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BMJ. 2006 Jul 8; 333(7558): 78–82.
PMCID: PMC1489205

Current concepts in the diagnosis and treatment of typhoid fever

Zulfiqar A Bhutta, Husein Lalji Dewraj professor and chairman1

Although advances in public health and hygiene have led to the virtual disappearance of enteric fever (more commonly termed typhoid fever) from much of the developed world, the disease remains endemic in many developing countries. Typhoid fever is caused by Salmonella enterica serovar Typhi (S typhi), a Gram negative bacterium. A similar but often less severe disease is caused by S paratyphi A and, less commonly, by S paratyphi B (Schotmulleri) and S paratyphi C (Hirschfeldii). The common mode of infection is by ingestion of an infecting dose of the organism, usually through contaminated water or food. Although the source of infection may vary, person to person transmission through poor hygiene and sewage contamination of water supply are the most important.

Have the epidemiology and burden estimates of typhoid changed?

Few established surveillance systems for typhoid exist in the developing world, especially in community settings, so the true burden is difficult to estimate. This is shown by recent revisions in the global estimates of the true burden of typhoid. In contrast to previous estimates, which were 60% higher,1 investigators from the US Centers for Disease Control and Prevention estimate that there are 21.6 million typhoid cases annually, with the annual incidence varying from 100 to 1000 cases per 100 000 population.2 The global mortality estimates from typhoid have also been revised downwards from 600 000 to 200 000, largely on the basis of regional extrapolations.2 Recent population based studies from South Asia suggest that the incidence is highest in children aged less than 5 years, with higher rates of complications and hospitalisation, and may indicate risk of early exposure to relatively large infecting doses of the organisms in these populations.3-5 These findings contrast with previous studies from Latin Americaw1 and Africa,w2 which suggested that S typhi infection caused a mild disease in infancy and childhood.

There may be other factors that affect the changing epidemiology of typhoid. Although the overall ratio of disease caused by S typhi to that caused by S paratyphi is about 10 to 1, the proportion of S paratyphi infections is increasing in some parts of the world (Dong Mei Tan, personal communication 2005).6 Also, in contrast to the Asian situation, the HIV and AIDS epidemic in Africa has been associated with a concomitant increase in community acquired bacteraemia due to non-typhoidal salmonellae such as S typhimurium,7,8 an illness that may be clinically indistinguishable from typhoid. The exact reasons for these differences in the epidemiology and spectrum of salmonella infections between Asia and Africa remain unclear.

Summary points

Despite advances in technology and public health strategies, typhoid fever remains a major cause of morbidity in the developing world

In some areas typhoid fever disproportionately affects young children and may reflect high rates of transmission through food and water

Recent emergence of drug resistance—especially to common, first line antibiotics and quinolones—has made it very difficult and expensive for health services to manage the disease

Rapid and appropriate diagnostics are key to the management of typhoid in terms of public health

Although effective vaccines are available, there are no plans for large scale vaccination programmes in infants and children

Another worrying development has been the emergence of drug resistant typhoid. After sporadic outbreaks of chloramphenicol resistant typhoid between 1970 and 1985, many strains of S typhi developed plasmid mediated multidrug resistance to the three primary antimicrobials used (ampicillin, chloramphenicol, and co-trimoxazole).9 This was countered by the advent of oral quinolones, but chromosomally acquired quinolone resistance in S typhi and S paratyphiw3 has been recently described in various parts of Asia, possibly related to the widespread and indiscriminate use of quinolones.10,11

Can typhoid be diagnosed clinically where it matters?

Typhoid fever is among the most common febrile illnesses encountered by practitioners in developing countries. The advent of antibiotic treatment has led to a change in the presentation of typhoid, and the classic mode of presentation with a slow and “stepladder” rise in fever and toxicity is rarely seen. However, rising antimicrobial resistance has been associated with increased severity of illness and related complications.

Many other factors influence the severity and overall clinical outcome of the infection. They include the duration of illness before the start of appropriate treatment, the choice of antimicrobial, the patient's age and exposure or vaccination history, the virulence of the bacterial strain, the quantity of inoculum ingested, and several host factors affecting immune status. Recent data from South Asia indicate that the presentation of typhoid may be more dramatic in children younger than 5 years, with higher rates of complications and hospitalisation.3-5 Diarrhoea, toxicity, and complications such as disseminated intravascular coagulation are also more common in infancy, with higher mortality. Table 1 shows some of the common clinical features and complications of typhoid in children and adults based on our experience in Karachi of hospitalised children and those diagnosed and treated in a community setting,5,12 indicating the significantly higher morbidity and complications among children presenting to hospital.

Table 1
Common clinical features of typhoid fever in childhood in hospital and community settings in Karachi, Pakistan. Values are numbers (percentages)

The presentation of typhoid fever may be altered by coexisting morbidities and early administration of antibiotics. In areas where malaria is endemic and where schistosomiasis is common the presentation of typhoid may be atypical.13,14 Multidrug resistant typhoid and paratyphoid infections are more severe with higher rates of toxicity, complications, and mortality than infections with sensitive strains.12 This may be related to the increased virulence of multidrug resistant S typhi as well as a higher number of circulating bacteria.15 Although clinical diagnosis of typhoid may be difficult, there are indications that simple algorithms can be developed for diagnosis and patient triage in endemic areas.16 Such algorithms would have implications for diagnostic and treatment protocols in endemic areas: in particular, diagnosis and triage of typhoid among febrile children must be included among the protocols for integrated management of childhood illnesses in South Asia, which currently largely focus on malaria as a cause of fever without localising signs.

Sources and selection criteria

We evaluated all recent clinical reviews of typhoid fever in the electronic data bases (Medline, PubMed, Embase, and the Cochrane Library) for the past 10 years (1996-2006) in all languages to identify critical reviews and systematic reviews on the risk factors, diagnosis, treatment, and prevention of typhoid and paratyphoid fever. The focus was on clinical publications on epidemiology, diagnosis, and treatment, but we also studied other related reviews and publications.

Although several reviews of typhoid fever and treatment are available, there have been few systematic reviews and meta-analyses of treatment strategies, with only one Cochrane review of treatment options and none on appropriate diagnostics for typhoid.

The main search terms used were “typhoid fever,” “paratyphoid fever,” “enteric fever,” “typhoidal salmonellosis,” and “Salmonella” in combination with “Typhi” or “Paratyphi.” We also perused relevant reports from the World Health Organization and Centers for Disease Control and Prevention and the abstracts from five international symposiums on typhoid fever and other salmonelloses (Bangkok 1994, Bali 1997, Taipei 1999, Karachi 2002, and Guilin 2005).

We carried out a manual search of the bibliographies of key articles and reviews. In all, we studied 156 recent articles in depth, of which 44 are cited in this review.

The challenge of appropriate diagnostics in typhoid

Although the mainstay of diagnosing typhoid fever is a positive blood culture, the test is positive in only 40-60% of cases,17 usually early in the course of the disease. Stool and urine cultures become positive after the first week of infection, but their sensitivity is much lower. In much of the developing world, widespread antibiotic availability and prescribing is another reason for the low sensitivity of blood cultures. Although bone marrow cultures are more sensitive, they are difficult to obtain, relatively invasive, and of little use in public health settings.

Other haematological investigations are non-specific. Blood leucocyte counts are often low in relation to the fever and toxicity, but the range is wide; in younger children leucocytosis is a common association and may reach 20 000-25 000/mm3.12 w4 Thrombocytopenia may be a marker of severe illness and accompany disseminated intravascular coagulation. Liver function test results may be deranged, but significant hepatic dysfunction is rare.

The classic Widal test measures antibodies against O and H antigens of S typhi and is more than 100 years old.w5 Although robust and simple to perform, this test lacks sensitivity and specificity, and reliance on it alone in areas where typhoid is endemic may lead to overdiagnosis.w6 Newer diagnostic tests have been developed—such as the Typhidotw7 w8 or Tubex,w9 w10 which directly detect IgM antibodies against a host of specific S typhi antigens—but these have not proved to be sufficiently robust in large scale evaluations in community settings. A nested polymerase chain reaction using H1-d primers has been used to amplify specific genes of S typhi in the blood of patients and is a promising means of making a rapid diagnosis.w11 Table 2 compares the performance of the various tests for typhoid.w12-w14

Table 2
Laboratory diagnosis of typhoid

Despite these new developments, the diagnosis of typhoid in much of the developing world is made on clinical criteria. This poses problems, since typhoid fever may mimic many common febrile illnesses without localising signs. In children with multisystem features, the early stages of enteric fever may be confused with conditions such as acute gastroenteritis, bronchitis, and bronchopneumonia. Subsequently, the differential diagnosis includes malaria; sepsis with other bacterial pathogens; infections caused by intra-cellular organisms such as tuberculosis, brucellosis, tularaemia, leptospirosis, and rickettsial diseases; and viral infections such as dengue fever, acute hepatitis, and infectious mononucleosis. There is thus an urgent need to develop a multipurpose “fever stick” that may allow the rapid and specific diagnosis of common febrile illnesses, especially malaria, dengue fever, and typhoid.w15

How has drug resistance affected treatment?

Early diagnosis of typhoid fever and prompt institution of appropriate antibiotic treatment are essential for optimal management, especially in children. Although most cases can be managed at home with oral antibiotics and regular follow-up, patients with severe illness, persistent vomiting, severe diarrhoea, and abdominal distension require hospitalisation and parenteral antibiotic treatment. In addition to antibiotics, supportive treatment and maintenance of appropriate nutrition and hydration are crucial (box 1).

Box 1: General principles for the management of typhoid

  • Rapid diagnosis and institution of appropriate antibiotic treatment
  • Adequate rest, hydration, and correction of fluid-electrolyte imbalance
  • Antipyretic therapy as required (such as paracetamol 120-750 mg taken orally every 4-6 hours)
  • Adequate nutrition: a soft, easily digestible diet should be continued unless the patient has abdominal distension or ileus
  • Close attention to hand washing and limitation of close contact with susceptible individuals during acute phase of infection
  • Regular follow-up and monitoring for complications and clinical relapse (this may include confirmation of stool clearance in non-endemic areas or in high risk groups such as food handlers)

Appropriate antibiotic treatment (the right drug, dose, and duration) is critical to curing typhoid with minimal complications.18 Standard treatment with chloramphenicol or amoxicillin is associated with a relapse rate of 5-15% or 4-8% respectively, whereas the newer quinolones and third generation cephalosporins are associated with higher cure rates.17 The emergence of multidrug resistant typhoid in the 1990s led to widespread use of fluoroquinolones as the treatment of choice for suspected typhoid, especially in South Asia and South East Asia where the disease was endemic.19 In recent years, however, the emergence of resistance to quinolones has placed tremendous pressure on public health systems in developing countries as treatment options are limited.20,21

Table 3 shows the World Health Organization's recommendations for treating uncomplicated and severe cases of typhoid fever.17 Studies of short course antibiotic treatment for multidrug resistant typhoid have shown that fluoroquinolones can achieve satisfactory cure rates,w16 w17 but parenteral ceftriaxone was associated with higher rates of relapse.w18 A recent Cochrane review of antimicrobial treatment of typhoid fever concludes that there is little evidence to support administration of fluoroquinolones to all cases of typhoid and that satisfactory cure rates can be achieved in drug sensitive cases with first line agents such as chloramphenicol.22 Although some open studies have suggested that cure rates may be better with oral fluoroquinolones compared with chloramphenicol,23 these case series also include multidrug resistant cases. Given the signs of rapidly increasing resistance of S typhi to fluoroquinolones, it is imperative that the widespread use of these antibiotics for fever and their availability over the counter are restricted, although it may already be too late.24 However, treatment regimens must restrict as much as possible the use of further second and third line antibiotics for treating typhoid in primary care settings.25

Table 3
Recommended antibiotic treatment for typhoid fever(adapted from WHO17 and Bhutta20)

The prognosis for a patient with enteric fever depends on the rapidity of diagnosis and treatment with an appropriate antibiotic. Other factors include the patient's age, general state of health, and nutrition; the causative Salmonella serotype; and the appearance of complications. Infants and children with underlying malnutrition and those infected with multidrug resistant isolates are at higher risk of adverse outcomes. Although additional treatment with dexamethasone (3 mg/kg for the initial dose, followed by 1 mg/kg every 6 hours for 48 hours) has been recommended among severely ill patients with shock, obtundation, stupor, or coma,w19 this must be done only under strictly controlled conditions and supervision, and signs of abdominal complications may be masked.

Despite appropriate treatment, some 2-4% of infected children relapse after initial clinical response to treatment.17 Individuals who excrete S typhi for more than three months after infection are regarded as chronic carriers. However, the risk of becoming a carrier is low in children and increases with age, but in general it occurs in less than 2% of all infected children.17

Box 2: Advice for travellers to areas where typhoid is endemic

  • Avoid undue exposure to possible infection through food and water (contaminated water, salads, street foods). Use bottled water whenever possible, otherwise use only boiled water
  • Two typhoid vaccines are available, both with proved efficacy of 60-80%, and should be taken at least two weeks before travel
    Oral Ty21a vaccine—Enteric coated capsules taken on alternate days for four doses. The vaccine is contraindicated in pregnant women, children under the age of 6 years, and immunocompromised patients. A booster may be required every five years Vi polysaccharide vaccine—0.5mlasasingle intramuscular dose for travellers older than 2 years. A booster may be required every two years
  • Further advice on typhoid prevention and vaccination can be obtained from
    Centers for Disease Control and Prevention (www.cdc.gov/travel)
    World Health Organization (www.who.int/ith)
    International Society of Travel Medicine (www.istm.org)

In summary, many challenges remain for the effective control and management of typhoid in endemic countries. Although these include establishing rapid clinical diagnosis and confirmation, the fact that both S typhi and S paratyphi are rapidly becoming resistant to commonly used antibiotics is of great concern. Addressing this issue would require a host of measures, including adequate investments in safe water and sanitation services, community education, control over antimicrobial prescribing and over the counter sales, and large scale vaccination strategies. Box 2 details some of the preventive strategies and advice for travellers to areas where typhoid is endemic.

Supplementary Material

[extra: Extra references]


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Object name is webplus.f2.gifExtra references w1-w19 are on bmj.com

Competing interests: None declared.


1. Institute of Medicine. New vaccine development: establishing priorities. Washington DC: National Academy Press, 1986.
2. Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull World Health Organ 2004;82: 346-53. [PMC free article] [PubMed]
3. Sinha A, Sazawal S, Kumar R, Sood S, Reddaiah VP, Singh B, et al. Typhoid fever in children aged less than 5 years. Lancet 1999;354: 734-7. [PubMed]
4. Brooks WA, Hossain A, Goswami D, Nahar K, Alam K, Ahmed N, et al. Bacteremic typhoid fever in children in an urban slum, Bangladesh. Emerg Infect Dis 2005;11: 326-9. [PMC free article] [PubMed]
5. Siddiqui FJ, Rabbani F, Hasan R, Nizami SQ, Bhutta ZA. Typhoid fever in children: some epidemiological considerations. Int J Infect Dis 2006;10: 215-22. Epub 2006 January 23. [PubMed]
6. Ochiai RL, Wang X, von Seidlein L, Yang J, Bhutta ZA, Bhattacharya SK, et al. Salmonella paratyphi A rates, Asia. Emerg Infect Dis 2005;11: 1764-6. [PMC free article] [PubMed]
7. Berkley JA, Lowe BS, Mwangi I, Williams T, Bauni E, Mwarumba S, et al. Bacteremia among children admitted to a rural hospital in Kenya. N Engl J Med 2005;352: 39-47. [PubMed]
8. Graham SM. Salmonellosis in children in developing and developed countries and populations. Curr Opin Infect Dis 2002;15: 507-12. [PubMed]
9. Rowe B, Ward LR, Threlfall EJ. Multidrug-resistant Salmonella typhi: a worldwide epidemic. Clin Infect Dis 1997;24(suppl 1): S106-9. [PubMed]
10. Renuka K, Sood S, Das BK, Kapil A. High-level ciprofloxacin resistance in Salmonella enterica serotype Typhi in India. J Med Microbiol 2005;54: 999-1000. [PubMed]
11. Shirakawa T, Acharya B, Kinoshita S, Kumagai S, Gotoh A, Kawabata M. Decreased susceptibility to fluoroquinolones and gyrA gene mutation in the Salmonella enterica serovar Typhi and Paratyphi A isolated in Kathmandu, Nepal, in 2003. Diagn Microbiol Infect Dis 2006;54: 299-303. [PubMed]
12. Bhutta ZA. Impact of age and drug resistance on mortality in typhoid fever. Arch Dis Child 1996;75: 214-7. [PMC free article] [PubMed]
13. Hathout S el-D. Relation of schistosomiasis to typhoid fever. J Egypt Public Health Assoc 1970;45: 145-56. [PubMed]
14. Nsutebu EF, Martins P, Adiogo D. Prevalence of typhoid fever in febrile patients with symptoms clinically compatible with typhoid fever in Cameroon. Trop Med Int Health 2003;8: 575-8. [PubMed]
15. Wain J, Diep TS, Ho VA, Walsh AM, Nguyen TT, Parry CM, et al. Quantitation of bacteria in blood of typhoid fever patients and relationship between counts and clinical features, transmissibility, and antibiotic resistance. J Clin Microbiol 1998;36: 1683-7. [PMC free article] [PubMed]
16. Vollaard AM, Ali S, Widjaja S, Asten HA, Visser LG, Surjadi C, et al. Identification of typhoid fever and paratyphoid fever cases at presentation in outpatient clinics in Jakarta, Indonesia. Trans R Soc Trop Med Hyg 2005;99: 440-50. [PubMed]
17. World Health Organization Department of Vaccines and Biologicals. Background document: the diagnosis, prevention and treatment of typhoid fever. Geneva: WHO, 2003:19-23. (www.who.int/entity/vaccine_research/documents/en/typhoid_diagnosis.pdf.)
18. Van den Bergh ET, Gasem MH, Keuter M, Dolmans MV. Outcome in three groups of patients with typhoid fever in Indonesia between 1948 and 1990. Trop Med Int Health 1999;4: 211-5. [PubMed]
19. Rowe B, Threlfall EJ, Ward LR. Does chloramphenicol remain the drug of choice for typhoid? Epidemiol Infect 1987;98: 379-83. [PMC free article] [PubMed]
20. Bhutta ZA. Typhoid fever. In: Rakel RE, Bope ET, eds. Conn's current therapy. Philadelphia PA: Saunders, 2006: 215-8.
21. Frenck RW Jr, Mansour A, Nakhla I, Sultan Y, Putnam S, Wierzba T, et al. Short-course azithromycin for the treatment of uncomplicated typhoid fever in children and adolescents. Clin Infect Dis 2004;38: 951-7. [PubMed]
22. Thaver D, Zaidi AK, Critchley J, Madni SA, Bhutta ZA. Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). Cochrane Database Syst Rev 2006;(1): CD004530. [PubMed]
23. Phongmany S, Phetsouvanh R, Sisouphone S, Darasavath C, Vongphachane P, Rattanavong O, et al. A randomized comparison of oral chloramphenicol versus ofloxacin in the treatment of uncomplicated typhoid fever in Laos. Trans R Soc Trop Med Hyg 2005;99: 451-8. [PubMed]
24. Okeke IN, Laxminarayan R, Bhutta ZA, Duse AG, Jenkins P, O'Brien TF, et al. Antimicrobial resistance in developing countries. Part I: recent trends and current status. Lancet Infect Dis 2005;5: 481-93. [PubMed]
25. Okeke IN, Klugman KP, Bhutta ZA, Duse AG, Jenkins P, O'Brien TF, et al. Antimicrobial resistance in developing countries. Part II: strategies for containment. Lancet Infect Dis 2005;5: 568-80. [PubMed]

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