Addressing the Global Disease Burden of Typhoid Fever

Salmonella ser Typhi infections are widely recognized as a major cause of morbidity globally, with an estimated 21 million cases and between 200 000 and 600 000 deaths annually.^{1 - 2} The divergent estimates likely represent differences in methods used for assessing age-specific burden of typhoid and attributable mortality.³ In some parts of the world, notably South Asia,⁴ young children represent a subgroup with the highest burden of typhoid and also may have disproportionately high rates of morbidity and complications.⁵ The report by Lynch et al⁶ in this issue of JAMA summarizes current knowledge about cases of typhoid fever in the United States and highlights the role of international travel, the need for broader immunization practices, and concerns regarding increases in antibacterial resistance.

In addition to the disease burden and mortality, emergence of drug resistance among S Typhi and Salmonella ser Paratyphi, which causes a clinically indistinguishable infection, over the last few decades poses major challenges.⁷ In the late 1980s and early 1990s, the emergence of S Typhi isolates resistant to first-line drugs including oral amoxicillin, chloramphenicol, and cotrimoxazole, so-called multidrug-resistant S Typhi (MDRST), was associated with significantly higher rates of complications and mortality.⁵ The availability of generic fluoroquinolones, which initially had preserved activity, in many parts of the world permitted a treatment option in primary care settings, and this group of antibiotics soon became the standard of care for typhoid among older children and adults.⁸ The emergence of nalidixic acid–resistant S Typhi (NARST) isolates from parts of South and Southeast Asia,⁹ followed by clinical and laboratory fluoroquinolone resistance,¹⁰ has now created a specter of highly resistant strains of S Typhi that require treatment with a diminishing range of alternative antibiotics.¹¹ Similarly, there has been an increasing emergence of infection with strains of S Paratyphi group A that have resistance to nalidixic acid, coupled with either decreased sensitivity or, in some cases, clinical resistance to fluoroquinolones. Such infections have occurred in several countries in South and Southeast Asia, and, as with MDRST, there has been the inevitable spread to developed countries as a result of transcontinental travel.^{6 - 7}

The article by Lynch and colleagues⁶ underscores the importance of travel in the global spread of S Typhi and, in particular, NARST isolates. From 1999 to 2006, less than one-third of confirmed S Typhi infections reported to the US Centers for Disease Control and Prevention were sensitive to first-line antibiotics. Almost two-thirds of infected individuals had traveled to South or Southeast Asia and 21% of infections were indigenously acquired, either from a carrier (17%) or during a local outbreak (21%). Similar findings have been reported from the United Kingdom,¹² emphasizing that in an era of frequent transcontinental travel, all countries are at risk of infection with superresistant S Typhi organisms.

The implications of these findings for global strategies for the prevention and control of typhoid are substantial for both developed and developing countries. Public health authorities and treating clinicians in developed countries must be alert to the possibility of drug-resistant typhoid, particularly among patients who have had international travel recently. In addition, guidelines for empirical therapy of suspected typhoid must be adjusted to account for infection with a resistant strain. For developing countries, the current situation also offers an opportunity for defining rational drug therapy of infection with both resistant and sensitive strains of typhoid.

Many isolates of S Typhi (even NARST strains) remain sensitive to first-line antibiotics such as chloramphenicol and amoxicillin, and these agents may be reasonable alternatives for treatment of infection with sensitive S Typhi isolates.¹³ A recent meta-analysis of treatment trials for typhoid suggests that among sensitive cases of typhoid, cure rates with oral first-line agents may be comparable with fluoroquinolones.¹⁴ The current situation also offers an opportunity to evaluate alternative regimens and combination therapies for treatment of drug-resistant typhoid.¹⁵ For example, treatment with antimicrobials such as third-generation cephalosporins and even macrolides (azithromycin) has resulted in favorable outcomes, although the cost of therapy with these agents remains prohibitive for use in developing countries.

The report by Lynch et al⁶ provides continued impetus for consideration of mass vaccination strategies using inexpensive vaccines such as the typhoid Vi polysaccharide (Vi-CPS) vaccine. Recent findings from a phase 4 effectiveness trial of a Vi-CPS vaccination program in a slum population of Kolkata, India,¹⁶ suggest that the mass vaccination program resulted in significant protection against typhoid fever (2-year protective effectiveness, 61%; 95% confidence interval, 45%-71%). Results from other large-scale trials from the region are also awaited and may provide supportive evidence for vaccination strategies targeting sections of populations at risk (slum dwellers, schoolchildren, and food handlers).The finding that travel to and from South Asia was especially associated with risk of infection with drug-resistant strains of S Typhi has considerable implications for preventive vaccination for travelers to the region.

In addition, the persistent burden of typhoid in many regions of India despite rapid economic progress underscores the importance of investments in water, sanitation, and hygiene interventions at scale. These infrastructure investments have lagged behind other Millennium Development Goal targets¹⁷ but have the potential to significantly reduce the overall burden of typhoid.

The article by Lynch et al⁶ is also an important reminder that despite high burden and risk of adverse outcomes, typhoid remains an orphan disease. Although the disease continues to affect a large proportion of young children, typhoid is not a focus of either the tropical diseases research group or the child and adolescent health departments at the World Health Organization.¹⁸ In 2007, the vaccines and biological group reviewed the global burden and made a recommendation for school-based vaccination strategies for control.¹⁹ However, progress on the development of improved vaccines for typhoid, especially those that may reduce disease burden among young children, remains slow. For instance, even though evidence for the efficacy of Vi conjugate vaccine in young children has been available for a long time, development of the vaccine and combination vaccines effective against paratyphoid has lagged.²⁰

Typhoid remains a deadly disease in many developing countries and, as the article by Lynch et al⁶ clearly demonstrates, has the potential for worldwide spread, with considerable effects on the global burden of infection with gastrointestinal pathogens. This, coupled with increasing reports of the emergence of multidrug-resistant nontyphoid salmonellas in vulnerable groups in many developing countries, particularly those in Africa and Southeast Asia, with infections often characterized by disease symptoms similar to those of typhoid,²¹ clearly illustrates the need for a global strategy of containment of Salmonella infection, linked, if possible, to vaccination and to the rational use of key antimicrobial drugs.