TH

UPDATED 25 JANUARY 2016

OUTBREAK RESPONSE, DIVISION OF PUBLIC HEALTH SURVEILLANCE AND RESPONSE
CENTRE FOR ENTERIC DISEASES

Typhoid:
NICD recommendations
for diagnosis, management
and public health response
Version 1 (June 2011)
Previously called ‘Health Care Workers’ Handbook on Typhoid’
Developed by:
The National Institute for Communicable Diseases (NICD)
a division of the National Health Laboratory Service (NHLS),

in collaboration with:
The South African National Department of Health
U.S. Centres for Disease Control and Prevention – South Africa

Version 2 (January 2016)

Updated by:
The Outbreak Response Unit, andthe Centre for Enteric Diseases of
The National Institute for Communicable Diseases (NICD)
a division of the National Health Laboratory Service (NHLS),

Prefix and Disclaimer

This material is intended for use by healthcare professionals. While the greatest care has been taken in the
development of the document, the National Department of Health and the National Institute for
Communicable Diseases of the National Health Laboratory Service do not accept responsibility for any
errors or omissions. All healthcare professionals should exercise their own professional judgement in
confirming and interpreting the findings presented in the handbook.

Guidelines_typhoid_20160125 Page 2 of 20
Quick Reference Guide - Typhoid

Typhoid case definitions: Page 6 Diagnosis of typhoid Page 7

Typhoid is diagnosed by culture of the organism
A typhoid ‘case under investigation’: Salmonella Typhi from any clinical specimen.
A person presenting with a documented fever >/= 1. Blood culture is the specimen of choice. Submit
o
38.5 C, and any of: blood cultures as soon as possible. Blood
 Gastrointestinal symptoms (abdominal pain, cultures may be positive in up to 50-80% of
nausea and vomiting or constipation), cases
 Relative bradycardia, 2. Stool culture may be useful, especially in
 ‘Rose spots’ (erythematous macula-papular children. Organisms are shed in the stool only
lesions) or after the first week of illness
 Hepatosplenomegally or leucopaenia. 3. Bone marrow aspirate is positive in 90% of
 A travel history within the last month to an area cases but is an invasive specimen.
with a confirmed outbreak of typhoid is highly 4. Urine cultures may be useful.
suggestive.
Serological testing is not recommended for the diagnosis
A confirmed case of typhoid: of typhoid
The isolation of Salmonella Typhi from a clinical
specimen in the presence of symptoms compatible
with typhoid. Treatment of a case of typhoid: Page 10
If typhoid is clinically suspected, commence treatment
A typhoid carrier: immediately. Do not wait for laboratory results
The isolation of Salmonella Typhi from a clinical
specimen in a person who is asymptomatic. Ciprofloxacin is the drug of choice for the treatment of
uncomplicated typhoid fever in South Africa.
 The paediatric dose if 15mg/kg/day in two
REMEMBER TO EXCLUDE MALARIA IN
divided doses x 7 days.
ALL RETURNING TRAVELLERS WHO
 Adults are treatment with 500-750mg po bd x 7
PRESENT WITH FEVER. At least two negative
days
malaria smears are required
Refer to page 11 and 12 for treatment of complicated
typhoid, and typhoid carriers
Public health response to a case of typhoid:
1. Notify the department of health Page 12
2. Confirm the diagnosis by verifying laboratory results,
and patient details.
3. Review the case management and treatment Notification of cases and additional support:
4. Interview the patient and complete a case Laboratory support: National Institute for
investigation form to ascertain risk factors for Communicable Diseases, Centre for Enteric Diseases,
exposure and likely source of infection Arvinda Sooka arvindas@nicd.ac.za (011-386-6235), or
5. Identify contacts at risk of infection, and confirm that after-hours, the NICD doctor-on-call 082 883 9920:
they are well, and are not carrying typhoid.
Public health support and notification of cases: Notify
6. Follow up the patient with three stool specimens to
the Provincial Communicable Diseases Control Officer,
confirm that s/he is not a carrier. or the NICD Outbreak Response unit (011-555-0542) or
outbreak@nicd.ac.za.

Guidelines_typhoid_20160125 Page 3 of 20
 Table of Contents
Quick Reference Guide - Typhoid.....................................................................................................................................3
1 Background on typhoid fever ....................................................................................................................................5
1.1 Aetiologic agent ..................................................................................................................................................5
1.2 Clinical features ..................................................................................................................................................5
1.3 Transmission ......................................................................................................................................................6
1.4 Burden of disease ...............................................................................................................................................6
1.5 Epidemiology and high risk individuals ...............................................................................................................6
2 Case definitions ..........................................................................................................................................................6
2.1 A typhoid ‘case under investigation’: ..................................................................................................................6
2.2 A confirmed case of typhoid: ..............................................................................................................................7
2.3 A typhoid carrier:.................................................................................................................................................7
3 Diagnosis .....................................................................................................................................................................7
3.1 Differential diagnosis ..........................................................................................................................................7
3.2 Specimen collection for laboratory diagnosis......................................................................................................7
3.2.1 Blood culture – *Diagnostic test of choice* .....................................................................................................8
3.2.2 Stool culture ...................................................................................................................................................8
3.2.3 Bone marrow aspirate culture ........................................................................................................................9
3.2.4 Extra-intestinal complications and focal infections .........................................................................................9
3.2.5 Urine cultures .................................................................................................................................................9
3.2.6 Serology and other tests ................................................................................................................................9
4 Treatment and case management ...........................................................................................................................10
4.1 Supportive management...................................................................................................................................10
4.2 Treatment of acute uncomplicated typhoid fever ..............................................................................................10
4.3 Treatment of severe and complicated typhoid fever .........................................................................................11
4.4 Treatment of persistent infections and chronic carriers ....................................................................................12
4.5 Infection prevention and control........................................................................................................................12
4.6 School and work restrictions .............................................................................................................................12
5 Public health response to a single case .................................................................................................................12
6 Public health response to a cluster or outbreak ....................................................................................................14
7 Prevention and control .............................................................................................................................................15
7.1 Safe water ........................................................................................................................................................15
7.2 Food safety .......................................................................................................................................................16
7.3 Sanitation..........................................................................................................................................................16
7.4 Vaccination .......................................................................................................................................................16
7.5 Travellers ..........................................................................................................................................................17
7.6 Post exposure prophylaxis................................................................................................................................17
8 Resources and additional information....................................................................................................................17
9 Appendix 1: Suspected/confirmed typhoid fever case investigation form..........................................................18

Guidelines_typhoid_20160125 Page 4 of 20
1 Background on typhoid fever
1.1 Aetiologic agent
Typhoid fever, also called enteric fever, is caused by a bacterial infection with Salmonella enterica
subspecies enterica serotype Typhi or serotypes Paratyphi A, B or C. For the purposes of these guidelines,
hereafter we refer to these only as Salmonella Typhi causing typhoid fever disease.

1.2 Clinical features

Few clinical features reliably distinguish typhoid fever from other causes of febrile illnesses. Infection in the
absence of treatment manifests after an average incubation period of 10-14 days (range 5-21 days) as a
multistage febrile illness.

Acute typhoid fever:

Systemic illness characterised by:
 Fever (30-100% of cases): remittent during the first week, rising in a stepwise fashion and becomes
sustained (lasting > 48 hours) after the first week.
 Headache (43-90%).
 Gastrointestinal symptoms (8-79%), including:
o Abdominal pain/cramps (30-40%),
o Nausea and vomiting (usually not severe), and/or
o Constipation (10-38%) or diarrhoea (diarrhoea is more frequent in children and HIV-
infected adults).
 Relative bradycardia (17-50%),
 Erythematous maculopapular lesions (rose spots) (≈30%): flat, faint-pink spots 2-4cm in diameter
which develop on the chest, abdomen and back. These may be difficult to detect in dark-skinned
individuals.
 Hepatosplenomegaly (23-65%).
 Leukopenia (16-46%).
 Nonspecific symptoms, such as chills, diaphoresis, anorexia, cough, weakness, sore throat,
dizziness, and muscle pains, are frequent before the onset of fever.

Severe illness and extra-intestinal complications:

Up to 10-15% of patients may develop severe illness. This may include gastrointestinal bleeding (10-20%),
intestinal perforation (1-3%), septic shock, or acidosis.
Extra-intestinal complications may also occur, including:
 Central nervous system (3-35%): Encephalopathy. Cerebral oedema, subdural empyema, cerebral
abscess, meningitis, ventriculitis, transient Parkinsonism, motor neuron disorders, ataxia, seizures,
Guillain-Barré syndrome, psychosis.
 Cardiovascular system (1-5%): Endocarditis, myocarditis, pericarditis, arteritis, congestive heart
failure
 Pulmonary system (1-6%): Pneumonia, empyema, bronchopleural fistula
 Bone and joint (<1%): Osteomyelitis, septic arthritis
 Hepatobiliary system (1-26%): Cholecystitis, hepatitis, hepatic abscesses, splenic abscess,
peritonitis, paralytic ileus
 Genitourinary system (<1%): Urinary tract infection, renal abscess, pelvic infections, testicular
abscess, prostatitis, epididymitis
 Soft tissue infections: Psoas abscess, gluteal abscess, cutaneous vasculitis
 Haematological: Haemophagocytosis syndrome

The case fatality rate due to typhoid fever varies depending on presence of complications and timely
antimicrobial intervention. If left untreated, 12-30% of all infections may result in death; however, with
appropriate treatment mortality rates may be reduced to <1% within developing nations. Up to 32% of
severely ill or complicated typhoid cases may be fatal, depending on the country studied.

Guidelines_typhoid_20160125 Page 5 of 20
Chronic carriage:
Approximately 1-5% of infected persons experience a chronic carrier state following recovery from an acute
phase illness. These individuals may excrete the organism for years if left untreated, with the potential to
infect others, as well as develop recrudescent illness themselves. Chronic typhoid carriage has frequently
been associated with gallstones in the biliary tract of infected persons. Salmonella Typhi bacilli form
biofilms on the surface of gallstones, thereby protecting the bacteria from the host’s immune response, as
well as antimicrobial therapy. Prolonged Salmonella Typhi carriage, with intermittent febrile periods has
been also associated with intestinal/urinary schistosomiasis (a.k.a. bilharzia). The bacteria are able to
colonise adult Schistosoma spp. which shelter the bacteria from the host’s immune system and
antimicrobials.

1.3 Transmission
Humans are the only known hosts of Salmonella Typhi. Bacteria are shed in the faeces of an infected person
and transmitted from person to person via ingestion of food or water contaminated by these faeces (faecal-
oral route). Large outbreaks of typhoid fever are often associated with contamination of a drinking water.
The organism can survive for several days in fresh water (e.g. ground water, pond-water) and seawater.
Furthermore, the organism can survive for prolonged periods (up to several months) in contaminated
foods. Outbreaks have been associated with contaminated eggs, oysters (fresh and frozen), ice-cream and
iced-drinks, raw fruits and vegetables, fish and various meats. Contamination of food can occur through
food handlers (e.g. vendors who may be asymptomatic carriers), irrigation of gardens/crops with sewage-
contaminated water or fertilizers, as well as the sharing of food items among cases.

1.4 Burden of disease

Worldwide, an estimated 21 million typhoid fever cases, resulting in 200,000 deaths, occur each year.
Incidence is highest in developing countries within Asia (including south-central Asia and south-east Asia)
and parts of Africa. Typhoid is endemic within South Africa; however, the local burden of disease is
unknown. In addition to endemic disease, the epidemic potential of typhoid fever was previously
demonstrated in South Africa. Examples include Delmas (Mpumalanga Province), where repeated
outbreaks of typhoid fever have been recorded; causing over 1000 cases during 1993, and over 400
suspected cases and three deaths in 2005.

1.5 Epidemiology and high risk individuals

Within endemic settings typhoid fever is closely associated with poor food hygiene, and inadequate water
and sanitation infrastructures. In these settings, school-aged children (5-15 years) are most frequently
affected. In more industrialised settings with lower transmission rates, travellers make up a large
proportion of cases; hence, disease is more frequently observed in older age groups. South Africa observes
a mixed pattern of endemic disease (with continued potential for large scale epidemics), and sporadic cases
in more industrialised areas of the country. Travellers (local and international) returning from areas with
endemic transmission may account for a large proportion of cases in South Africa. Travellers present a risk
not only of transmitting illness within our local population, but also of introducing multidrug-resistant
strains that are observed more commonly in highly endemic countries (south-central Asia and south-east
Asia).

Persons with occupations as food handlers, or those who provide care for patients, children or the elderly,
represent specific high-risk groups due to their potential to widely transmit infection. They, therefore,
require specific considerations during the public health response to identified cases, and should be
restricted form these activities until these investigations have been complete.

2 Case definitions
2.1 A typhoid ‘case under investigation’:
A person presenting with a documented fever >/= 38.5oC, and any of:
Guidelines_typhoid_20160125 Page 6 of 20
  Clinical symptoms of typhoid, including gastrointestinal symptoms (abdominal pain, nausea and
vomiting or constipation), relative bradycardia, ‘rose spots’ (erythematous macula-papular lesions),
splenomegaly and/or hepatomegaly, leucopaenia
 A travel history within the last month to an area with a confirmed outbreak of typhoid;

2.2 A confirmed case of typhoid:

The isolation of Salmonella Typhi, Salmonella ParaTyphi from a clinical specimen in the presence of
symptoms compatible with typhoid.

2.3 A probable case of typhoid

A clinically compatible case that is epidemiologically linked to a confirmed case, in an outbreak situation.

2.4 A typhoid carrier:

Typhoid carriers may be ‘convalescent carriers’ or ‘chronic carriers’.
 A convalescent carrier is a person who is still excreting Salmonella Typhi or Salmonella Paratyphi
after two courses of appropriate antibiotic therapy, but has been excreting for less than 12 months
 A chronic carrier is a person who continues to excrete Salmonella Typhi or Salmonella Paratyphi for
12 months or more.

3 Diagnosis
3.1 Differential diagnosis
Typhoid fever may be clinically indistinguishable from other causes of an enteric-fever like syndrome,
including Yersinia enterocolitica, Yersinia pseudotuberculosis, Campylobacter fetus or other non-typhoidal
Salmonella infections. Therefore, laboratory testing is advisable in all patients presenting with clinically
compatible characteristics of typhoid fever (see Section 1.2 above).

Supportive laboratory tests and epidemiological clues may also be considered in differentiating typhoid
fever from enteric-fever like syndromes. Leukopenia (low white cell count) is reported in 16-46% of cases.
The absence of eosinophils is also common among patients. Hepatic transaminases (ALT and AST) may be
raised in up to two-thirds of cases. Epidemiological clues may include the patient’s age, place of residence
and history (e.g. travel, water source, consumption of food outside of the home). Within endemic settings,
typhoid fever is more frequently observed in infants and pre-school children than in the older population.
Infection is historically associated with households with poor hygiene or poor sanitation and water
infrastructures. In areas without wide-spread endemic transmission, including parts of South Africa, typhoid
fever frequently affects travellers to highly-endemic settings (e.g. Asia). Food-handlers also play an
important role in transmission, and eating outside of the home (e.g. from street vendors) can be important
predictors of infection.

Other causes of febrile illness, and possibly concurrent infections, in returning travellers should also be
considered. These alternative diagnoses could include malaria, dengue, hepatitis, etc.

3.2 Specimen collection for laboratory diagnosis

The definitive diagnosis of typhoid fever requires the isolation of Salmonella Typhi from blood, bone
marrow or a specific anatomical lesion (e.g. abscess). Blood culture is the diagnostic test of choice. The
procedures and limitation of the various laboratory tests are described below.

Guidelines_typhoid_20160125 Page 7 of 20
3.2.1 Blood culture – *Diagnostic test of choice*
Blood culture is the diagnostic test of choice given the limitations of testing other specimen types.
Furthermore, blood culture provides the means for conducting antimicrobial resistance testing, which is
important in treatment choice (see Section 3.1). The sensitivity of blood culture is 50-80%. It is limited by
the small numbers of Salmonella Typhi bacilli present in blood and the use of antibiotics before specimen
collection, and varies by volume of blood collected and the system used for culturing.

Procedures for blood culture with vary depending on the testing system used by the laboratory. Prior to
specimen collection, contact your local laboratory (or referral laboratory if blood cultures not performed at
local level) and identify the system they use. The majority of NHLS laboratories utilise a BacT/ALERT® system
for blood cultures. The following steps apply to this system. If an alternative system is used by your local
laboratory, follow the manufacturer’s guidelines.

1. Skin preparation: Clean the venepuncture site thoroughly with an alcohol prep pad. Allow to air
dry. Do not re-palpate the vein after cleaning.

2. Bottle preparation: Inspect blood culture bottles prior to use. Ensure the bottle and sensor on the
bottom of the bottle is intact. The sensor is normally a uniform greyish-green colour. Discard any
bottle found to be damaged or with a yellow sensor (i.e. indicating contamination of the broth).

3. Venepuncture and bottle inoculation: Within the BacT/ALERT® system, the choice of blood culture
bottle is dependent on the age of the patient and if antibiotics were taken prior to specimen
collection. Perform the venepuncture and inoculate the appropriate bottles for your patient as
follows:
a. Adult and school-aged children without prior antibiotic treatment – inoculate 2 x standard
AEROBIC blood culture bottles (blue top) with 10ml of blood in each bottle (i.e. 20ml blood
total).
b. Adult and school-aged children with prior antibiotics – inoculate 2 x FAN® AEROBIC blood
culture bottles (green top) with 10ml of blood in each bottle (i.e. 20ml blood total).
c. Infants and pre-school children – inoculate 2 x Paediatric FAN® blood culture bottles
(yellow top) with up to 4ml of blood in each bottle.

4. Labelling and forms: All specimens should be labelled and accompanied by standard NHLS clinical
specimen submission forms, including: patient details, clinical presentation, relevant history and
healthcare practitioner’s details. Indicate “culture for typhoid” on the form.

5. Transport: Once blood culture bottles have been inoculated, they should be incubated
immediately at 37°C until transport arrives. Do not refrigerate inoculated bottles. Send specimens
to your local NHLS laboratory as per standard procedures. Specimens may be referred to a regional
NHLS laboratory depending on capacity at local laboratory.

3.2.2 Stool culture

The isolation of Salmonella Typhi from stool is suggestive of acute typhoid fever when associated with a
clinically compatible illness; however, stool culture does not replace blood culture as a diagnostic specimen
due to a number of limitations. Firstly, bacilli are shed in stool only after the first week of illness. Secondly,
only 30% of adult cases, and 60% of paediatric cases, will have a positive stool culture. Thirdly, typhoid
carriers may also have a positive stool culture. Nevertheless, stool culture plays a role in public health
investigations following identification of a case, and is important in identifying carriers (see Section 4).
Where indicated, stool culture may be submitted as per standard procedures:

1. Specimen collection: Stools should be collected in a sterile wide-mouthed plastic container.

2. Inoculation of transport medium (where applicable): If stool cannot be processed within 2 hours,
place the stool specimen in Cary-Blair transport medium. Collect a small amount of stool by
inserting a sterile, cotton-tipped, swab into the stool and rotating it. If mucous and shreds of

Guidelines_typhoid_20160125 Page 8 of 20
 intestinal epithelium are present, these should be sampled with the swab. Immediately insert the
swab into the transport medium. The swab should be pushed completely to the bottom of the
medium. Cut off and discard the top portion of the swab-stick that is protruding above the edge of
the container, leaving the cotton tip in the transport medium. Replace the screw cap on both
containers and tighten firmly. Submit both the stool and the inoculated transport medium
containers for laboratory testing.

3. Labelling and forms: All specimens should be labelled and accompanied by standard NHLS clinical
specimen submission forms, including: patient details, clinical presentation, relevant history and
healthcare practitioner’s details. Indicate “culture for typhoid” and the nature of the specimen (i.e.
stool or rectal swab) on the form.

4. Transport: Send specimens to your local NHLS laboratory as per standard procedures. Specimens
may be referred to a regional NHLS laboratory depending on capacity at local laboratory. If there is
a delay in transport (or processing in the laboratory) immediately place both containers in a
refrigerator (at 4°C), or a cold-box, until collected by the courier. Do not freeze.

Rectal swabs may be collected where a stool specimen cannot be obtained, but these are inferior
specimens with reduced sensitivity. Rectal swabs should be collected by moistening a sterile swab in
transport medium (Cary-Blair). Insert swab gently into the rectal sphincter (2 to 3 cm) and rotate to sample
anal crypts. Remove swab and check for visible faeces. Immediately insert the swab into the transport
medium, label the specimen, and transport to laboratory as per steps 2-4 above.

3.2.3 Bone marrow aspirate culture

Bone marrow culture is considered the most sensitive (90%) of the clinical specimens for isolation of
Salmonella Typhi; however, sample collection is painful and invasive, and requires technical expertise and
appropriate surgical equipment. Furthermore, the sensitivity of blood culture is approaching that of bone
marrow culture due to recent advances in technology. Therefore, bone marrow culture is not routinely
recommended to diagnosis of typhoid fever. A bone marrow aspirate may be indicated in patients who
have been previously treated, who have a long history of illness and for whom there has been a negative
blood culture with the recommended volume of blood. Furthermore, bone marrow aspirates collected for
other indications (e.g. cytopenias) may be subjected to culture for Salmonella Typhi.

3.2.4 Extra-intestinal complications and focal infections

In patients who present with extra-intestinal complications (e.g. endocarditis, pneumonia, meningitis,
arthritis or focal abscesses) an appropriate specimen from the site of the focal infection may be submitted
for Salmonella Typhi culture. For example, these may include: sputum, CSF, synovial fluid or pus. Blood
cultures (as above) should still be obtained for these patients, and laboratory results should be interpreted
in line with the patient’s clinical presentation/history.

3.2.5 Urine cultures

Salmonella Typhi may be excreted in urine; therefore, although not routinely suggested for laboratory
diagnosis, the culture isolation of Salmonella Typhi from urine is indicative of acute typhoid fever or chronic
carriage depending on the clinical presentation of the patient.

3.2.6 Serology and other tests

Aside from culture, serological (such as the Widal test) and other laboratory tests are not recommended for
the diagnosis of typhoid fever due to a number of limitations:
 High rates of false-negative results. Up to 10% of true-positive do not produce detectable
antibody titres.
 High rates of false-positive results. False-positive results are frequent due to cross-reaction with
other pathogens (including non-typhoidal Salmonella and malaria), immunological disorders and
chronic diseases.

Guidelines_typhoid_20160125 Page 9 of 20
  Results are difficult to interpret. Quantitative measures of antibody titres, knowledge about the
baseline titres present in the local population, and paired sera samples are required to correctly
interpret serology test results. Laboratories often do not give quantitative measures of the
antibody titre. Background agglutinins and antibodies vary significantly between population groups
and are dependent on endemicity and typhoid vaccine use in that population. Paired sera,
collected 7-14 days apart, are required to identify a rise in antibody titre.

4 Treatment and case management

Early diagnosis and prompt administration of appropriate antimicrobial therapy prevents severe
complications of typhoid fever and results in case-fatality rates of <1%. The choice of antimicrobial therapy
depends on the susceptibility of Salmonella Typhi strains in the area of residence or travel. Obtaining a
thorough patient history including recent travel and previous antibiotic use is, therefore, necessary for all
suspected cases to inform treatment choice.

4.1 Supportive management

More than 90% of typhoid patients can be managed with oral antibiotics, reliable care and close medical
follow-up for complications or failure to respond to therapy. After initial diagnosis, patients may be
discharged home on appropriate treatment, if they are clinically stable. However, patients with persistent
vomiting, severe diarrhoea, and complications (intestinal or extra-intestinal) require hospitalisation and
intravenous (IV) antibiotic therapy. Supportive measures, such as oral or intravenous hydration, the use of
antipyretics, appropriate nutrition and blood transfusions, also play an important role where indicated.

4.2 Treatment of acute uncomplicated typhoid fever

Note: If typhoid fever is clinically suspected, commence

treatment immediately. Do not wait for laboratory results.

Multidrug resistant (MDR) S. Typhi first emerged in the 1980s, and is defined as S. Typhi strains resistant to
the three antibiotics that were commonly used to treat typhoid fever, namely: ampicillin, chloramphenicol
and cotrimoxazole. MDR-typhoid fever is now widespread globally, including South Africa (where it was first
described in 1987).

Strains of S. Typhi that are MDR remain susceptible to ciprofloxacin. Therefore, ciprofloxacin is currently the
treatment of choice for typhoid fever in South Africa. Ciprofloxacin offers several advantages over other
drugs, including: rapid clearance of fever and symptoms, low rates of post treatment carriage (<2%), oral
administration, and availability at most healthcare facilities. Treatment should be commenced immediately
following a clinical diagnosis of suspected typhoid fever. Do not wait for laboratory results; however,
specimens should ideally be collected prior to commencement of antimicrobial therapy.

Of great concern is the widespread emergence of S. Typhi strains with decreased susceptibility to
ciprofloxacin. Presently, approximately 15% of S. Typhi in South Africa have decreased susceptibility to
ciprofloxacin (reported as either intermediately resistant or resistant to ciprofloxacin). Studies have shown
that patients with S. Typhi with decreased susceptibility to ciprofloxacin have delayed response, clinical
treatment failure and increased mortality if treated with ciprofloxacin (even if treated with maximal doses
for prolonged duration). Recommended treatment for typhoid fever with decreased susceptibility to
ciprofloxacin is azithromycin or ceftriaxone/cefotaxime.

Table 1: Recommended antimicrobial treatment for acute uncomplicated typhoid fever according to
ciprofloxacin susceptibility*

Paediatrics Adults**
Susceptibility Antibiotic Dose Days Dose Days

Susceptible to Ciprofloxacin 15 mg/kg/day po in two 5-7 500-750 mg po 12 5-7

Guidelines_typhoid_20160125 Page 10 of 20
ciprofloxacin divided doses (i.e. 12 hourly
hourly)

Intermediately
resistant OR Ceftriaxone 50-75 mg/kg/day IV in
resistant to two divided doses (i.e. 12
ciprofloxacin OR hourly) 10-14 1-2 g IV 12 hourly 10-14

Cefotaxime
40-80 mg/kg/day IV in 2
divided doses (i.e. 12 10-14
hourly)

*Ciprofloxacin susceptibility as determined using 2012 CLSI breakpoints for Salmonella spp
**Pregnant women should preferably be treated with azithromycin, ceftriaxone or cefotaxime since ciprofloxacin is an
FDA-category C agent and not advised for use during pregnancy.

4.3 Treatment of severe and complicated typhoid fever

Severe typhoid fever, patients unable to tolerate oral treatment due to vomiting and/or severe diarrhoea,
and/or patients with intestinal/extra-intestinal complications may require hospitalisation and parenteral
treatment. Once patients have clinically improved, treatment can be completed with oral antibiotics (e.g.
oral ciprofloxacin). Table 2 outlines the treatment recommendations.

Table 2: Recommended antimicrobial treatment for severe or complicated typhoid fever according to
ciprofloxacin susceptibility*

Paediatrics Adults**
Susceptibility Antibiotic Dose Days Dose Days

Susceptible to Ciprofloxacin*** 15 mg/kg/dose (max 500 10-14 500-750 mg po 12 10-14

ciprofloxacin mg) po 12 hourly hourly

OR
OR
10 mg/kg/dose (max 400 10-14
mg) IV 8 hourly 400 mg IV 8 hourly 10-14

Intermediately Ceftriaxone 50-75 mg/kg/day IV in 10-14 1-2 g IV 12 hourly 10-14

resistant OR two divided doses (i.e. 12
resistant to OR hourly)
ciprofloxacin
Cefotaxime 10-14
40-80 mg/kg/day IV in 2
divided doses (i.e. 12
hourly)

* Ciprofloxacin susceptibility as determined using 2012 CLSI breakpoints for Salmonella spp
** Pregnant women should preferably be treated with ceftriaxone or cefotaxime since ciprofloxacin is an FDA -
category C agent and
not advised for use during pregnancy
***Oral or intravenous ciprofloxacin may be used for severe disease
.

Guidelines_typhoid_20160125 Page 11 of 20
Intestinal bleeding, perforations or ulcerations are life-threatening and may require immediate fluid
resuscitation, surgical interventions (e.g. closure, drainage of peritoneum, and/or small-bowel restriction
for multiple-perforations) and broad-spectrum antimicrobial coverage for polymicrobial peritonitis.

Concurrent treatment with high-dose dexamethasone (initial dose 3mg/kg followed by eight doses of
1mg/kg every 6 hours for 48 hours) should be considered for patients with severe typhoid fever with sign of
typhoid-meningitis (e.g. shock, obtundation, stupor or coma). Administering dexamethasone has been
shown to reduce fatalities among such patients; however if used, patients must be monitored closely
because dexamethasone may mask abdominal complications. Furthermore, steroid treatment beyond 48
hours may increase the relapse rate.

4.4 Treatment of persistent infections and chronic carriers

Up to 1-5% of acute cases develop convalescent or chronic carriage of Salmonella Typhi. These patients
should be treated for a prolonged duration with an appropriate oral antimicrobial, the strain specific
resistance profile dictating the choice of antimicrobial. In the case of convalescent or chronic carriers
infected with S. Typhi strains susceptible to ciprofloxacin, the recommended treatment is ciprofloxacin
(15mg/kg/day po in two divided doses) for 4-6 weeks. At present, there is no data as to which treatment is
optimal for S. Typhi carriers of strains with decreased susceptibility to ciprofloxacin, and expert advice
should be sought in such cases.

Investigation and management of anatomic abnormalities and concurrent infections also plays and
important role in treatment of chronic carriers. Antimicrobial agents will likely be ineffective in patients
with gallbladder, biliary or kidney stones. In these patients, surgery (e.g. cholecystectomy) combined with
antimicrobial treatment may be indicated. Concurrent schistosomal infections (a.k.a. bilharzia) also play an
important role in development of urinary carriage of Salmonella Typhi in South Africa. Such cases should be
treated first with an appropriate dose of praziquantel to eradicate Schistosoma spp prior to initiating
antimicrobial treatment. Chronic suppressive antimicrobial therapy may be considered in patients with
persistent carriage, or relapse, after appropriate investigations and treatment to eradicate Salmonella Typhi
infection has been attempted.

4.5 Infection prevention and control

Hospitalised patients should be cared for using standard precautions. Contact precautions should be used
for diapered or incontinent persons for the duration of illness or to control institutional outbreaks.

It is important to educate the case and care givers with regards to the preventative steps to reduce the risk
of transmission (see Section 6), including good hiegne practices (e.g. handwashing).

4.6 School and work restrictions

Suspected and confirmed cases that do not require hospital admission for treatment, should be restricted
from school/work until 24 hours after symptoms (especially diarrhoea) subside, in order to minimise the
risks for transmission. Persons who work as food handler, or if the case provides care for patients, children
or the elderly, should be excluded from those activities until at least 3 consecutive negative cultures,
meeting the criteria outlined in Step 6 below, are obtained (see Section 4).

5 Public health response to a single case

All cases of typhoid fever infection pose a public health risk in terms of spreading infection and potentially
causing an outbreak. The following steps should be followed by healthcare workers following the
identification of a suspected or confirmed case.

1. Notify the Department of Health: Typhoid fever is a category B notifiable medical condition; therefore
all healthcare professionals are required by law to notify any suspected or confirmed case of typhoid
fever to their local Department of Health. Complete a GW17/5 form and fax/mail this to the local health
Guidelines_typhoid_20160125 Page 12 of 20
 authority within 7 days of identifying the case. If a laboratory diagnosis is available, attached the
laboratory report to the notification; however, notifications should not be withheld pending laboratory
results. Should a laboratory diagnosis be obtained after the initial notification is sent, complete a
second GW17/5 form and resend this, and the laboratory report, to the local authority.

2. Confirmed the diagnosis: Review laboratory results with reference to Section 2. Request a blood
culture if a laboratory diagnosis has not yet been obtained or if a non-confirmatory test has been done
(e.g. serology).

3. Review case management and treatment: Ensure the case is receiving appropriate treatment for
typhoid fever and any concomitant infections (see Section 3).

4. Interview the case: Interviews may be conducted utilising the case investigations form provided
(Appendix 1). It is especially important to obtain the following information:
a. Occupation. If the case is a food handler, or if the case provides care for patients, children or
the elderly, they should be excluded from those activities until at least 3 consecutive negative
cultures, meeting the criteria outlined in Step 6 below, are obtained.
b. Source of infection. Investigate the source of infection, perform additional environmental
investigations where indicated and intervene where a source can be identified.

5. Educate the case and care-givers: Conduct health promotion to educate the case/care-givers about
typhoid fever infection and transmission. Emphasise the importance of good hygiene practices, in
particular hand washing before eating and preparing food, and after going to the toilet to prevent
further infections.

6. Case follow-up: All confirmed typhoid fever cases should be followed-up as outlined below:
a. Collect three clearance stool samples for Salmonella Typhi culture (as per Section 2.2.2). Rectal
swabs may be collected if stool cannot be obtained. The first sample should be obtained one
week after completion of antibiotics. Subsequent samples should be collected 48 hours apart. If
case originally had a positive urine culture, a history of urinary tract infection and/or a history
of schistosomiasis (bilharzia), collect urine samples for culture in addition to stool samples.

All three cultures negative: If three Any of the three samples culture-positive::
consecutive cultures are all negative as per 1. Consider retreatment (second course of
above criteria  release the case from antibiotics – as per section 3.2, Table 1).
surveillance 2. Collect another three clearance stool samples
(first sample one week after completing
antibiotics; subsequent samples collected 48
hours apart).

All three cultures negative: If three consecutive cultures are all Any of the three samples
negative  release the case from surveillance culture-positive

Convalescent carrier:
1. Consider 4-6 weeks of treatment
with appropriate antimicrobial (see
section 3.4).
2. Repeat stool samples monthly.

Guidelines_typhoid_20160125 Page 13 of 20
 A negative monthly sample Positive monthly samples
Collect two further samples 48 hours apart 1. Continue monthly stool sample
collection
2. Consider investigation for possible
causes of prolonged carriage (see
section 3.4)

All three samples negative Positive monthly samples after 12 months

 release the case from surveillance of repeat sampling: Chronic carrier
Refer for specialist opinion and
management.

7. Contact management: Identify contacts at risk of infection, which may include: household members,
care givers of the case, and people who may have eaten the implicated food/water/beverages. The
following response should be completed for all contacts at risk of infection:
a. Collect 2 stool/rectal swab samples, ≥48 hours apart, for Salmonella Typhi culture (as per
Section 2.2.2).
b. Interview all contacts by completing the line-list at the end of the case questionnaire (Appendix
1)
c. Educate all contacts on typhoid fever infection, transmission, prevention, and recognising
symptoms and seeking medical care if these occur.
d. If any cultures are found to be positive, refer that contact for treatment and complete the
response steps 1-7 for that person. If any laboratory-confirmed contacts are employed as food
handlers, or caring for patients/children/elderly, they should be excluded from these activities
and redeployed as far as possible. Identification of Salmonella Typhi from stool is suggestive of
typhoid fever when associated with a clinically compatible illness. Salmonella Typhi in the
absence of clinical illness may be suggestive of Salmonella Typhi carriage.

6 Public health response to a cluster or outbreak

An outbreak of typhoid fever is defined as two or more epidemiologically-linked suspected or confirmed
cases. All outbreaks must be immediately notified to health authorities for investigation and response.
These activities should be coordinated by the local level Department of Health offices in collaboration with
stakeholders, which may include:
 District, Provincial and National Department of Health: Communicable Disease Control,
Environmental Health, Epidemiology and Surveillance, Disaster Management, Infection Control, etc.
 NHLS diagnostic laboratories, NICD-NHLS Outbreak Response Unit and Enteric Diseases Reference
Unit (EDRU), private laboratories.
 Intersectoral stakeholders when required, e.g.: Department of Water Affairs, Department of
Agriculture, Department of Education, etc.

Investigation and response efforts will differ depending on the situation; however, the following elements
should always be included:

 Verify the diagnosis and confirm the existence of an outbreak:

o Conduct laboratory testing on all (or as many as possible) suspected typhoid fever cases as
per Section 2.

Guidelines_typhoid_20160125 Page 14 of 20
 o Conduct preliminary interviews to establish if any epidemiological links between cases
exists. Links between cases may include: common place of residents, gatherings, foods
consumed, travel, etc.

 Communication: Rapid communication and reporting of information, even if only preliminary, is

essential to coordinating an efficient and effective response to potential outbreaks. Communicate
findings frequently to all stakeholders concerned.

 Case finding, investigations and follow-up:

o Establish systems at local level for detecting new cases and for recording existing cases. This
may should include establishing a line-list at each local healthcare facility (clinic and
hospitals) for monitoring the outbreak.
o Investigate cases using a standardised case investigation for (see appendix 1 for example)
to identity factors/histories that are common between cases (i.e. identify the source). Data
collected should be rapidly analysed and shared with stakeholders to inform ongoing and
future response.
o If feasible (i.e. a small cluster of cases), complete the steps outlines in section 4 for each
case.

 Review case management and treatment: Ensure all cases are receiving appropriate treatment for
typhoid fever and any concomitant infections (see Section 3) to reduce morbidity and mortality.

 Conduct environmental investigations: Where indicated food, water and/or other environmental
samples may be collected for the Salmonella Typhi culture. Such samples should be collected by
qualified Environmental Health practitioners as per standard protocols.

 Control and prevention:

o If a source infection can be identified, respond rapidly to interrupt this, and prevent
additional infections.
o Conduct health promotion campaigns on the prevention of typhoid fever in the local
community (see section 6.

7 Prevention and control

The prevention of typhoid fever is primarily based on ensuring access to safe water, food safety and proper
sanitation infrastructures. Health promotion and education is paramount to raising public awareness about
these practices and inducing behaviour change within a community. This intervention should especially be
implemented for each and every known case and his/her contacts. Vaccination against typhoid are available
in South Africa; however, these are only indicate for laboratory staff that work regularly with the pathogen
and may also be considered for travellers for highly endemic settings. The limitations of these vaccines
should be noted and should note detract against the primary measures of preventing infections.

7.1 Safe water

Both sporadic cases and outbreaks of typhoid fever have been associated with poor quality water for
drinking and other domestic activities (cooking, washing, etc.). An overall reduction in disease burden may
be achieved through ensuring access to safe water throughout the community. Likewise, provision of safe
water may play a role in controlling outbreaks (when suspected as the source) as well as preventing
additional settings within the household setting. Response measures may include:
 In areas with access to municipal water systems: enhanced monitoring of water throughout the
supply systems (from point of treatment to consumer outlets), and ensuring appropriate water
treatment (e.g. adequate chlorine concentrations to disinfect the water).
 In areas without access to treated water:

Guidelines_typhoid_20160125 Page 15 of 20
 o Monitoring of drinking water sources, and treating of these if practical (e.g. in the case of
JoJo tanks, wells).
o Provision of alternative water sources (e.g. supply safe/treated water using water-tankers,
JoJo tanks)
o Distribute resources and conduct health promotion activates for point-of-use disinfection
water within households. Disinfection methods may include boiling and/or chemical
disinfectants (chlorine bleach, tablets, etc.). Safe storage and use of water also plays an
important role in preventing secondary spread in households (for example: use plastic
narrow-mouthed containers with covers to avoid recontamination after treatment).

7.2 Food safety

Contaminated food plays and important role in the transmission of typhoid fever. Following identification of
a case, food safety should be promoted with households to prevent transmission to close contacts. This
should include:
 Wash hands with soap and clean water before preparing and eating food, and after going to the
toilet.
 Wash all surfaces and equipment used for food preparation with soap and clean water.
 Cook food thoroughly, avoid raw (uncooked) food (especially shellfish and meats). Eat only cooked
and still hot food or reheat it.
 Use only safe water for preparing food, beverages and ice (or treat water before using).
 Wash and peel all fruit and vegetables before eating (especially when eaten raw)
 Do not use fertilisers that contain human-waste (excreta or faeces) on vegetable gardens or crops.

Acute cases and proven carriers who handle, process and/or serve food (especially in commercial settings)
should be excluded from these activities pending treatment and follow-up testing (as per Section 4).

In outbreak situations, food safety behaviours should be reinforced at a community level. Food safety
inspections at restaurants and street vendors, and ensuring compliance with regulations, will also play an
important role in preventing infections.

7.3 Sanitation
Provision of proper sanitation infrastructures will also reduce the burden of typhoid fever, as well as other
enteric diseases, within a community. Ensure appropriate systems for human-waste disposal and sewage
treatment for all community members, monitor these systems continually, and maintain proper functioning
at all times. In areas without municipal sewage systems, toilets (e.g. pit-latrines) should be built, regularly
serviced and maintained to ensure safe functioning. Restrict access of the general public to sanitation
infrastructure to prevent human-excreta from being used as fertilisers. Rapid provision of safe sanitation
infrastructures (e.g. building pit-latrines) or investigating, and fixing faults in existing sanitation systems,
may also play a role in controlling outbreaks.

7.4 Vaccination
Vaccination is indicated for laboratory staff that work regularly with Salmonella Typhi. It may also be
considered for travellers to highly endemic countries (see Section 6.5).

The Vi purified polysaccharide antigen vaccine (available as Typhim Vi® (Sanofi Pasteur) and Typhix®
(GlaxoSmithKline)) is currently the only typhoid vaccine registered for use in South Africa. This vaccine is
administered as single dose (deep subcutaneous or intramuscular) and becomes effective 2-3 weeks after
injection. It offers protection against Salmonella Typhi for 60-75% of recipients, and remains effective for a
minimum duration of 3 years, but may be as long as 10 years. Children < 18 months old may show a
suboptimal response to polysaccharide antigen vaccines. Furthermore, typhoid is rare in children < 2 years
old; therefore, the decision to immunise should be based on risk of exposure. Limited data are available on
use during pregnancy; therefore, should only be considered when benefits outweigh risks. This vaccine does
not protect against Salmonella Paratyphi infection.

Guidelines_typhoid_20160125 Page 16 of 20
Typhoid vaccination is not recommended for contacts of identified cases due to the extended duration
required to infer protection. However, vaccinations may be considered in the control of outbreaks in certain
situations, but the limited effectiveness of this strategy must be acknowledged and such campaigns should
not detract from the primary control interventions (i.e. safe water, food safety and proper sanitation).
Routine typhoid vaccinations have shown to be effective in controlling disease in endemic settings;
however, this is currently not recommended in South Africa.

7.5 Travellers
Returning travellers make up a large proportion of typhoid fever cases detected in South Africa. Travellers
should be advised to:
 Drink only water that is bottled or bring it to a rolling boil for at least 1 minute. Bottled carbonated
water is generally safer than uncarbonated water.
 Avoid ice and food products (e.g. ice cream) that are potentially made with contaminated water.
 Eat foods that have been thoroughly cooked and that are hot and steaming. Avoid raw vegetables
and fruits that cannot be peeled.
 Peel the fruit and vegetables yourself after washing your hands with soap. Do not eat the peelings.
 Avoid foods and beverages from street vendors and informal sellers.

Travellers to highly endemic areas (including south-central Asia, south-east Asia and parts of Africa), or
areas with ongoing typhoid fever outbreaks, may consider vaccination. These may be obtained from most
travel clinics and should be given at least 2 weeks before departure. Given the limitations of vaccination, it
is important to emphasise scrupulous personal, food and water hygiene at all times during travel.

7.6 Post exposure prophylaxis

Post exposure prophylaxis for health care workers and contacts of persons with confirmed typhoid is not
advised. The infective dose of typhoid is 105 organisms/ml. Therefore the risk of transmission is low. A
‘watch and see’ approach is advised, with investigation of any febrile illness occurring within 21 days of
contact.

8 Resources and additional information

Further questions from health professionals can be addressed to:
 The NICD Hotline - 082 883 9920 *strictly for use by health professionals only*

Further questions from the general public and all other queries can be directed to:
 The Department of Health Communicable Disease Control hotline: 0861-DOH-CDC (0861-364-232)

Additional information on typhoid fever is available from the following references:

 Centers for Disease Control and Prevention (CDC). Typhoid fever: General information. Available online:
http://www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever/. Last accessed 29 April 2011.
 World Health Organization (WHO). Background document: The diagnosis, treatment and prevention of
typhoid fever. Available online: http://whqlibdoc.who.int/hq/2003/WHO_V&B_03.07.pdf. Last accessed
29 April 2011.
 World Health Organization (WHO). Health topics: Typhoid fever. Available online:
http://www.who.int/topics/typhoid_fever/en/. Last accessed 29 April 2011.
 World Health Organization (WHO). Typhoid vaccines: WHO position paper. Weekly epidemiological
record, 2000: 75(21), 257-264.

Guidelines_typhoid_20160125 Page 17 of 20
 9 Appendix 1: Suspected/confirmed typhoid fever case investigation
form
INTERVIEWER DETAILS
1. Interviewer name: 2. Date of interview: DD / MM / YYYY
3. Interviewer phone no.: 4. Department:

PATIENT DETAILS
5. First name & Surname:

6. Age/DOB: 7. Gender: □ Male □ Female

8. Phone no.:
9. Town/City: District: Province:
10. Occupation: 11. Place Of Work:

12. Works in a food handling trade? □Y □N

13. Works in a child/elderly/health care-giving setting? □Y □N
If yes to 12 or 13, was the case restricted from these activities? □Y □N
DISEASE PRESENTATION

14. Date of onset? DD / MM / YYYY

15. Symptoms: □ Fever □ Vomiting □ Abdo Cramps □ Malaise/Fatigue
(tick all that apply) □ Headache □ Constipation □ Myalgia □ Respiratory symptoms (e.g. cough)
□ Nausea □ Diarrhoea □ Anorexia □ Rose Spots
□ Other, Specify:
16. Complications (list all):

17. Outcome: □ Recovered □ Still ill □ Died, date of death: DD / MM / YYYY

CLINIC/HOSPITAL DETAILS
18. Name of the clinician: 15. Phone no.:
st
19. Facility name: 17. Date of 1 consultation: DD / MM / YYYY
20. Name of referring facility (if applicable):

21. Admitted to hospital? □Y □N If yes, duration of stay? days

22. Was the case notified to DoH? □ Y □ N □ Unknown

LABORATORY INVESTIGATIONS
23. Date of specimen collection: DD / MM / YYYY
24. Lab name: 25. Lab number:

27. Test performed for typhoid diagnosis: □ Blood Culture □ Stool Culture
□ Other, specify:
29. Result of above test: □ Pos □ Neg □ Unknown □ Other, Specify:
30. Follow-up testing: (tick all tests performed)
□ Stool culture 1 Date collected: DD / MM / YYYY Result: □ Pos □ Neg
□ Stool culture 2 Date collected: DD / MM / YYYY Result: □ Pos □ Neg

□ Stool culture 3 Date collected: DD / MM / YYYY Result: □ Pos □ Neg

□ Additional/other follow-up tests, give details:

Guidelines_typhoid_20160125 Page 18 of 20
 EXPOSURE QUESTIONS
31. Have you travelled outside of your home town/city within 1 month before your illness started? (include local and international travel)
□Y □N
If yes, list all places/countries visited:
date departed: DD / MM / YYYY date returned: DD / MM / YYYY
32. Have you had any visitors from outside your home town/city within 1 month before illness onset? (include local and international travel)
□Y □N
If yes, where did they come from:

33. Have you been in contact with anyone with similar illness to yours in the 1 month before your illness started? □Y □N
If yes, list names and contact details:
Name Phone no. Address

34. Have you eaten at any of the following places within 1 month before your illness started?
Type Name/Address/Phone no.
Café / Restaurant □Y □N
Street vendor / Market place □Y □N
Fast food □Y □N
.
Other, specify: □
35. Housing type: □Formal housing □Dwelling outside house □Informal settlement □Traditional house □Hostel/Institution
36. Number of people living in the house:

37. Source of drinking water: □ Municipal tap in house or on property □ Municipal tap off the property (communal tap)
□ Jo-Jo tank □ Borehole water □ Open source water (e.g. from a river, stream, dam, etc.)
□ Other, specify?
38. Do you store water in your home? □Y □N
If yes, in what type of container is water stored? (tick all that apply)
□
Plastic container □
Metal container □
Open container □ Closed container with lid
How is water removed from the container? (tick all that apply)
□ With hands □ With a spoon/cup/jug □ With a tap □ Other, specify:
39. What type of toilet do you have in your home?
□ Flush toilet □ Chemical toilet □ Pit latrine □ No toilet □ Other, specify:
40. Do you have a kitchen/special area for preparing food only in your home? □Y □N

41. Who prepares most of the meals in your home? (name and relationship to case):
Does he/she wash hands before preparing food? □Y □N
Has he/she ever had a similar illness to yours? □Y □N

42. Do you grow your own vegetables at home? □Y □N

If yes, from where do you get the water for your vegetable garden?
What do you use to fertilise your vegetable garden?
Additional notes / comments / actions taken:

Guidelines_typhoid_20160125 Page 19 of 20
 ENVIRONMENTAL ASSESSMENT
45. List all environmental samples collected: (if applicable)

Type of sample Place / Address where collected Lab no. Result

(food/water/milk)

Name of lab(s) processing samples:

CONTACT TRACING
1. Identify contacts at risk of infection, including: household members, care-givers of the case, and people who may have eaten the implicated food or water/beverages.
2. Investigate all contacts as per guidelines. List all below:

Name Age Sex History of typhoid Occupation Address Stool sample Lab result Referred for
(years) (M/F) fever (Y/N) collected (Y/N) treatment (Y/N)

Healthcare Workers Handbook on Typhoid Fever: Last updated January 2016. 20