Journal of Rawalpindi Medical College (JRMC); 2014;18(2):209-212

Original Article
Azithromycin Versus Ofloxacin in Treatment of Enteric
Fever in Children
Ammara Manzoor, Tariq Mahmood, Rubina Zulfiqar
Department of Paediatrics ,Holy Family Hospital and Rawalpindi Medical College, Rawalpindi

Abstract year 2000, about 22 million new cases of typhoid fever

Background: To compare the clinical efficacy of
Azithromycin versus Ofloxacin in the treatment of
typhoid fever in terms of the proportion of children
becoming afebrile on 5th day of treatment.
Methods: In this randomized controlled trail 230
patients of Typhoid fever, age ranging from 2-12
years, were included. One hundred and fifteen
patients were given Azithromycin and 115 patients
were given Ofloxacin randomly. Patients were
randomly divided into two groups . Group A was
given Azithromycin 10 mg/kg/day once daily orally
for 7 days.Group B was given Ofloxacin
15mg/kg/day in two divided doses orally for 7 days.
Both the groups were observed for duration of
becoming afebrile on 5th day of treatment.
Investigation to be done during hospital stay was
Typhidot (IgM antibodies) . Chi-square test was
used to compare efficacy (afebrile on day 5) of both
drugs.P-value < 0.05 was considered significant.
Results: The age range was from 5 to 12 years with
a mean age of 7.7 2.45. 125 (54.3 %) were males and
105 (45.7 %) were females. 59.1% patients became
afebrile on 5th day of treatment while 40.9 % patients
failed to become afebrile.In the Azithromycin group
69.6 % patients became afebrile on day 5th . In the
Ofloxacin group, 48.7% became afebrile on day 5 th .
Proportion of patients becoming afebrile on 5 th day
of treatment was significantly higher in the
azithromycin group as compared to Ofloxacin group
(p= 0.01)
Conclusion: Azithromycin is more effective in
children with typhoid fever in terms of greater
proportion of children becoming afebrile on day 5 th
of treatment
Key Words: Azithromycin, Ofloxacin, Enteric
fever
Introduction
Typhoid fever is a major health problem .It is an
important cause of mortality and morbidity world
wide but with high incidence in developing countries
of Asia. It is endemic in Pakistan and India. A recent
estimate of disease burden worldwide showed that in
were reported with 210,000 deaths due to typhoid
fever and 5.4 million cases of paratyphoid fever1. A
study conducted in May 2004 showed that South East
Asia and Central Asia are the regions in which
incidence of typhoid fever is high, 100/100,000
cases/year. Rest of Asia, Africa, Caribbean, Latin
America, part of Europe and North America are the
regions with medium incidence of typhoid fever, 10-
100/100,000 cases/per year. The rest of the developed
world have low incidence of typhoid fever,
<10/100,000 cases/year2. Pakistan has a high incidence
of typhoid fever. It is the 4th commonest cause of death
. According to a report of WHO, the incidence of
typhoid fever in Pakistan is 573.2 per 100,000 persons
per year. 3,4
Risk factors for transmission of typhoid fever and
paratyphoid fever include over crowding, poor hand
washing and poor personal hygiene, eating street food,
using water without boiling, sharing food, consuming
iced drinks, lower socioeconomic group, and poor
sanitory conditions in houses. Typhoid fever is
frequently transmitted in summer and during rainy
season due to contamination of water used for
drinking5
The incubation period of typhoid fever is one to two
weeks.6 After ingestion of contaminated food or water,
the bacteria enters into the lamina properia of
intestine, from where it is taken up by macrophages
which then spread the organism via lymphatics to
various organs of host causing disease manifestations.7
The clinical picture of the disease may be mild or
severe enough to cause fatal complications and death
of the patient. Patients may present with high grade
fever, anorexia, nausea, vomiting and diarrhea or
sometimes abdominal pain, pallor, constipation,
jaundice, myalgias, arthralgias and
hepatosplenomegaly or encephalopathy, or ileus
intestinal perforation. Factors that determine the
severity of the disease include, the duration of illness
before starting appropriate therapy, age of the patient,
previous vaccination, immunity of the host, dose of
inoculating organism and choice of antibiotic being
used for treatment. 8

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Journal of Rawalpindi Medical College (JRMC); 2014;18(2):209-212

Gold standard for diagnosis of typhoid fever is blood
culture and bone marrow culture. Other tests which
are commonly used include Typhidot test and PCR. 9
Case fatality rate of typhoid fever is 10 % without
proper treatment however it can be reduced to 1 %
with proper treatment with antibiotics 10. About 15 %
of infected patients with salmonella died in past in
pre-antibiotic era. The survivors used to have
prolonged disability and illness lasting for weeks or
even for many months. Antibiotic therapy is necessary
for treatment of typhoid fever.11
Multi Drug Resistance (MDR) is the term used to
describe the resistance to all first line antimicrobials
used for treatment of typhoid fever including
ampicillin, Trimethoprim-Sulfamethoxazole and
chloramphenicol. Due to these MDR strains,
fluroquinolones are the drugs of choice 12. A study was
conducted in India in 2001 that showed 100%
susceptibility of all isolated Salmonella strains to
Ciprofloxacin.13Increased use of fluoroquinolones
Investigation to be done during hospital stay was
Typhidot (IgM antibodies) . Chi-square test was used
to compare efficacy (afebrile on day 5) of both drugs.P-
value < 0.05 was considered significant.
Results
The age range was from 5 to 12 years with a mean
age of 7.7 2.45 (Figure 1). Majority (54.3 %) were
males . The weight of the children ranged from 10 to
40 kg with a mean weight of 237.48 kg. In the
Azithromycin group majority (69.6 %) became afebrile
on day 5th .In the Ofloxacin group 48.7% patients
became afebrile on day 5th.The proportion of patients
becoming afebrile on day 5th was higher in the
azithromycin group as compared to Ofloxacin
group(p=0.01)(Table 1)
40
35

again created problem in treatment of typhoid fever 30

due to emergence of strains that were resistant to
Fluoroquinolones.14,15 25

This resistance again forced the physicians to search

count

20
for newer antibiotics to which salmonella is sensitive.
Among newer fluoroquinolones, Gatifloxacin is a 15

better alternative. 3rd generation Cephalosporins like

Ceftriaxone are now commonly being used for the 10

treatment of typhoid fever.16 Treatment of 5

Std. Dev = 2.45
Mean = 7.7
ciprofloxacin resistant typhoid fever now narrows N = 230.00
0
down to 3rd and 4th generation cephalosporins, 2.0 4.0 6.0 8.0 10.0 12.0
Azithromycin, Penams and Tigecycline.17 3.0 5.0 7.0 9.0 11.0

age in years
Patients and Methods:
This randomized controlled trail was conducted in Figure 1- Age distribution of study groups
Pediatric Department of Holy Family Hospital, Table 1: Frequencies of patients becoming afebrile
Rawalpindi ,from March 2012 to September
on day 5th: Azithromycin versus Ofloxacin groups
2012.Sample size was calculated by WHO calculator.
Total 230 diagnosed patients of Typhoid fever, age antibiotic given
range from 2-12 years, were included. Patients had azithromycin ofloxacin Total
fever >37C in the presence of at least one or more of AFEBRILE yes 80 56 136
69.6% 48.7% 59.1%
the signs and symptoms , i.e., persistent headache,
No 35 59 94
abdominal pain or discomfort, splenomegaly /
30.4% 51.3% 40.9%
hepatomegaly, rose spots on skin and vomiting.One
Total 115 115 230
hundred and fifteen patients were given Azithromycin
100.0% 100.0% 100.0%
and 115 patients were given Ofloxacin randomly.
Patients were randomly divided into two groups, A p=0.001
and B . Group A was given Azithromycin 10 Discussion
mg/kg/day once daily orally for 7 days.Group B was The results of present study revealed children
given Ofloxacin 15mg/kg/day in two divided doses between age group 7-11 years, mostly infected with
orally for 7 days. Both the groups were observed for typhoid fever. This is in contrast to a study which
duration of becoming afebrile on 5th day of treatment. showed that children less than 5 years of age are at

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Journal of Rawalpindi Medical College (JRMC); 2014;18(2):209-212
high risk.18,19 Males were reported more than females
in our study groups and it may be due to the reason
that male children have easy access to street foods.
Similar results were also obtained in Bangladesh in
which male patients were more in number than the
female patients infected with typhoid fever.20, 21 In the
Azithromycin group 69.6 % patients became afebrile
on day 5. The proportion of patients becoming afebrile
on day 5 was significantly higher in the Azithromycin
group as compared to Ofloxacin group; p= 0.01).A
case series reported from south India showed that
fluoroquinolone use in fluoroquinolone reduced
susceptibility strains should be done with great
caution. 22 Another study compared different
antimicrobial regimens for the treatment of MDR
(multidrug resistant) (nalidixic acid resistant) Na (r)
typhoid fever. Vietnamese children and adults with
uncomplicated typhoid fever were entered into an
open randomized controlled trial. Ofloxacin (20mg/kg
of body weight/day for 7 days), azithromycin
(10mg/kg/day for the first 3 days) were compared.
The clinical cure rate was 64% with ofloxacin, 76%
with ofloxacin-azithromycin, and 82% (51/62) with
azithromycin . The mean (95% confidence interval,
fever, clearance time for patients treated with
azithromycin (5.8 days [5.1 to 6.5 days]) was shorter
than that for patients treated with ofloxacin-
azithromycin (7.1 days [6.2 to 8.1 days]) and ofloxacin
(8.2 days [7.2 to 9.2 days]) (p < 0.001). 23 According to
another study conducted in Amirtasir India, the safety
of ofloxacin and azithromycin is equal in treatment of
typhoid fever with no major side effects. However
azithromycin is an effective alternative in conditions
when ofloxacin is contraindicated. 24
In a study it was shown that about 20 % of patients of
typhoid fever treated with Ofloxacin had positive fecal
cultures immediately in their post treatment period.
This transient fecal carriage in post treatment period
has the potential to allow further transmission of S.
typhi among the family and close contacts. 23
About 80% of the patients among this study group
who were treated with Azithromycin in a dose of
10mg/kg/day once daily for 7 days had an average
fever clearance time on day 5 of treatment and this
was comparable to results of another study in which
azithromycin was compared in terms of fever
clearance time. 23
Studies have examined a regimen of azithromycin
at a dose of 20 mg/kg/day (maximum, 1 g/day) in
children or 1 g/day in adults given for 5 days. Of the
Egyptian children, 94% (30/32) were cured of the
211
disease, with a mean fever clearance time of 4.5 days25.
Of Vietnamese adults, 96% (42 out of 44) were cured,
with a mean duration of fever of 5.4 days. 26 The
slightly lower cure rate in our study as compared to
these studies may be due to higher doses of
azithromycin used in these studies. Azithromycin can
be used safely for the treatment of typhoid fever in
children.27
The persistence of fever in some patients of our
study may be due to the continued production of
pyrogenic cytokines.28 This shows that time taken to
clear fever may not be an adequate measure of
antibiotic efficacy, and consequently may not be an
appropriate end point in typhoid therapy trials. Some
investigators also did not specify whether clinical
failures were excluded or included in calculations of
mean fever clearance time.
In this study, a 7-day course of azithromycin was more
effective as an initial oral treatment for uncomplicated
typhoid fever. Appropriate treatment of typhoid fever
is a clinical as well as a public health challenge due to
rising levels of drug resistance and limited evidence
for use of newer agents like Azithromycin, particularly
for children.
Conclusions
1.Azithromycin is a better choice than Ofloxacin in
terms of shorter time of fever clearance.
2. Clinical burden of typhoid fever ,along with
emergence of resistance to antibiotics which were
considered appropriate for its treatment , needs
exploration of more antibiotic therapies .
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