Shiraz E Medical Journal, Vol. 2, No.

2, April 2001

In the name of God

Shiraz E Medical Journal

Vol. 2, No. 2, April 2001
http://semj.sums.ac.ir/vol2/apr2001/typhoidRx.htm

Treatment of Typhoid Fever.

Kazemifar A R.

* Resident, Department of Internal Medicine, Shiraz University of Medical Sciences, Shiraz,

Iran.

Abstract:
Chloramphenicol, Cotrimoxazole, Quinolones, Third generation cephalosporins, in
addition to steroids are studied here. Chloramphenicol is the gold standard antibiotic, which clears blood from S typhi in a few hours and stool in a few days. Oral
administration is preferred. However, resistance, relapse, bone marrow suppression and etc. are major disadvantages. Resistance against cotrimaxazole is high.
Quinolones (e.g., ciprofloxacin which is the drug of choice in multidrug resistance)
and third generation cephalosporins (e.g., ceftriaxone which is the best choice in
children) are used in areas with a high prevalence rate of multidrug-resistant salmonella infection. Glucocorticoid administration is controversial, although it reduces the mortality in severe cases if used for 48 hours, steroid treatment over 48
hours may increase relapse rate. Surgical therapy is usually needed for complications (e.g., bowel perforation). Relapse of typhoid fever should be treated the
same as patients with the first attack. Chronic fecal carriers (asymptomatic excretion for a year or more) should receive high doses of Ampicillin or Amoxicillin
(100mg/kg/d) plus probenecid (30mg/kg/d) or Co-trimoxazole(160/800 mg twice
daily) for at least 6 weeks. Those who have gallstone need cholecystectomy. Iranian studies show that cefixime is effective on all strains.
Typhoid fever is a severe systemic infectious disease. Treatment with appropriate antibiotics is essential for recovery. In this article we review some current
antibiotics used for the treatment of typhoid fever.

Chloramphenicol:

improvements

Chloramphenicol, which other antibiotics

must be compared with, has been the
"gold standard" therapy since its introduction in 1948.1 Within a few hours after administration

S. typhi disappears

from the blood. Stool cultures frequently

become negative in few days. Clinical

are

evident

within

48

hours and fever and other signs of the

disease commonly abate within 3 to 5
days. The patient usually becomes afebrile before the intestinal lesions heal. As
a result intestinal hemorrhage and perforation may occur at a time when the
clinical condition is rapidly improving.

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Shiraz E Medical Journal, Vol. 2, No. 2, April 2001

The dose of chloramphenicol prescribed

tential advantages over other antimicro-

for adults with typhoid fever is 1g every

bials in the treatment of typoid fe-

6h for 2 weeks. Although both intrave-

ver.10,18,19,

nous and oral routes have been used the

orally twice daily for 10 days) remains

response is more rapid with oral admin-

the drug of choice for the treatment of

6,24

25

Ciprofloxacin

multidrug

cal reduces typhoid fever mortality from

27

(MDRT)

approximately 20% to 1% and duration

Ofloxacin, Norfloxacin, Flerofloxacin, Pe-

of fever from 14-28 days to 3-5 days.1,2

floxacin and lomefloxacine have been

Chloramphecol therapy has been asso-

effective in small clinical trials.27

Other

typhoid

mg

Treatment with chlorampheni-

istion.

resistant

(500

quinolones,

fever

including

ciated with emergence of:

Short course therapy with Ofloxacin (10-

2,4

A high relapse rate (10-25%)

Resistance1,3
- A high rate of chronic carriage4
- Bone marrow toxicity5 and aplastic
anemia8
- High mortality rates in some recent
series from the developing world.3
-

Chloramphenicol is bacteriostatic both for

clinical isolates and against salmonella
typhi cultured in human macrophages.7
Cotrimoxazole:
Cotrimoxazole is a second line drug for

15 mg/kg) divided twice daily for 2 to 3

days appears to be simple, safe, and effective in the treatment of uncomplicated
multidrug resistant typhoid fever.20
It is recommended that quinolones be
avoided in children younger than 10
years or pregnant women. However, quinolones have been used to treat multidrug resistant typhoid in children and
pregnant patients without adverse effects.26

typhoid fever but resistance is an increasing problem. In adults TMP-SMX

appears to be effective when the dose is
800mg of sulfa plus 160 mg of trimetoprim. every 12 hours for 15 days.24
Quinolones:

Third generation cephalosporins:

A few studies showed that shorter coursers of cefriaxone (once daily for 3 to 5
days) are not as effective and safe as 2
to 3 weeks of chloranmphenicol.

10,11

Cef-

triaxone is the best choice for chil-

In areas with a high prevalence rate of

dren,3,11 because of concerns about qui-

multidrug-resistant salmonella infection

nolone-induced arthropathy and cartilage

(e.g. Indian subcontinent, southeast Asia

damage in this age group.12 After initial

and Africa) all patients suspected to ty-

control of typhoid fever symptoms with a

phoid fever should be treated with a

parenteral

"Quinolone" or third generation "Cepha-

losporin, many practitioners switch to an

10

losporin".

third

generation

cepha-

oral agent to complete 10 to 14 days of

therapy. Oral cefixime (10 to 15 mg/kg

Quinolones are penetrant macrophages,

twice daily) needs further study for the

which acheive high concentrations in the

initial treatment of multidrug resistant

bowel and bile lumina and thus have po-

typhoid fever.29

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Shiraz E Medical Journal, Vol. 2, No. 2, April 2001

First

and

second

generation

cepha-

replacement, and administration of an

losporins are clinically ineffective and

inexpensive

despite adequate in vitro killing activity

regimen including chloramphenicol, gen-

should not be used to treat typhoid fe-

tamicin and metronidazole, reduced mor-

13,14,15,16

ver.

broad-spectrum

antibiotic

tality rates from 25-30% to well under

10%.

Other antibiotics:
Introduction of effective antibiotic therAminoglycosides

are

clinically

ineffec-

apy has resulted in a low incidence of

tive17 in treatment of typhoid fever. In

such great complications like intestinal

some studies it has been shown that

perforation and hemorrhage, but reports

Azithromycin (500mg P.O qd for 7 days)

from some regions including Indian sub-

as effective as chloramphenicol given to

continent indicate a high incidence (near

patients with chloramphenicol susceptible

10%) need for surgery because of intes-

21,26,28

infections.

tinal perforation among patients with typhoid f ever.30 In these areas with low

Role of Steroids:

access to health facilities specially for

The role of glucocorticoides in the management of infectious diseases in man

remains controversial, although experimental data obtained both in vitro and in
experimental infections in animals provide evidence of a beneficial effect of
such treatment. Their use in the treat-

those who are emaciated, medical therapy alone with broad spectrum antibiotics
has been used for intestinal perforation
but results are not always acceptable,
and this should not be the routine approach.
Treatment of relapse:

ment of severe typhoid fever has been

Patients with relapse of typhoid fever

shown to be beneficial.30

should be treated the same as patients

Based on a study from Jakarta which

with the first attack. Chronic fecal carri-

showed a significant reduction in mortal-

ers (asymptomatic excretion for a year or

ity in patients with severe typhoid fever (

more) should receive high doses of Am-

i.e. CNS symptoms, shock, dissiminated

picillin or Amoxicillin (100mg/kg/d) plus

intravascular

probenecid

coagulation),

Dexa-

(30mg/kg/d)

or

Co-

methasone (3mg/kg as a loading dose

trimoxazole(160/800 mg twice daily ) for

over 30 min, followed by 1mg/kg every

at least 6 weeks.31 Patients with chole-

6h for 24h to 48h) used along with par-

cysti-

enteral

tis or gall stones may require cholecystec

antimicrobials

seems

to

re-

duce mortality.22 Steroid treatment over

tomy.21,31

48h may increase the relapse rate.23

Iranian studies:
Treatment of complications:

There are few published studies about

In referent not clear double layer closure

typhoid fever treatment in Iran. Rastegar

of the site of perforation, aggressive fluid

lari, et al from Tehran reported that

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Shiraz E Medical Journal, Vol. 2, No. 2, April 2001

41.9%,

33.9%,

38.7%,

58.1%

and

1.6% of isolated strains were resistant to

chloramphenicol,

Co-trimoxazole,

am-

picillin, tetracycline and gentamycin respectively. About one third (33.9%) of

the strains showed multiple resistance to
the first four mentioned antibiotics. All
strains

were

susceptible

to

cefixime

(MICs less than 1 mcg/ml). It was concluded that cefixime due to its effectiveness, oral administration and shorter
courses of treatment could be the therapy of choice in cases of typhoid fever
caused

by

multiple

drug

resistant

strains.29
In another study from Ahwaz, based on
antibiograms, there was 79%, 30%,
30.6% and 7.6% resistance to Ampicillin,
Chloramphenicol,

Co-trimoxazole

and

Ceftizoxime respectively. Mean time of

defervescence with Ceftizoxime was 8.5

3- Bhulta ZA, Naqvi SH, et al. Multidrugresistant typhoid in children: presentation and
clinical features. Rev Infect dis. 1991; 13:
832-836.
4- Hornick RB, et al. Typhoid fever : pathogenesis and immunologic control. N. Engl. J.
Med. 1970; 283: 686-691.
5- Wallerstein Ro, et al. Statewide study of
chloramphenicl therapy and fatal aplastic
anemia. JAMA 1969; 208: 2045-2050.
6- Ti TT, et al. Chloramphenicol concentrations
in sera of patients with typhoid fever being
trailed with oral or intravenous preparation.
Antimicrob agents chemother. 1990; 34:
1804-1811.
7- Chang HR, Valdoianu IR, Pechere JC. Effects of Ampicillin, Ceftriaxone, Chloramphenicol,
pefloxacine
and
trimethoprimSulfamethoxazole on salmonella typhi within
human monocyte-derived macrophages. J
Antimicrob chemother. 1990; 26: 684-694.
8- Gerald T.Keusch Salmonellosis. In Hanison's principles of Internal Medicine. 14th edition McGraw-Hill Co. 1998. 951-4.
9- Bhatt BD, et al. Salmonella arizonae infections in lations associated with rattlesnake flok
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days compared to 4-5 days with otherthree antibiotics.32

10- Akalin HE. Quindolones in the treatment of

typhoid fever Drugs 1999; 58 suppl 2: 52-4.

Tips:

11- Moosa A, Rubidge CJ. Once daily ceftriaxone vs. chloramphenicol for treatment of
typhoid fever in children. Pediatr infect Dis J.
1989; 8: 696-699.

> Quinolones are highly effective treatment for multidrug resistant typhoids.
> Aminoglycosides are clinically ineffective

in

treatment

of

typhoid

fever.

> Azithromycin may have a role in the

short

treatment

of

typhoid

fever.

> Steroid may reduce mortality in severe

typhoid fever.
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