 12.5–16.3 million) cases of typhoid and paratyphoid fevers occurred in 2017 [1] with an estimated 135 900 (95% UI 76 900–218 900) deaths. Marchello et al [2] undertook a systematic review of studies providing incident data and estimated a pooled incidence of 267.6 (95% confidence interval [CI], 182.8–368.2) typhoid cases per 100 000 per year in Asia with rates from the 6 sites in India of 497.2 (95% CI, 291.9–754.8) cases per 100 000 population. Their review found no incident data from the United States (US), as much of the disease in North America is imported.

In the US, typhoid fever is a notifiable disease, and approximately 350 culture-confirmed cases are submitted to Centers for Disease Control and Prevention (CDC) annually. Local and state public health departments send epidemiologic information from culture-confirmed cases to CDC’s National Typhoid and Paratyphoid Fever Surveillance system (NTPFS) and submit isolates to CDC’s National Antimicrobial Resistance Monitoring System (NARMS) laboratory for antimicrobial susceptibility testing. A previous analysis of cases between 1999 and 2006 of laboratory-confirmed typhoid fever had suggested that 79% of cases of typhoid fever in the US were related to overseas travel [3] with an overall rate of travel-associated typhoid fever over this period of 1.6 cases per 1 million travelers arriving in the country. In this issue of Clinical Infectious Diseases, McAteer et al [4] reviewed data on a consecutive 5131 typhoid cases reported to the NARMS and NTPFS between 1999 and 2015, and summarized information on 1992 children, comprising 39% of total reported cases. As noted previously, the vast majority (83%) of children with confirmed typhoid had traveled internationally and most likely acquired the infection overseas from parental visits to friends and family. Even among younger children 6–23 months age, more than two-thirds had a history of travel, and among those with known travel status, the likelihood of acquiring fluoroquinolone-resistant typhoid infection was much greater among families visiting friends and relatives in South Asia, especially Pakistan [4].

Although the review did not include more recent data from the last few years, given the lag in reporting, the authors do allude to the recent emergence of extensively drug-resistant (XDR) typhoid among travelers to and from Pakistan [5, 6]. These isolates are resistant to ceftriaxone and fluoroquinolones as well as commonly used first-line antibiotics (eg, ampicillin, chloramphenicol, and co-trimoxazole) in Pakistan. Although some cases of XDR typhoid among travelers from Pakistan could have gone undetected prior to 2018, the more definitive recent analysis covering the period February 2019–July 2019 identified 96 cases with typhoid returning from Pakistan [7]. Of the 30 cases, 20 were in the pediatric age group, with one-third <5 years of age. Ceftriaxone resistant isolates are not just restricted to Pakistan, and of much concern is the emergence of ceftriaxone resistant cases distinct from the Pakistan isolates from other geographies such as Iraq [8].

These XDR strains of typhoid are sensitive to just a limited repertoire of antibiotics including azithromycin and injectable carbapenem antibiotics. Of some concern are reports that we may also be witnessing the emergence of macrolide-resistant strains of Salmonella Typhi. Azithromycin resistance has been reported from surveillance studies in India spanning a 25-year period with increasing minimum inhibitory concentrations and reduced susceptibility in 7% of the isolates [9]. More recently, in Bangladesh, Hooda et al [10] reported 12 azithromycin-resistant Salmonella Typhi strains and 1 Salmonella Paratyphi A strain with a single mutation in the AcrB protein at position 717. There is concern that with increasing azithromycin use for community-acquired infections and now as part of the armamentarium of coronavirus disease 2019 (COVID-19) management, strains with R717 mutations may spread and be acquired by XDR strains, thus leaving expensive injectable carbapenem antibiotics as the only treatment option.

The overall low case fatality rates and link to travelers in much of the pediatric typhoid in the US is reassuring and consonant with previous findings of pediatric typhoid from a global review of clinical presentation and outcomes [11]. With US residents and citizens increasingly visiting family and friends in various parts of the world where drug-resistant typhoid may be widespread, measures must be instituted to protect families and surveillance systems set in place to reduce risk of transmission. It is also notable that among the pediatric cases with travel history reviewed by McAteer et al [4], 204 of 1270 (16%) were domestically acquired, comparable to the 18% of cases so acquired between 1999 and 2010 [12]. These locally acquired cases are a cause for concern and underscore the need for close surveillance and possible screening of families returning from areas with endemic XDR typhoid to identify carriers. While the risk of widespread transmission of XDR typhoid is small, localization of outbreaks using space-time scanning may make targeting easier [12].

The implications for policy are clear. We need to do whatever is possible to protect the antibiotic pipeline, including restricting the use of the remaining repertoire of orally administrable antibiotics, especially azithromycin [13]. Every effort should be made to increase investments in strategies to reduce the burden of typhoid at the source, by accelerating investments in public health measures, water, sanitation, hygiene, and food safety [14]. The increased emphasis on these measures and personal protection in the wake of the current COVID-19 pandemic may make it possible to integrate these measures for prevention of a range of diseases.

Notwithstanding the above, the development of newer-generation typhoid conjugate vaccines (TCVs) [15], some with a protective efficacy of 81% in field studies [16], offers a unique opportunity for prevention, especially among travelers to endemic areas, and must be instituted. Following a detailed review of the evidence, the World Health Organization’s Strategic Advisory Committee for Vaccines approved the use of TCVs in 2018 [17]. The global vaccine alliance Gavi has since made a window of financing possible for TCV introduction in Gavi-eligible low- and middle-income countries, and modeling studies indicate that the vaccine would be cost-effective in countries with a disease burden of typhoid >300 cases per 100 000 population [18]. In the US, given the clustering of imported cases among children traveling to and from South Asia, parts of Africa, and Latin America, TCVs should be made available within the traveler vaccination strategies in addition to reinforcement of other stringent preventive measures and advice. Given the important historic role that investments in safe water and foods as well as personal hygiene have played in the control of typhoid [19], it is imperative that future strategies for typhoid control and mitigation of the spread of antimicrobial-resistant strains of the pathogen include all potential public health control measures including the use of effective vaccines [20].

Note

Potential conflicts of interest. The author: No reported conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

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