Typhoid and paratyphoid fever: a clinical seminar

Abstract

Rationale for review: Enteric fever (EF) caused by Salmonella enterica subspecies enterica serovar Typhi (Salmonella Typhi) and S. Paratyphi (Salmonella Paratyphi) remains an important cause of infectious morbidity and mortality in many low-income countries and, therefore, still poses a major infectious risk for travellers to endemic countries.

Main findings: Although the global burden of EF has decreased over the past two decades, prevalence of EF remains high in Asia and Africa, with the highest prevalence reported from the Indian subcontinent. These statistics are mirrored by data on travel-related EF. Widespread and increasing antimicrobial resistance has narrowed treatment options for travel-related EF. Ceftriaxone- and azithromycin-based therapies are commonly used, even with the emergence of extremely drug-resistant typhoid in Pakistan. Preventive measures among locals and travellers include provision of safe food and water and vaccination. Food and water precautions offer limited protection, and the efficacy of Salmonella Typhi vaccines is only moderate signifying the need for travellers to be extra cautious.

Recommendations: Improvement in the diagnosis of typhoid with high degree of clinical suspicion, better diagnostic assays, early and accurate detection of resistance, therapy with appropriate drugs, improvements in hygiene and sanitation with provision of safe drinking water in endemic areas and vaccination among travellers as well as in the endemic population are keys to controlling typhoid. While typhoid vaccines are recommended for travellers to high-risk areas, moderate efficacy and inability to protect against Salmonella Paratyphi are limitations to bear in mind. Improved Salmonella Typhi vaccines and vaccines against Salmonella Paratyphi A are required.

Enteric fever, Salmonella Typhi, Salmonella Paratyphi, travel, antimicrobial resistance, typhoid vaccines

Introduction

Enteric fever (EF) is a severe infection caused by Salmonella Typhi and Paratyphi A, B and C and was once a frequent infection in Europe and North America. However, with improvement of sanitation and safe food and water, endemic EF declined dramatically in developed countries. EF continues to remain a serious problem in many low-income countries, impacting both the endemic population and international travellers. Pleomorphic clinical presentations, rise of Salmonella Paratyphi as a dominant pathogen in some areas, need of a better early diagnostic test and widespread resistance to antibiotics pose a problem despite the overall decreasing global burden. Imported travel-related infection is now the leading form of EF in most industrialized countries.¹ The ever-growing number of international travellers—now well over a billion annually worldwide—² has inadvertently created a global ‘surveillance system’ for EF epidemiology. Lack of reliable vaccines that cover both Salmonella Typhi and Salmonella Paratyphi further contributes to the problem of travel-related EF. In addition, rising multidrug resistance in EF has led to treatment challenges as well.

This review summarizes aspects of the changing epidemiology of EF, impact of drug resistance and current treatment options and effectiveness of current typhoid vaccines, in endemic populations and international travellers.

Epidemiology

In 2017, an estimated 14 million cases of EF occurred worldwide, resulting in about 136 000 deaths.³ More than 80% of these cases occurred in South and South East Asia and in Sub-Saharan Africa (Figure 1). Supplementary Table 1, available at JTM online, depicts the morbidity and mortality associated with EF globally. The incidence among children between 2 and 4 years and young adults was high in the Indian subcontinent.^4–6 Population-based studies under the Diseases of the Most Impoverished project in urban slums of Pakistan and India estimated the blood culture-proven typhoid incidence between 184.9 and 493.5 cases per 100 000 person years, respectively, among 5- to 15-year-old children.⁷ A recent systematic review utilizing hospital-based data showed almost 10% of acute febrile illnesses seeking hospital care in India are due to EF, although rates appear to be declining.⁸ In some Asian countries such as Nepal, while Salmonella Typhi has shown a decreasing trend, Salmonella Paratyphi A numbers are on the increase, maintaining EF as a persistent problem.^9,10 Overall, a recent multinational, blood culture-based surveillance study in South Asia suggests that Salmonella Typhi contributes about 80% of all EF cases.¹¹ The Surveillance of Enteric fever in India study spans the breadth of India and is soon to publish its data and is likely to have the most accurate burden of disease estimates in India.¹²

Figure 1

Incidence rates (per 100 000) of typhoid and paratyphoid fevers, by country, in 2017 (from TLID 2019)% ‘Incidence rates (per 100 000) of typhoid and paratyphoid fevers, by country, in 2017%’. Unfilled locations are those for which GBD does not produce estimates. The inset maps detail smaller locations. ATG = Antigua and Barbuda. FSM = Federated States of Micronesia. GBD = Global Burden of Diseases, Injuries, and Risk Factors Study. Isl = Islands. LCA = Saint Lucia. TLS = Timor-Leste. TTO = Trinidad and Tobago. VCT = Saint Vincent and the Grenadines. “Permission obtained: Stanaway et al.²³

In Southeast Asia, historically high rates of EF have declined, probably due to improved access to safe water and sanitation. Mass Salmonella Typhi vaccination campaign since the 1970s has also contributed to falling rates of typhoid fever with the paratyphoid burden remaining static. An estimate in 2013 from sub-national studies in Thailand showed a burden of 0.9–8.6 cases (mainly imported from neighbouring countries) per 100 000 population¹³ and 21.3 cases per 100 000 person years in Hue region of central Vietnam with an overall decreasing trend in subsequent years.¹⁴ In contrast, there has been a recent report of a high incidence of typhoid 100 per 100 000 persons per year in Myanmar suggesting a need for urgent intervention.¹⁵

Till recently, it was believed that Africa had a relatively low burden of EF; however, this was disproved by the Typhoid Fever Surveillance in Africa Program (TSAP). Based on 13 sentinel centres in Sub-Saharan Africa, TSAP showed adjusted incidence rates ranging from none in Sudan to 383 per 100 000 person years in Burkina Faso.¹⁶ Further blood culture-based studies have shown Salmonellosis to be the most frequent bloodstream infection in African children, with half the cases being Salmonella Typhi.^17,18 A systematic review by Jong Hoon Kim et al. on the typhoid fever occurrence in Africa had inconsistent and heterogeneous data documentation of typhoid prevalence, in the past; however, systematic documentation in the recent years shows an increased incidence of typhoid in many countries in Africa.¹⁹

The Severe Typhoid Fever in Africa study (SETA), an expansion of the TSAP prospective sentinel-based surveillance, is likely to provide valuable information regarding the burden, severity and long-term sequelae of Typhoid fever in Africa and thus aiding the introduction of typhoid vaccine in Africa.²⁰ Apart from continuous monitoring and evaluation processes based on the World Health Organization (WHO) and European Centre for Disease Prevention and Control standards, the long-term follow-up component in the SETA study allows for an assessment of the socioeconomic burden.^21,22

Surprisingly, most Latin American countries have documented a major decline in burden of EF with estimated incidences being 10- to 100-fold lower from those described in Africa (Figure 1).²³

The epidemiology of EF in travellers

EF is second only to malaria as a cause of severe and potentially life-threatening travel-related infection^24–26 The likelihood of travel-related EF correlates with local incidence, although other travel parameters may also influence the epidemiology. Studies from the USA,²⁷ the UK,²⁸ Israel²⁹ and other countries reveal that most of the travel-related EF appears to originate in Asia, especially the Indian subcontinent and Indonesia in Southeast Asia… A study of Swedish returning travellers showed that the incidence of EF acquisition in Asia was highest, at about 0.5 cases/10⁶ days of travel (or 18.25/100 000 travel-years, a rate which is similar to the range in the local population).³⁰ Being born in India and visiting friends and relatives (VFRs) as the reason for travel were also strongly associated with EF.³¹

In parallel with reports of declining rates of EF in many endemic countries, some data suggest a decline in the risk of travel-related EF. A Dutch study, for example, shows that rates of EF in non-immunized travellers outside South Asia are very low and falling.³² Data from the UK as well as the USA show stable absolute numbers of EF patients.^33,34

Since the late 1980s, there has been a steady increase in EF caused by Salmonella Paratyphi A among travellers.^26,34 Vaccination of travellers against Salmonella Typhi (no vaccine is available for Salmonella Paratyphi A) could have contributed to this trend. Similarly, both large outbreaks³⁵ and a general increase in prevalence of Salmonella Paratyphi A were noted in endemic populations.⁹ Mass immunization has probably played a role in decline of S. typhi infections in some parts of India.⁸

Interestingly, data from UK show that Salmonella Paratyphi A infection now may contribute to almost 50% of all EF cases (mostly acquired in the Indian subcontinent), but overall seem to followed a declining trend.³⁶

The historically perceived low frequency of EF in Africa was probably due to the infrequent reports of EF from the USA and Israel.^37–39 However, studies among travellers to Africa from France found an increased incidence of EF among children most of who were VFRs.⁴⁰ In addition, a global literature review on typhoid paratyphoid outbreak patterns showed that Africa nearly equalled the Indian subcontinent as a source of travel-related EF again due to VFRs⁴¹ (mostly from India, Pakistan or Bangladesh), contributing to 80–90% cases of EF in the USA.

Transmission

In low-income countries, transmission occurs usually through contaminated food and water systems, leading to a high burden of disease. The traditional risk factors for typhoid fever in endemic areas include poverty, overcrowding, contaminated water, poor sanitation and hygiene (WASH) and poor food handling practices, intake of contaminated food from street vendors and flooding.⁴² Typhoid seems to follow a seasonal trend with most cases observed following rainfall especially in most of the South Asian and South East Asian countries presumably as flooding during rainfall leads to contamination of drinking water sources with sewage.³³ In the Middle East, typhoid is commoner in seasons of drought reflecting microbiological contamination of the scarce drinking water sources. Agricultural contamination, i.e. usage of wastewater for crop irrigation in Chile, led to a spike in typhoid incidence.⁴³

In travellers, most cases are sporadic and data on seasonality of the disease is limited⁴⁴ and may reflect more the seasonality of travel than the fluctuating risk at the destination country. In addition, rather than being season-related, outbreaks among travellers are often a result of point-source infection (‘TyphoidMary’-type outbreaks, i.e. Salmonella-carrier-related food-borne infection) as happened to Israeli travellers in Nepal, in the largest ever recorded outbreak of Salmonella Paratyphi A infection.⁴⁵

The Disease: Pathogenesis and Clinical Aspects

Human volunteer experiments established an infecting dose of 10⁵–10⁹ organisms with an incubation period ranging from 4 to 14 days, depending on the inoculating dose of viable bacteria (Figure 2). After ingestion, Salmonella Typhi/Paratyphi invades the gut mucosa reaching Peyer’s patches in the intestine and then the mesenteric lymphoid system, passing into the blood stream via the lymphatics. Patients are asymptomatic during this primary bacteremia (Figure 2). The blood-borne bacteria are disseminated throughout the body, especially in the reticuloendothelial system where they replicate within macrophages. After a period of replication, bacteria are shed back into the blood causing a secondary bacteremia, which coincides with the onset of clinical symptoms and signs. Infection and inflammation within the small intestine’s Peyer’s patches underlie the most important complications of EF: ulceration leading to bleeding, perforation and death. In some cases, bacteria pass via the bile to the gall bladder, establishing a chronic carrier state (Figure 2).

Figure 2

Pathogenesis of typhoid fever. Permission obtained: Meltzer and Schwartz¹⁴⁰.

Risk factors for EF

In the host, decreased gastric acid barrier may increase the likelihood of EF: evidence of past infection with Helicobacter pylori is associated with EF.⁴⁶ Medications that decrease gastric acid such as proton pump inhibitors increase the risk from any enteric infections including Salmonella, although studies have mostly addressed the association with non-typhoidal salmonellosis.⁴⁷

The role of gender in EF is not clear, although most studies in endemic countries have documented a high male-to-female ratio^11,48 as did studies in travellers.⁴⁹ However, studies in endemic countries are confounded by gender-related differential access to healthcare; a unique insight into this bias is provided by a 60-year longitudinal study from China, which shows how gender difference shave disappeared with time.⁵⁰ Studies in travellers are also biased—this time by the high male/female ratio in travel to resource-poor countries. As an extreme example, the gender distribution of travel-related EF reported from Qatar showed that 84% of cases were male.⁵¹ This reflects the fact that the overwhelming majority of cases originated in the mostly male population of migrant workers from the Indian subcontinent. When travellers were studied in other regions, gender appeared to have little effect on EF epidemiology.⁵² Similarly, gender differences nearly disappeared during a point-source outbreak among travellers.⁴⁵ Thus, it is likely that gender plays little role in the pathogenesis of EF.

Genetic risk factors of EF

Within the environmental context, specific genetic polymorphisms may modify the risk of EF in an individual. Polymorphisms involving the PARK2/PACRG gene clusters, which modify the degradation of intracellular signalling molecules and dampen macrophage response, are associated with increased risk of EF.⁵³ Haplotypes involving specific alleles of the genes that determine the major histocompatibility complexes and tumour necrosis factor alpha—HLA-DRB1^*0301/6/8, HLA-DQB1^*0201-3 and TNFA^*2 (-308)—are linked to susceptibility to EF.⁵⁴ A single nucleotide polymorphism involving the VAC14 gene associated with lipid metabolism is shown to increase virulence in Salmonella Typhi.⁵⁵

Salmonella Typhi attaches to the cystic fibrosis transmembrane conductance receptor (CFTR) in the gut membrane during establishment of infection. Heterozygotes of the CFTR mutation F508 deletion seem to exhibit resistance to the development of typhoid fever.

Environmental risk factors for acquiring EF are higher in developing countries due to the lack of hygiene and sanitation, unavailability of safe drinking water and open defecation. The organism is hardy and survives in contaminated water and food for months or days, coupled with the ability to evade immune mechanisms in the host, typhoid fever continues to be a cause for concern in developing nations and thus, a threat to a non-immune traveller.

Clinical Features

The incubation period depends on the infecting dose and usually varies from 2 to 3 weeks (range 4–30 days). In a case series of Israeli travellers infected with Salmonella Paratyphi A in Nepal, the incubation time was almost uniformly 3 weeks.⁴⁵

The clinical manifestations of EF are often indistinguishable from other acute febrile illnesses. Classically, the fever pattern in EF starts insidiously and becomes high spiking with a step-ladder pattern as the disease progresses and then becomes persistent. However, in travellers, the disease often starts abruptly and produces chills, closely resembling malaria, although rigors are rare. Fever is often associated with headache, dry cough and myalgia and may thus be initially mistaken for influenza. Abdominal symptoms occur in most patients in the form of abdominal pain, constipation or diarrhoea. Towards the end of first week of febrile illness, relative bradycardia develops and spleen may become palpable. Relative bradycardia is neither universal nor specific for EF and may be seen in other infectious diseases (e.g. malaria, dengue, Mycoplasma, leptospirosis, rickettsiosis and legionellosis).

Rose spots are blanching 2- to 4-mm maculopapular lesions present in less than a quarter of patients with typhoid or paratyphoid fever commonly seen in the abdomen or chest. They are often missed in dark-skinned patients and are rarely seen in travellers. During the febrile episodes, patients may have confusion and apathetic affect. In contrast, children under 5 years commonly report diarrhoea, nausea, febrile seizures and have prominent neurological manifestations.

By 3rd week, if left untreated, complications may develop. Complications are more common when there is a delay in hospitalization following symptom onset, as shown by a systematic meta-analysis done by Cruz Espinoza et al.⁵⁶ Encephalopathy, intestinal bleeding from Peyer’s patches and intestinal perforation in the ileum or colon are commonly reported. Gastrointestinal bleeding complicates up to 10% of hospitalized patients but is often self-limited; life-threatening bleeding is rare. Encephalopathy may vary from an apathetic affect, confusion or delirium to coma is encountered rarely among Western travellers. Myocarditis is rare and probably under diagnosed and is likely an important cause of death in typhoid patients, including travellers.^29,57,58

Although traditionally paratyphoid fever was considered as a milder disease than typhoid, this is not true for Salmonella Paratyphi A infections. Clinical studies from Nepal on both travellers⁵⁹ and locals⁶⁰ showed the clinical picture to be indistinguishable for both pathogens.⁴⁹

About 10–15% of patients may relapse with clinical EF within a month; 10% of patients will continue to shed Salmonella Typhi up to 3 months and 1–4% for more than a year. The latter, termed chronic carriers remain asymptomatic but contribute to the transmission of EF. Carrier state is more common in people with biliary disease and women and was purported to eventually predispose to gall bladder cancer. Among travellers, with appropriate antimicrobial therapy relapses or chronic carrier states are rarely seen. Overall mortality with EF is <1% in the antibiotic era.

Diagnosis

As noted above, most EF cases present as undifferentiated fever, and many other infections including malaria, dengue, leptospirosis and rickettsiosis may be indistinguishable clinically. In returning travellers, the time from departure from the endemic area till fever onset and length of the febrile illness are important clues. A fever onset more than 2 weeks after return and persisting >2 weeks after return excludes arboviral infections and limits the differential diagnosis. Hence, a protracted febrile illness of >1-week duration among travellers returning from the Indian subcontinent should be ruled out through blood cultures.

Blood culture has remained the gold standard for the diagnosis of EF since the early 1900s,⁶¹ although sensitivity declines late in the disease course. In contrast to reports from low-income countries, blood cultures are positive in nearly all EF cases in travellers and remain the main diagnostic tool⁴⁹. Most travel-related EF is reported in adults, whereas the bulk of endemic disease is paediatric, and diagnostic tests may perform differently in these populations. However, Australian and French studies have shown that blood cultures were in fact positive in 90% of paediatric travel-related cases.^40,62

Bone marrow cultures are invasive and painful but have sensitivities varying from 80 to 96%.⁶³ A systematic literature review demonstrated a sensitivity of 96% in bone marrow culture vs 66% in blood culture.⁶³ Blood culture is often negative if antibiotics were given, although in these cases, bacteria may still be isolated from bone marrow.

Stool and rectal swab cultures may be positive the 3rd week of EF; however, results need to be interpreted with caution in endemic population, since it may reflect a chronic carrier state rather than acute disease. When considering a stool polymerase chain reaction (PCR), a recent history of oral typhoid vaccination should be documented avoiding unnecessary treatment or consideration of alternative diagnosis.⁶⁴

Salmonella Typhi expresses many immunogenic structures on its surface without much variation across global distribution.⁶⁵ Unfortunately, serological tests for EF including the Widal test are all hampered by high rates of false-positive as well as false-negative results.^66–68 Latex tests like TUBEX^® and Typhidot^® were limited likewise.^7,69–72 Comparison of various serological tests in o Typhoid added as Table 1.

Table 1

Comparison of various diagnostic tests used for typhoid detection

Test	Sensitivity	Specificity	Other details
TUBEX® TF69–71	78% (95% CI 71–85%)	87% (95% CI 82–91%)	Colorimetric assay—detects IgM directed against Salmonella Typhi O9 lipopolysaccharide antigen
Test-It Typhoid69–71	69% (95% CI 59–78%)	90% (95% CI 78–93%)	Lateral flow assay IgM antibodies against S. Typhi O antigen
Typhidot69–71	84% (95% CI 73–91%)	79% (95% CI 70–87%).	Detects specific IgM and IgG antibodies against the 50 kDa bacterial outer membrane protein (OMP)
TPtesta68	96.0% (95% CI: 87.1–99.8%)	96.6% (95% CI: 90.7–99.2%)	Utilizes circulating IgA antibodies against the bacteria using ELISA
Widal test72	73.5 (95% CI: 60.9–86.1%)	75.7% (Range: 13.8–98%)	Detects IgM and IgG antibodies, against O (surface polysaccharide) antigen and H (flagellar) antigen

The table compares the performance of common serological tests for the diagnosis of enteric fever from endemic areas

^aEvaluated only in a small number of studies

Nucleic acid tests like PCR perform poorly when directly tested with clinical samples, probably as a result of the fewer organisms present in the blood during infection.⁶⁵ Combined culture –PCR methods may improve sensitivity, as demonstrated in Salmonella Typhi human infection model⁷³ as well as in a field study for Salmonella Paratyphi A as well as Salmonella Typhi.⁷⁴

Summary panel: (diagnosis)

1. The relatively low organism burden in EFs makes detection difficult by both blood culture and PCR.

2. Blood culture remains the reference standard for the diagnosis of typhoid despite being expensive, slow and often unavailable in the endemic areas.

3. Bone marrow cultures may increase the diagnostic yield in patients pre-treated with antibiotics.

4. The available point-of-care diagnostic platforms using serology have low sensitivity and specificity for stand-alone clinical use, especially in the endemic settings.

5. Novel rapid diagnostic tests with reasonable sensitivity and specificity probably multiplexed with other acute febrile illness aetiologies are urgently needed.

Treatment

Multidrug-resistant (MDR) Salmonella Typhi (resistant to amoxicillin, chloramphenicol and trimethoprim–sulfamethoxazole) has been associated with a single dominant lineage: H58 that has a complex of MDR elements on plasmids as well as chromosomal integration sites. Phylogeographical analysis reveals that these H58 lineages are replacing antibiotic-sensitive isolates from Asia to Africa and contributing to an ongoing unrecognized MDR epidemic globally (Supplementary Figure 1 is available at JTM online).^75,76

Concomitant with the emergence of MDR EF, fluoroquinolones were widely introduced and were for a period considered a ‘magic-bullet’, i.e. the optimal treatment for EF: a short course of orally administered and highly effective therapy.⁷⁷ Tragically, widespread promiscuous use has led to rapid emergence of quinolone-resistant and MDR Salmonella Typhi and Paratyphi. Initially, nalidixic acid-resistant (NAR) strains predominated: in such strains fluoroquinolone failures were reported, although in one clinical trial gatifloxacin was still effective.⁷⁸ Since then, fully quinolone-resistant strains with clinical failure have emerged and dominated in Asia.⁷⁹

Similar data are not available from South and Central America; however, data from the Latin American Antimicrobial Resistance Surveillance Network (ReLAVRA) show that strains with reduced quinolone susceptibility, as well as one ceftriaxone-resistant strain, have been recorded.⁸⁰

Thus, azithromycin and third-generation cephalosporins: specifically, ceftriaxone, have emerged as salvage drugs in South Asia. However, the conjunction of high prevalence of EF as well as extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (E. coli and K. pneumonia) in South Asia raised concerns for the emergence of ESBL-producing Salmonella Typhi/Paratyphi. A few such extremely drug-resistant (XDR) strains were already detected in Nepal in 2006.⁸¹ However, the current Pakistani outbreak of XDR Salmonella Typhi with resistance to chloramphenicol, amoxicillin, co-trimoxazole, fluoroquinolones and ceftriaxone has led to the use of carbapenem as last resort drugs.⁸² Whole genome sequencing of 80 XDR Salmonella Typhi clones revealed a plasmid encoding additional resistance elements, including bla_CTX-M-15 ESBL, as well as the qnrS fluoroquinolone resistance gene. While most cases of ceftriaxone-resistant EF were reported from Pakistan, the situation is still rapidly evolving: some autochthonous cases of the Pakistani clone have been reported in India, and an additional independent focus of transmission has emerged in Iraq.⁸³

Summary panel: (treatment)

1. Steady development of resistance to many antibiotics has complicated therapy of uncomplicated EF.

2. Most isolates causing EF remain susceptible to azithromycin and third-generation cephalosporins.

3. Local resistance patterns, ability to take oral medications and severity of the disease decide the choice of antibiotic used.

4. Fever clearance in EF on optimal antibiotic therapy is typically slow, lasting even up to a week.

5. Adjunctive steroid therapy is beneficial in severe EF, especially in patients with central nervous system involvement and shock.

Antimicrobial resistance data and the treatment of EF

Data from travellers has largely mirrored the increasing antimicrobial resistance in countries endemic for EF (Supplementary Figure 2 is available at JTM online). Travellers are at high risk for acquiring and transmitting drug-resistant organisms to a non-immune vulnerable population incurring public health and economical losses.⁸⁴ MDR and quinolone-resistant strains of Salmonella Typhi and Paratyphi A seem to be dominant among travellers returning with EF from Asia. The pattern of resistance varies in different regions of south Asia—strains from India and Bangladesh show a decline in MDR strains but increase in fluoroquinolone non-susceptibility, whereas there is a predominance of MDR in Pakistan and Nepal and emerging XDR strains in Pakistan.⁸⁵ These data were replicated in reports from Israel,^45,49 the USA,^39,86 Europe⁸⁷ and Australia.⁸⁸ The preponderance of NAR strains made ceftriaxone the mainstay of treatment of travel-related EF. Although the cure rate with ceftriaxone is high, a long fever defervescence limits its use. An outbreak investigation of S. Paratyphi A in Israeli travellers revealed that combination therapy of ceftriaxone–azithromycin nearly halved the fever clearance time in comparison to ceftriaxone alone; an MDR + NAR Salmonella Paratyphi A outbreak among Israeli travellers in Nepal.⁴⁵ These results have since been corroborated in a prospective trial in the local population in Nepal⁸⁹ where this combination therapy for 7 days with relapses reported. However, numbers were small and further validation is required through large clinical trials.

This promising regimen is now threatened by the emergence in 2016 of XDR ceftriaxone-resistant Salmonella Typhi strains from Pakistan with documentation even among travellers^90–93 requiring use of carbapenem and azithromycin. However, it is reasonable to fear that the current high burden of plasmid-based (and therefore easily transmissible) carbapenemases among Enterobacteriaceae in Asia will result in the emergence of carbapenem-resistant Salmonella spp. The recent co-isolation of ceftriaxone-resistant Salmonella Typhi and of carbapenemase-producing Enterobacteriaceae in a single traveller to Pakistan is evidence of this grave risk.⁹¹

Table 2 is adapted from Supplementary Figure 2, available at JTM online, and relevant literature and provides recommendations for empirical therapy in returning travellers with suspected/confirmed typhoid fever.^{7,11,14,16,94–96}

Table 2

Recommendations for empirical therapy in returning travellers with suspected typhoid fever

Region of travel		AMR pattern	Uncomplicated typhoid fever (oral drugs)	Complicated typhoid fever (may need IV preparations)
South Asia7,11	India	Decreasing MDR (resistance to chloramphenicol, co-trimoxazole and ampicillin) resistance, high level resistance to fluoroquinolones, negligible resistance to ceftriaxone. Few reports of azithromycin resistance, re-emerging sensitivity to older drugs	First line: Azithromycina Alternative: Cefixime Chloramphenicol Co-trimoxazole	Ceftriaxone or Cefotaxime Azithromycin
	Pakistan	Variable MDR resistance, high level fluoroquinolone resistance, moderate incidence of ceftriaxone resistance with/without XDR strain	Azithromycin	Carbapenems: Ertapenem Meropenem
	Nepal	Variable MDR resistance, high level resistance to fluoroquinolones, negligible resistance to ceftriaxone	Azithromycin	Ceftriaxone
	Bangladesh	Variable MDR resistance, high level resistance to fluoroquinolones, negligible resistance to ceftriaxone. Few reports of azithromycin resistance	Azithromycin	Ceftriaxone
South East Asia7,14,94	Vietnam, Myanmar and Cambodia	Variable MDR and fluoroquinolone resistance, susceptible to cephalosporins	Cefixime Azithromycin	Ceftriaxone Cefotaxime Ertapenem
	Indonesia, Malaysia, Papua New Guinea, Laos	Decreased ciprofloxacin susceptibility (DCS), susceptible to other groups of antimicrobials	Azithromycin Cefixime Ciprofloxacinb	Ceftriaxone Cefotaxime
Africa16	Ghana	High incidence of MDR with susceptibility to other drugs	Ciprofloxacin Cefixime Azithromycin	Ciprofloxacin Ceftriaxone Cefotaxime
	South Africa, Kenya, Tanzania, Congo, Nigeria	MDR with DCS	Cefixime Ciprofloxacinb Azithromycin	Ceftriaxone Cefotaxime
	Burkina Faso	Susceptible	Ciprofloxacin Ofloxacin Ampicillin Co-trimoxazole Chloramphenicol	Ciprofloxacin
South and Central America95,96	El Salvador Mexico	No MDR reported, possible DCS	Co-trimoxazole Ampicillin Ciprofloxacin	Ciprofloxacin Ceftriaxone

^aIn regions with rising MIC to AZT noted – Cotrimoxazole or high dose Amoxicillin can be considered for oral therapy

^bIn regions where no fluroquinolone resistance is noted, treatment can start with ciprofloxacin/ofloxacin. Gatifloxacin was shown to have reduced fever clearance time and treatment failures when compared to cefixime

Supplementary Table 2, available at JTM online, contains major comparative studies evaluating treatment options for EF in the last 10 years.^{78,79,89,97–101}

Prevention

EF can be prevented by interrupting the faecal–oral transmission of Salmonella spp. Improved food and water hygiene and sanitation infrastructure significantly reduce the transmission as evidenced by the near eradication of EF from industrialised countries.¹⁰² However, implementing infrastructure change to EF endemic regions requires considerable financial resources and time. Typhoid outbreaks common since 1990 have been prevented following implementation of improvement in drinking water and health education among the public or WASH strategies.¹⁰³

For non-immune travellers, however, the ability to avoid food and water-borne enteric pathogens through dietary precautions is challenging; therefore, other measures such as vaccination may be required.

Vaccination

As the treatment of travel-related EF becomes more challenging, vaccination as prevention assumes importance. The promise of typhoid vaccines was first realized during the Boer war, and the introduction of the triple TAB vaccines (against Salmonella Typhi and Paratyphi A, B) dramatically decreased EF morbidity in the First World War.¹⁰⁴ TAB whole-cell killed vaccines were up to 80% effective but were eventually phased out in the late 1990s due to high incidence of adverse reactions, with up to 34% of recipients reporting fever and systemic symptoms.^105,106

Currently, two vaccines are licensed for preventing EF due to Salmonella Typhi, but none against Salmonella Paratyphi. The Vi polysaccharide vaccine consists of purified Vi capsular polysaccharide (Vi-PS). The estimated efficacy of a single 25 μg intramuscular dose of Vi-PS vaccine at 1 year is 69% [63–74%] and 59% at 2 years [45–69%].¹⁰⁷ Like other polysaccharide vaccines, Vi-PS vaccine is not licensed for use in children under 2 years of age due to poor immunogenicity. Additionally, protection is short lived, lasting only 2–3 years.^108,109 This can be given concurrently with other vaccines in children (2–16 years of age) safely and is available in combination with hepatitis A (ViVaxim).¹¹⁰ The live attenuated oral vaccine (Ty21a) is an attenuated strain of Salmonella Typhi, which induces local gut mucosal immunity as well as systemic antibody and cell-mediated responses.^111,112 Vaccine efficacy is estimated to be 54% at 2 years [40–71%] following the administration of three doses.¹¹³ Adverse events are infrequent with extremely rare reports of anaphylaxis globally.¹¹⁴ However, this vaccine is not licensed for use in children under the age of 6 years.¹¹⁵

In 2008, the WHO recommended the programmatic use of Vi-PS and Ty21a vaccines in controlling epidemic as well as endemic typhoid fever.¹¹³ Despite these recommendations, uptake of both vaccines in endemic regions has been limited to mainly sporadic school-based vaccination programmes in South Asia and South-East Asia.¹¹³ These vaccines have, however, been widely used by travellers to endemic areas as per the recommendation of travel health bodies.

Typhoid conjugate vaccines (TCVs), in which Vi polysaccharide is covalently linked to a carrier protein, are designed to protect against encapsulated bacterial pathogens and induce a T-cell-dependent response. In addition, they are immunogenic in infants and may induce longer lasting protection. Vi-TT (Typbar-TCV™, Bharat Biotech, Hyderabad) is a WHO pre-qualified vaccine consisting of 25 μg of Vi polysaccharide antigen conjugated to tetanus toxoid carrier protein. This vaccine has been administered to children as young as 6 months of age and has demonstrated superior immunogenicity to Vi-PS.¹¹⁶

Recent evaluation of antibody kinetics from immunogenicity trials of Vi-TT in India estimated efficacy of Vi-TT to be 80–88% with high antibody titres among vaccinated children even after 12 months.^116,117 Additional efficacy data will be generated with the introduction of TCV in Navi Mumbai, India, and from four Phase III effectiveness studies conducted as part of the TyVAC consortium.¹¹⁸ These studies will measure direct vaccine protection in children aged 9 months to 16 years over a 2-year period in Malawi, Nepal¹¹⁹ and Burkina Faso¹²⁰ and total population effectiveness in a population-based cluster-randomized trial conducted in Bangladesh.¹²¹ Such trials require a remarkable amount of engagement with the public and efficient communication by the study team to local government regarding the study.^122–124 TCVs are also likely to be cost-effective if administered routinely to infants in medium- or high-incidence settings, at a modest cost.^113–116 Other TCVs currently in the process of licensure or development include the Vi-rEPA, Vi-DT, Vi-CRM₁₉₇ and other Vi-tetanus toxoid conjugates, which have completed Phase I and II/III trials.^116,128,129 Finally, the compartmental model of endemic typhoid transmission by Samantha Kaufhold and group studied the predicted impact of TCVs on the prevalence of resistant strains in typhoid. They concluded that TCVs by reducing the total typhoid cases shall result in a concurrent reduction of the number of resistant typhoid strains but without affecting the current proportion of AMR strains.¹³⁰

Vaccine introduction into a country depends on multiple factors like burden of the disease to financial constraints and support from international organizations such as WHO and GAVIi. Studies assessing epidemiological burden of typhoid help appropriately tailored national immunisation policies. For example, in Bangladesh, a bimodal peak in the incidence of typhoid prompted vaccination in infants between 6 and 9 months and a catch-up vaccination between 18 and 20 years.¹³¹ In addition, genetic sequencing on drinking water samples from a community can aid identification of areas needing blood culture surveillance and thus assist policy for implementation of typhoid vaccines.¹³² TyVAC has defined strategies to overcome impending challenges for TCV introduction into GAVIi-supported countries based on evidence of efficacy, vaccine supply and local parameters including financial support/independence etc.¹³³

EF vaccine prevention in travellers

No data are available regarding efficacy of conjugate vaccines in travellers due to the low incidence of EF among travellers. As numbers of immunocompromised travellers also increase, the evaluation of antibody response following typhoid vaccination in this population is required.¹³⁴ The newly developed Vi antigen-based conjugate vaccines are considered to offer improved Salmonella Typhi protection but do not protect against Salmonella Paratyphi A.

The live attenuated Ty21a vaccine may provide some protection against Salmonella Paratyphi A,⁴⁹ although field studies in highly endemic areas have shown no conclusive evidence of efficacy.^70,71,135 For both vaccine types, protective efficacy against Salmonella Typhi may be overcome by a high inoculum and believed to be of relatively short duration.

Despite WHO prequalification and SAGE recommendation for TCV use in endemic settings in 2018,¹³⁶ a shift to TCV use in travellers is not likely to occur in the short term as TCVs are not licensed in Europe or North America. In a controlled human infection model study of TCV (which best mimics the status of a traveller from a non-endemic country), even with inocula as low as 10⁴ CFUs, a protective efficacy of 50–60% was recorded. On post hoc analysis, an efficacy of 87.1% for Vi-TT was observed as compared with 52. 3% Vi-PS, with a decreased severity among participants given Vi-TT vaccine.¹³⁷ A number of TCVs are in the pipeline at various phases of development and have the potential to protect young travellers, but efficacy data are awaited.¹³⁸

There are currently no licensed vaccines available for paratyphoid fever. Candidate paratyphoid vaccines in development include live attenuated vaccines and lipopolysaccharide conjugate vaccines. The increasing global burden of paratyphoid fever should make a bivalent vaccine, providing protection against both Salmonella Typhi and Salmonella Paratyphi A, a public health priority.¹³⁹

Conclusions

Although global rates of EF cases are falling, it continues to be an important public health problem in many resource-poor countries, especially in South, Southeast Asia and Sub-Saharan Africa. Travel-related EF is mostly acquired in the Indian subcontinent. In this region, MDR and quinolone-resistant Salmonella Typhi and Salmonella Paratyphi A predominate. Ceftriaxone and azithromycin remain the main treatment options, with added benefit when used in combination but lack well-conducted trials. The recent emergence in Pakistan of ESBL-producing, XDR Salmonella Typhi has further complicated the therapy of EF. In this era of worsening resistance, prevention through vaccination assumes great importance. However, current vaccines provide suboptimal protection against Salmonella Typhi and do not cover Salmonella Paratyphi A at all. Hence, vaccines that protect against both pathogens are needed urgently.

Conflict of interest

None.

Author’s contribution

Dr Abi Manesh and Dr Eyal Meltzer have equally contributed to reviewing articles and generation of the manuscript. Dr Celina Jin, Carl Britto, Divya Deodhar, Sneha Radha have reviewed the manuscript. Dr Eli Schwartz^2,3 have done the final review of the manuscript. Dr Priscilla Rupali¹ have contributed to the generation of the manuscript and did the final review of the manuscript.

Author notes

Co-first authors Abi Manesh, Eyal Meltzer