MANAGEMENT OF SEVERE TYPHOID FEVER
Department of Internal Medicine, Faculty of Medicine
Islamic University of Sumatera Utara – Medan
Typhoid fever, also called enteric fever, or simply ‘typhoid’, is a systemic illness
caused by a Gram negative organism, Salmonella enterica subspecies enterica
serovar Typhi (Salmonella typhi), whereas paratyphoid fever is caused by any
of the three serovars of Salmonella enterica subspecies enterica, namely S.
paratyphi A, S. schottmuelleri (also called S. paratyphi B), and S.hirschfeldii
(also called S. Paratyphi C). Type A is the most common pathogen worldwide.
Typhoid fever characterised by: 1) fever that is intermittent during the first week,
but becomes sustained (lasting > 48 hours) thereafter; 2) headache (43-90%), 3)
gastrointestinal symptoms such as abdominal pain/cramps, nausea and vomiting,
constipation or diarrhoea. Other uncommon clinical signs include a relative
bradycardia, a skin rash (‘rose spots’) which are faint-pink spots 2-4 cm in
diameter which develop on the chest, abdomen and back, hepatosplenomegaly.
Both outpatients and inpatients with typhoid fever should be closely monitored
for the development of complications. Timely intervention can prevent or reduce
morbidity and mortality. The parenteral fluoroquinolones are probably the
antibiotics of choice for severe infections. In severe typhoid the
fluoroquinolones are given for a minimum of 10 days. Patients with changes in
mental status, characterized by delirium, obtundation and stupor, should be
immediately evaluated for meningitis by examination of the cerebrospinal fluid.
If the findings are normal and typhoid meningitis is suspected, adults and
children should immediately be treated with high-dose intravenous
dexamethasone in an initial dose of 3 mg/kg by slow i.v. infusion over 30
minutes and if, after six hours, 1 mg/kg is administered and subsequently
repeated at six-hourly intervals for two days.in addition to antimicrobials.
Patients with intestinal haemorrhage need intensive care, monitoring and blood
transfusion. Intervention is not needed unless there is significant blood loss.
Surgical intervention for suspected intestinal perforation is indicated. If
perforation is confirmed, surgical repair should not be delayed longer than six
hours. Metronidazole and gentamicin or ceftriazone should be administered
before and after surgery.
Keywords: Severe Typhoid - intestinal haemorrhage – typhoid meningitis –
Typhoid fever is caused by Salmonella typhi, a Gram-negative bacterium. Often less severe
disease is caused by Salmonella serotype paratyphi A.. Typhoid is spread via faeco-oral
transmission. The infective dose (the minimum number of organisms required to cause
infection) is relatively high at around 100,000 organisms. Typhoid may be spread from person-
to-person by direct contact, or through ingestion of contaminated food or water. Infection
becomes apparent after an incubation period of 10-14 days (range 5-21 days). . Clinical
characteristic typhoid fever as a syatemic illness are: 1) fever that is intermittent during the first
week, but becomes sustained (lasting > 48 hours) thereafter; 2) headache (43-90%), 3)
gastrointestinal symptoms such as abdominal pain/cramps, nausea and vomiting, constipation
or diarrhoea. Other uncommon clinical signs include a relative bradycardia (a lower heart rate
than would be expected in the presence of fever and illness), a skin rash (‘rose spots’) which
are faint-pink spots 2-4cm in diameter which develop on the chest, abdomen and back,
hepatosplenomegaly (enlarged liver and spleen. The symptoms of typhoid overlap with a
number of other infectious diseases important in the tropical region such as malaria, dengue
fever and leptospirosis..
Diagnostic criteria of Typhoid Fever are Confirmed enteric fever: Fever ≥38°C for at least three
days, with a laboratory-confirmed positive culture (blood, bone marrow, bowel fluid) of S.
typhi. Probable enteric fever: Fever ≥38°C for at least three days, with a positive serodiagnosis
or antigen detection test but without S. Typhi isolation. Chronic carrier state: Excretion of S.
typhi in stools or urine (or repeated positive bile or duodenal string cultures) for longer than one
year after the onset of acute enteric fever; sometimes, S. typhi may be excreted without any
history of enteric fever.
2. General management
Supportive measures are important in the management of typhoid fever, such as oral or
intravenous hydration, the use of antipyretics, and appropriate nutrition and blood
transfusions if indicated. More than 90% of patients can be managed at home with oral
antibiotics, reliable care and close medical follow-up for complications or failure to
respond to therapy. However, patients with persistent vomiting, severe diarrhoea
and abdominal distension may require hospitalization and parenteral antibiotic therapy..
3. Antimicrobial therapy
Efficacy, availability and cost are important criteria for the selection of first-line antibiotics to
be used in developing countries. The fluoroquinolones are widely regarded as optimal for the
treatment of typhoid fever in adults. They are well tolerated and more rapidly and reliably
effective than the former first-line drugs, chloramphenicol, ampicillin, amoxicillin and
trimethoprim-sulfamethoxazole. The fluoroquinolones attain excellent tissue penetration, kill
S. typhi in its intracellular stationary stage in monocytes/macrophages and achieve higher active
drug levels in the gall bladder than other drugs. They produce a rapid therapeutic response, i.e.
clearance of fever and symptoms in three to five days, and very low rates of post-treatment
carriage. However, the emergence of MDR strains has reduced the choice of antibiotics in many
areas. There are two categories of drug resistance: resistance to antibiotics such as
chloramphenicol, ampicillin and trimethoprim-sulfamethoxazole (MDR strains) and resistance
to the fluoroquinolone drugs. Resistance to the fluoroquinolones may be total or partial.
In developing countries Chloramphenicol or Thiamphenicol, are still widely prescribed for the
treatment of typhoid fever. The optimal dosage is 75 mg per kg per day for 14 days divided into
four doses.. The usual adult dose is 500 mg given four times a day. Oral administration gives
slightly greater bioavailability than intramuscular or intravenous administration of the succinate
salt. Trimethoprim-sulfamethoxazole, can be used orally or i.v. in adults at a dose of 160 mg
TMP plus 800 mg SMZ twice daily for 14 days. Of the third-generation cephalosporins, oral
cefixime 20 mg per kg per day for adults. Azithromycin in a dose of 500 mg (10 mg/kg) given
once daily for seven days has proved effective in the treatment of typhoid fever in adults. A
dose of 1 g per day for five days was also effective in adults. If intravenous antibiotics are
required, i.v. cephalosporins can be given in the following doses: ceftriaxone, 50 75 mg per kg
per day (2 4 g per day for adults) in one or two doses; cefotaxime, 40 80 mg per kg per day (2
4 g per day for adults) in two or three doses; and cefoperazone, 50-100 mg per kg per day (2 4
g per day for adults) in two doses. Ciprofloxacin, ofloxacin and pefloxacin are also available
for i.v. use.
4. Management of Severe Typhoid Fever
In severe typhoid the fluoroquinolones are given for a minimum of 10 days (Table 1). Both
outpatients and inpatients with typhoid fever should be closely monitored for the development
of complications. Timely intervention can prevent or reduce morbidity and mortality. Typhoid
fever patients with changes in mental status, characterized by delirium, obtundation and stupor,
should be immediately evaluated for meningitis by examination of the cerebrospinal fluid. If
the findings are normal and typhoid meningitis is suspected, should immediately be treated with
high-dose intravenous dexamethasone in addition to antimicrobials. If dexamethasone is given
in an initial dose of 3 mg/kg by slow i.v. infusion over 30 minutes and if, after six hours, 1
mg/kg is administered and subsequently repeated at six-hourly intervals on seven further
occasions. 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. Mortality can be reduced by some 80-90% in these high-risk patients.[1,3,7].
Once patients have clinically improved, treatment can be completed with oral antibiotics
(e.g.oral ciprofloxacin). 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. Metronidazole and gentamicin or
ceftriazone should be administered before and after surgery because a fluoroquinolone is not
being used to treat leakage of intestinal bacteria into the abdominal cavity. Early intervention
is crucial, and mortality rates increase as the delay between perforation and surgery
Table1. Treatment of Severe Typhoid Fever.
Management of severe typhoid need to early diagnostic and appropiate administration of
the sensitive antibiotic by IV and monitoring and control of the complication, such as
dehydration, gastrointestinal bleeding and surgical intervention if perforation occure.
Metronidazole and gentamicin or ceftriazone should be administered before and after
surgery because a fluoroquinolone is not being used to treat leakage of intestinal bacteria
into the abdominal cavity. Early intervention is crucial, and mortality rates increase as the
delay between perforation and surgery lengthens.
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