OVERVIEW: What every practitioner needs to know

Are you sure your patient has enteric fever? What should you expect to find?

  • Enteric (typhoid) fever is a systemic disease characterized by fever and abdominal pain caused by dissemination of Salmonella Typhi or Salmonella Paratyphi type A, B, or C. Fever (38.8-40.5°C; 101.8-104.9°F) is documented at presentation in more than 75% of cases and is typically prolonged, continuing up to 4 weeks if untreated. Symptoms reported on initial medical evaluation include headache (80%), chills (35-45%), cough (30%), sweating (20-25%), myalgias (20%), malaise (10%), and arthralgia (2-4%). Gastrointestinal (GI) symptoms include anorexia (55%), abdominal pain (30-40%), nausea (18-24%), vomiting (18%), and diarrhea (22-28%) more commonly than constipation (13-16%).

  • Early physical findings of enteric fever include coated tongue (55%), rash (“rose spots”; 30%), abdominal tenderness (4-5%). hepatosplenomegaly (3-6%), epistaxis, and relative bradycardia at the peak of high fever (<50%). Rose spots (Figure 1) are a faint, salmon-colored, blanching, maculopapular rash located primarily on the trunk and chest. The rash is evident in approximately 30% of patients at the end of the first week and resolves without a trace after 2 to 5 days. Patients can have two or three crops of lesions, and Salmonella can be cultured from punch biopsies of these lesions. The faintness of the rash makes it difficult to detect in highly pigmented patients.

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  • The development of severe disease, which occurs in approximately 10 to 15% of patients, depends on host factors (i.e., immunosuppression, antacid therapy, previous exposure, and vaccination), strain virulence and inoculum, and choice of antibiotic therapy. Gastrointestinal (GI) bleeding (10-20%) and intestinal perforation (1-3%) most commonly occur in the third and fourth weeks of illness and result from hyperplasia, ulceration, and necrosis of the ileocecal Peyer patches at the initial site of Salmonella growth in the intestines. Neurologic manifestations occur in 2 to 40% of patients and include meningitis, Guillain-Barré syndrome, neuritis, and neuropsychiatric symptoms (described as “muttering delirium” or “coma vigil”), with picking at bedclothes or imaginary objects.

How did the patient develop enteric fever? What was the primary source from which the infection spread?

  • In contrast to other Salmonella serotypes, the etiologic agents of enteric fever (S. Typhi and S. Paratyphi serotypes A, B, and C) have no known hosts other than humans. Most commonly, food- or water-borne transmission results from fecal contamination by ill or asymptomatic chronic carriers acquired during travel to developing countries. Sexual transmission between male partners has been described. Healthcare workers occasionally acquire enteric fever after exposure to infected patients or during processing of clinical specimens and cultures.

Which individuals are of greater risk of developing enteric fever?

  • Conditions that decrease either stomach acidity (younger than 1 year of age, antacid ingestion, Helicobacter pylori infection, or achlorhydric disease) or intestinal integrity (inflammatory bowel disease, prior GI surgery, or alteration of the intestinal flora by antibiotic administration) increase susceptibility to Salmonella infection.

  • Immunosuppression, including cell-mediated immunodeficiency, such as human immunodeficiency virus (HIV) infection, may increase the risk of acquiring enteric fever but does not increase disease severity or risk of complications as it does for nontyphoidal Salmonella infection.

Beware: there are other diseases that can mimic enteric fever:

  • Because the clinical presentation of enteric fever is relatively nonspecific, diagnosis needs to be considered in any febrile traveler returning from a developing country, particularly the Indian subcontinent, the Philippines, or Latin America. Other diagnoses that should be considered in these travelers include malaria, prodrome of viral hepatitis, yellow fever, Q fever, brucellosis, dengue fever, rickettsial infections, leptospirosis, babesiosis, amebic liver abscesses, schistosomiasis, tuberculosis, and acute HIV infection.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • Hematological abnormalities associated with enteric fever are nonspecific and include leukopenia, anemia, and subclinical disseminated intravascular coagulopathy.

  • Other laboratory abnormalities associated with enteric fever include elevated creatinine kinase and liver enzymes (e.g., aspartate transaminase and alanine transaminase; often 300-500U/dL). Creatinine clearance is usually normal. Patients rarely develop proteinuria and immune complex glomerulonephritis; irreversible loss of renal function has not been reported. Nonspecific ST- and T-wave electrocardiographic abnormalities are uncommon.

Results that confirm the diagnosis

  • The definitive diagnosis of enteric fever requires the isolation of S. Typhi or S. Paratyphi from blood, bone marrow, other sterile sites, rose spots, stool, or intestinal secretions.

  • The sensitivity of blood culture is only 40 to 80%, probably because of high rates of antibimicrobial use in endemic areas and the small quantities of S. Typhi (i.e., <15 organisms/mL) typically present in the blood of patients with enteric fever. Almost all S. Typhi in blood are associated with the mononuclear cell-platelet fraction. Thus, culturing blood clots, centrifugating blood and culturing the buffy-coat fraction, or using the lysis centrifugation method can substantially reduce the time to isolation of the organism and improve sensitivity. Bacteremia is more frequently detected and is of higher grade during the first week of clinical illness.

  • Enteric fever is the only bacterial infection of humans for which bone marrow examination is recommended routinely; however, the sensitivity is variable (55-90%). Higher colony counts are present in the bone marrow compared with blood and, unlike blood culture, are not reduced by up to 5 days of prior antimicrobial therapy.

  • The duodenal string test is a useful, noninvasive technique to sample duodenal secretions with a sensitivity of up to 58%.

  • Children have a higher incidence of positive stool cultures compared with adults (60 vs 27%), and stool cultures may become positive during the third week of illness in untreated patients. Thus, the optimal diagnostic approach in both children and adults is to culture blood, bone marrow, gastric or duodenal secretions, and stool. Using this approach, the diagnosis can be established in more than 90% of patients.

  • A number of serologic tests, including the classic Widal test for “febrile agglutinins,” have been developed to detect S. Typhi antibody. The Widal test is neither sensitive (47-77%) nor specific (50-92%) and may lead to over-diagnosis of enteric fever in endemic areas.

  • Newer commercially available kits for the rapid serologic diagnosis of enteric fever typically detect immunoglobulin (Ig)M antibody to lipopolysaccharide or outer membrane proteins of S. Typhi. These kits perform better among hospitalized patients than those evaluated in the community setting for enteric fever.

  • Measuring antibody against the capsular polysaccharide Vi antigen may be useful in distinguishing chronic carriage from acute infection with S. typhi, because chronic carriers often have a high antibody titer to this antigen.

What imaging studies will be helpful in making or excluding the diagnosis of enteric fever?

  • Imaging studies are not routinely needed in the diagnosis of enteric fever but may assist in identifying uncommon complications, such as intestinal perforation or splenic abscesses, when clinically suspected.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

  • Infectious disease consultation should be considered for any returning traveler with fever.

If you decide the patient has enteric fever, what therapies should you initiate immediately?

  • The initial choice and route of antibiotics depends on the susceptibility of the S. Typhi and S. Paratyphi strains in the area of residence or travel, the severity of illness, and the age fo the patient.

  • For treatment of drug-susceptible enteric fever, fluoroquinolones are the most effective class of agents, with cure rates of approximately 98% and relapse and fecal carriage rates less than 2%. Experience is most extensive with ciprofloxacin. Different fluoroquinolones have not been compared directly.

  • Travelers to southern Asia are at highest risk for infections that are nalidixic acid-resistant or multidrug-resistant (resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole). Nalidixic acid (a non-fluorinatede quinolone antibiotic) susceptibility is used as a marker for fluoroquinolone susceptibility.

  • The increased incidence of nalidixic acid resistant S. Typhi in southern Asia is likely related to the widespread availability of fluoroquinolones available over the counter. The increasing resistance is now limiting the use of this class of agents for treating enteric fever. Patients who have these strains should be treated with ceftriaxone, azithromycin, or high-dose ciprofloxacin.

  • For multidrug-resistant (MDR) enteric fever, third-generation cephalosporines including ceftriaxone, cefotaxime, and oral cefixime are effective. These agents clear fever in approximately 1 week, with failure rates of 5 to 10%, fecal carriage rates less than 3%, and relapse rates of 3 to 6%. Cephalosporins are associated with delayed defervescence and higher relapse rated compared to fluoroquinolones for the treatment of susceptible strains.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

  • Oral azithromycin is an option for treating mild-to-moderate enteric fever, including infection associated with MDR strains. Azithromycin results in defervescence in 4 to 6 days, with rates of relapse and convalescent stool carriage less than 3%. For treatment of nalidixic acid resistant strains, azithromycin reduces rates of treatment failure and duration of hospitalization compared to fluoroquinolones. Azithromycin may perform better than ceftriaxone.

  • High-dose fluoroquinolone therapy for 7 days for nalidixic acid resistant enteric fever has been associated with delayed resolution of fever and high rates of fecal carriage during convalescence. For these resistant strains, 10 to 14 days of high-dose ciprofloxacin is preferred.

  • Most patients with uncomplicated enteric fever can be managed at home with oral antibiotics and antipyretics. Patients with persistent vomiting, diarrhea, and/or abdominal distension should be hospitalized and given supportive therapy, as well as a parenteral third-generation cephalosporin or fluoroquinolone, depending on the susceptibility profile. Therapy should be administered for at least 10 days or for 5 days after fever resolution.

  • For empirical antibacterial treatment of a febrile traveler with possible enteric fever, oral azithromycin or intravenous (IV) ceftriaxone are recommended, depending on severity of illness and site of care.

  • See Table I for antibiotic therapy options.

Indication Agent Dosage (Route) Duration, days
Empirical treatment
  Ceftriaxonea 1–2g/day (IV) 7–14
  Azithromycin     1g/day (PO) 5
Fully susceptible
  Ciprofloxacinb (first line) 500mg twice a day (PO) or 400mg every 12 hours (IV) 5-7
  Amoxicillin(second line) 25mg/kg three times a day (PO or IV) 14
  Chloramphenicol 160/800mg twice a day (PO) 14-21
  Trimethoprim-sulfamethoxazole   7-14
Multidrug-resistant      
  Ciprofloxacin 500mg twice a day (PO) or 400mg every 12 hours (IV) 5-7
  Ceftriaxone 2-3g/day (IV) 7-14
  Azithromycin 1g/day (PO)c 5
Nalidixic acid-resistant
  Ceftriaxone 2-3g/day (IV) 7-14
  Azithromycin 1g/day (PO) 5
  High-dose ciprofloxacin 750mg twice a day (PO) or 400mg every 8 hours (IV) 10-14

aOr another third-generation cephalosporin [e.g., cefotaxime, 2g every 8 hours (IV), or cefixime, 400mg twice a day (PO)].

bOr ofloxacin, 400mg twice a day (PO) for 2 to 5 days.

cOr 1g on day 1 followed by 500mg/day PO for 6 days.

IV, intravenously; PO, by mouth.

2. Other key therapeutic modalities.

  • Supportive therapies, including antipyretics and intravenous fluid replacement, should be administered as needed.

  • In a randomized, prospective, double-blind study of critically ill patients with enteric fever (i.e., those with shock and obtundation) in Indonesia in the early 1980s, the administration of dexamethasone (3mg/kg initial dose followed by eight doses of 1mg/kg every 6 hours) with chloramphenicol was associated with a substantially lower mortality rate than treatment with chloramphenicol alone (10% vs 55%). Although this study has not been repeated in the “post-chloramphenicol era,” severe enteric fever remains one of the few indications for glucocorticoid treatment of an acute bacterial infection.

What complications could arise as a consequence of disease?

What should you tell the family about the patient's prognosis?

  • Rare complications whose incidences are reduced by prompt antibiotic treatment include disseminated intravascular coagulation, hematophagocytic syndrome, pancreatitis, hepatic and splenic abscesses and granulomas, endocarditis, pericarditis, myocarditis, orchitis, hepatitis, glomerulonephritis, pyelonephritis, hemolytic uremic syndrome, severe pneumonia, arthritis, osteomyelitis, and parotitis. Up to 10% of patients develop mild relapse, usually within 2 to 3 weeks of fever resolution and in association with the same strain type and susceptibility profile.

  • Up to 10% of untreated patients with typhoid fever excrete S. Typhi in the feces for up to 3 months, and 1 to 4% develop chronic asymptomatic carriage, shedding S. Typhi in either urine or stool for more than 1 year. Chronic carriage is more common among women, infants, and persons with cholelithiasis or concurrent bladder infection with Schistosoma haematobium.

  • The anatomic abnormalities associated with the latter conditions promote biofilm formation that is likely to promote prolonged carriage.

  • Chronic carriage of S. Typhi or S. Paratyphi A has been associated with an increased incidence of carcinoma of the gallbladder and of other GI malignancies.

  • Prompt administration of appropriate antibiotic therapy prevents severe complications of enteric fever reduces case-fatality rates from 1% to approximately 0.2%.

What-if scenarios

  • GI bleeding and intestinal perforation associated with enteric fever require immediate fluid resuscitation and surgical intervention, with broadened antibiotic coverage for polymicrobial peritonitis and treatment of GI hemorrhage, which may require bowel resection.

How do you contract disease and how frequent is this disease?

  • With improvements in food handling and water/sewage treatment, enteric fever has become rare in developed nations. Worldwide, however, there are an estimated 22 million cases of enteric fever, with 200,000 deaths annually. The incidence is highest (>100 cases per 100,000 population per year) in South-central and Southeast Asia; medium (10-100 cases per 100,000) in the rest of Asia, Africa, Latin America, and Oceania (excluding Australia and New Zealand); and low in other parts of the world. A high incidence of enteric fever correlates with poor sanitation and lack of access to clean drinking water.

  • The incidence of enteric fever among travelers from the United States is estimated at 3 to 30 cases per 100,000. Of 1,902 persons with enteric fever associated with S. typhi reported to the US Centers for Disease Control and Prevention (CDC) from 1999 to 2006, 79% were associated with recent international travel, most commonly to India (47%), Pakistan (10%), Bangladesh (10%), Mexico (7%), and the Philippines (4%). Only 5% of travelers diagnosed with enteric fever had received S. Typhi vaccination.

  • The risk of infection is highest in travelers visiting friends and relatives in countries where enteric fever is endemic. This may be due to lower compliance with pre-travel vaccination and failure to observe strict food and water precautions. Although the risk of acquiring enteric fever increases with the duration of stay, travelers can acquire enteric fever even during visits shorter than 1 week to countries where the disease is endemic.

  • According to data from the CDC, approximately 300 cases of typhoid fever and 150 cases of paratyphoid fever are reported annually in the United States. Most cases in the United States are associated with foreign travel, but 25 to 30% of reported cases of enteric fever are domestically acquired. Although the majority of these cases are sporadic, 7% of total cases were part of recognized outbreaks linked to contaminated food products and previously unrecognized chronic carriers.

  • A seasonal pattern with peak incidence rising during October to December during the post-monsoon period has been reported in India but not described for typhoid fever.

  • Transmission is by consumption of food or water that has been fecally contaminated by ill persons or chronic carriers.

  • In endemic regions, enteric fever is more common in urban than rural areas and among young children and adolescents. Risk factors include contaminated water or ice, flooding, food and drinks purchased from street vendors, raw fruits and vegetables grown in fields fertilized with sewage, ill household contacts, and lack of hand washing and toilet access. It is estimated that there is one case of paratyphoid fever for every four cases of typhoid fever, but the incidence of infection associated with S. Paratyphi A appears to be increasing, particularly in India, perhaps as a result of vaccination for S. typhi.

  • MDR strains of S. Typhi emerged in 1989 in China and southern Asia and have since disseminated widely. These strains contain plasmids encoding resistance to chloramphenicol, ampicillin, and trimethoprim (antibiotics long used to treat enteric fever).

  • With the increased use of fluoroquinolones to treat MDR enteric fever in the 1990s, strains of S. Typhi and S. Paratyphi with reduced susceptibility to ciprofloxacin (minimal inhibitory concentration [MIC], 0.125-1.0mcg/mL) have emerged in the Indian subcontinent, South Asia, and most recently in sub-Saharan Africa. Infections with these strains have been associated with clinical treatment failure. Testing of isolates for resistance to the first-generation quinolone nalidixic acid is used as a screen for fluoroquinolone resistance and detects most, but not all, strains with reduced susceptibility to ciprofloxacin.

  • Humans are the reservoirs for S. Typhi and S. Paratyphi causing enteric fever.

What pathogens are responsible for this disease?

  • Salmonella are now classified into two major species: Salmonella bongori and Salmonella enterica. Human pathogens are included in the S. enterica group. This group is further divided into six subspecies and thousands of serovars. The organisms are generally designated by the specific serovar.

  • The organisms responsible for enteric fever are Salmonella enterica, serovar Typhi and Salmonella enterica serovar Paratyphi A, B, and C.

How do these pathogens cause disease?

  • The infectious dose estimated from volunteer studies is 103 to 106 colony-forming units. Ingestion of larger doses is associated with higher attack rates and shorter incubation periods.

  • Ingested organisms that survive exposure to gastric acid penetrate the small intestinal epithelium, enter the lymphoid tissue in the Peyer’s patches, and disseminate via the lymphatic or hematogenous route.

  • Organisms penetrate the bowel mucosa by two mechanisms: via phagocytic microfold (M) cells, specialized epithelial cells that serve as sampling and antigen presenting cells in the gut-associated lymphoid system; and via direct penetration into nonphagocytic epithelial cells by a process referred to as bacteria-mediated endocytosis (BME). BME relies on the direct delivery of Salmonella proteins into the cytoplasm of epithelial cells by a specialized bacterial secretion system (type III secretion). These bacterial proteins mediate alterations in the actin cytoskeleton required for Salmonella uptake.

  • After crossing the epithelial layer of the small intestine, the organisms are phagocytosed by macrophages within the Peyer patches. These salmonellae survive the antimicrobial environment of the macrophage by sensing environmental signals that trigger alterations in regulatory systems of the phagocytosed bacteria, including PhoP/PhoQ that triggers the expression of outer-membrane proteins and mediates modifications in liposaccharides so that the altered bacterial surface can resist microbicidal activities and potentially alter host cell signaling.

  • In addition, S. Typhi encodes a second type III secretion system that directly delivers bacterial proteins across the phagosome membrane into the macrophage cytoplasm. This secretion system functions to remodel the Salmonella-containing vacuole, promoting bacterial survival and replication.

  • Once phagocytosed, typhoidal salmonellae disseminate throughout the body in macrophages via the lymphatics and colonize reticuloendothelial tissues in the liver, spleen, lymph nodes, and bone marrow. Patients have relatively few or no signs and symptoms during this initial incubation stage.

  • Subsequent signs and symptoms, including fever and abdominal pain, probably result from secretion of cytokines by macrophages and epithelial cells in response to bacterial products recognized by innate immune receptors when a critical number of organisms have replicated.

  • Over time, the development of hepatosplenomegaly is likely related to the recruitment of mononuclear cells and the development of a specific acquired cell-mediated immune response to S. Typhi colonization.

  • The recruitment of additional mononuclear cells and lymphocytes to Peyer patches during the several weeks after initial colonization/infection can result in marked enlargement and necrosis of the Peyer patches. This lymphoid hypertrophy and necrosis is probably responsible for abdominal pain, risk of ileal perforation, and secondary bacteremia.

What other additional laboratory findings may be ordered?

  • DNA probe and polymerase chain reaction (PCR) assays have been developed for detection of S. Typhi and S. Paratyphi in blood and are more rapid and sensitive than standard culture but are not yet commercially available and are impractical in many areas where typhoid is endemic.

How can this disease be prevented?

  • Given the high prevalence of the disease in developing countries that lack adequate sewage disposal and water treatment, this goal is currently unrealistic. Thus, travelers to developing countries should be advised to monitor their food and water intake carefully and to receive typhoid vaccination before travelling to at-risk countries (see updated Travelers’ Health guidelines at http://wwwnc.cdc.gov/travel).

  • Two typhoid vaccines are licensed and marketed internationally: Ty21a, an oral live attenuated S. Typhi vaccine (given on days 1, 3, 5, and 7, with a booster every 5 years); and Vi CPS, a parenteral vaccine consisting of purified Vi polysaccharide from the bacterial capsule (given in one dose, with a booster every 2 years).

  • The minimal age for vaccination is 6 years of age for Ty21a and 2 years of age for Vi CPS. Currently, there is no licensed vaccine for paratyphoid fever. Both are acceptable for typhoid vaccination and are tolerated well. In endemic regions, Ty21a vaccine prevents one-third to one-half of typhoid cases in the first two years after vaccination. Vi CPS vaccine prevents around two-thirds of cases in the first year after vaccination with a three year cumulative efficacy around 55%.

  • Vi CPS typhoid vaccine is poorly immunogenic in children younger than 5 years of age because of T cell–independent properties. In the recently developed Vi-rEPA vaccine, Vi is bound to a nontoxic recombinant protein that is identical to Pseudomonas aeruginosa exotoxin A. In a two-dose trial in 2- to 5-year-old children in Vietnam, Vi-rEPA provided 94% efficacy at 1 year and 89% cumulative efficacy at 46 months. This vaccine is not yet commercially available in the United States.

  • A meta-analysis of randomized clinical vaccine trials evaluating Ty21a, Vi CPS, and Vi-rEPA in populations in endemic areas indicated that the cumulative efficacy assessed at 2.5 to 3.8 years was higher for Vi-rEPA (89%) than for the Ty21a (48%) and Vi CPS (55%). Each of the vaccines was associated with similar rates of adverse events to placebo.

  • Typhoid vaccine is not required for international travel, but it is recommended for travelers to areas where there is a moderate to high risk of exposure to S. Typhi, particularly for those who are traveling to South Asia and other developing countries in Asia, Africa, the Caribbean, and Central and South America and who will have exposure to potentially contaminated food and drink, even when planning less than 2 weeks travel.

  • Laboratory workers who work with S. Typhi and household contacts of known S. Typhi carriers should be vaccinated.

  • Because vaccine protective efficacy can be overcome by a high inoculum common in food-borne exposure, immunization is an adjunct and not a substitute for avoiding high-risk foods and beverages.

  • WHO recommends typhoid vaccination targeted to high-risk groups and populations (e.g., pre-school and school-aged children), but to date implementation of typhoid vaccination programs in high-incidence countries has been limited.

  • See Table II for dosages and schedule for vaccination.

Typhoid vaccination Age (years) Dose/route Number of doses Dosing interval Boosting interval
Oral, live, attenuated Ty21a vaccine (Vivotif)
Primary series ≥6 1 capsule, oral 4 48 hours Not applicable
Booster ≥6 1 capsule, oral 4 48 hours Every 5 years
ViCapsular polysaccharide vaccine (Typhim Vi)
Primary series ≥2 0.50mL, intramuscular 1 Not applicable Not applicable
Booster ≥2 0.50mL, intramuscular 1 Not applicable Every 2 years

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Effa, EE, Lassi, ZS, Critchley, JA, Garner, P, Sinclair, D, Olliaro, PL, Bhutta, ZA. “Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever)”. Cochrane Database Syst Rev. 2011 Oct 5. pp. CD004530(Updated systematic review of randomized clinical trials comparing fluoroquinolones, cephalosporins, azithromycin, and older antibiotics for the treatment of enteric fever in children and adults).

Anwar, E, Goldberg, E, Fraser, A, Acosta, CJ, Paul, M, Leibovici, L. “Vaccines for preventing typhoid fever”. Cochrane Database Syst Rev. 2014 Jan 2. pp. CD001261(Updated systematic review of randomized clinical trials comparing protective efficacy of Ty21a, Vi polysaccharide, and a new modified, conjugated Vi vaccine in endemic populations).

Jackson, BR, Iqbal, S, Mahon, B. “Updated recommendations for the use of typhoid vaccine – Advisory Committee on Immunization Practices, United States, 2015”. MMWR Morb Mortal Wkly Rep. vol. 64. 2015 Mar 27. pp. 305-8. (Most recent recommendations from the Advisory Committee on Immunization Practices for typhoid vaccination).

Date, KA, Bentsi-Enchill, AD, Fox, KK, Abeysinghe, N, Mintz, ED, Khan, MI, Sahastrabuddhe, S, Hyde, TB. “Typhoid Fever surveillance and vaccine use – South-East Asia and Western Pacific regions, 2009-2013”. MMWR Morb Mortal Wkly Rep. vol. 63. 2014 Oct 3. pp. 855-60. (Overview on recent national-level progress in improving surveillance and vaccine use to prevent typhoid fever in high-risk countries)

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