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Indian Pediatr 2011;48: 533-536 |
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Efficacy and Safety of Azithromycin for
Uncomplicated Typhoid Fever: An Open Label Non-comparative Study |
Anju Aggarwal, #Apurba Ghosh, Sunil
Gomber, ##Monjori Mitra
and $AO Parikh
From the Department of Pediatrics, University College of
Medical Sciences and Guru Tegh Bahadur Hospital, New Delhi;
#Institute
of Child Health, 11, Dr Biresh Guha Street, Kolkata; ##Medclin Research
Pvt Ltd, Kolkata; and $Alembic Limited; India.
Correspondence to: Dr Monjori Mitra, Research Director,
Medclin Research Pvt Ltd, 195/2 ChakrobortyPara
Kolkata 700 107, West Bengal, India.
Email: [email protected]
Received: May 6, 2010;
Initial review: June 28, 2010;
Accepted: November 26, 2010.
Published Online: 2011
February, 28.
PII: S09747559INPE1000377-2
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Abstract
An open-labelled, non-comparative study was conducted
in 117 children aged 2-12 years to evaluate the efficacy and safety of
azithromycin (20mg/ kg/day for 6 days) for the treatment of
uncomplicated typhoid fever. Of the patients enrolled based on a
clinical definition of typhoid fever, 109 (93.1%) completed the study.
Mean (SD) of duration of fever at presentation was 9.1(4.5) days.
Clinical cure was seen in 102 (93.5%) subjects, while 7 were withdrawn
from the study because of clinical deterioration. Mean day of response
was 3.45±1.97. BACTEC blood culture was positive for Salmonella
typhi in 17/109 (15.5%) and all achieved bacteriological cure. No
serious adverse event was observed. Global well being assessed by the
investigator and subjects was good in 95% cases which was done at the
end of the treatment. Azithromycin was found to be safe and efficacious
for the management of uncomplicated typhoid fever.
Key words: Azithromycin, Children, Management Typhoid fever.
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Widespread emergence of
multidrug-resistant S. typhi has necessitated
the search for other therapeutic
options for typhoid fever. Fluoroquinolones have proven effective, but to
date they are not recommended for use in children, and quinolone-resistant
strains of S. typhi
have been reported [1]. Azalides, are
another class of antibiotics which have shown promise in
the treatment of typhoid
fever. Azithromycin, the first drug of this class and studies comparing
the efficacy of azithromycin with cefixime in adults and children with
typhoid fever have reported it to be safe and efficacious [2-4]. Few
studies are exclusively reported in children [5,6]. We planned this
open-labeled, study to assess the safety and efficacy of single daily dose
of azithromycin for uncomplicated typhoid fever in children.
Methods
This multicentre study was conducted with prior
approval of the study protocol from the Institutional Ethics Committee of
both participating institutions. We planned to enroll 120 children from
outpatient department of the two centres. Children aged 2-12 years with
fever (axillary/oral temperature
³38.5ºC)
for at least 4 days with clinical features suggestive of uncomplicated
typhoid fever (abdominal pain and tenderness, diarrhea or constipation,
and hepatosplenomegaly) were enrolled. Only those children whose
guardians were able to record body temperature and note down all
information in the case diary for assessment during study visits and were
telephonically available, were included. Written informed parental consent
was taken from all subjects prior to enrolment.
Children with complicated typhoid fever (those with
gastro-intestinal bleeding, suspected intestinal perforation, pneumonia,
stupor, coma) or those tak-ing antibiotics other than amoxicillin,
ampicillin, cotrimaxazole or chloramphenicol in the last 4 days were
excluded. Children with history of documented S. typhi and/or
paratyphi infection within last 12 weeks or history of hypersensitivity
reactions to azithromycin were also excluded.
On day of recruitment a complete medical, treatment and
vaccination history was recorded. Complete physical examination was
carried out and blood collected for complete blood count, malarial
parasite, BACTEC blood culture. BACTEC blood culture was carried out as
per standard procedure. Isolates were identified by standard
microbiological methods and disc susceptibility testing was performed by
the modified Kirby Bauer method. Study medication was dispensed and
monitoring instruction provided to the patient. The subjects received
azithromycin dispersible tablet/suspension at a dose of 20mg/kg/body
weight in a single daily dose for 6 days. Paracetamol 15mg/kg body weight
orally was used as antipyretic. No antibiotics other than the study
medications were dispensed.
Children were treated at their home and re-assessed in
the out-patient department on day 4, day 7 and day 10 after the start of
the treatment. On day 4 and day 7 temperature chart and symptom diary was
evaluated with a complete physical examination. Drug compliance was
assessed by history collecting the empty wrappers/bottles. The overall
compliance was categorized compliant if >80% of study medication
consumed according to prescribed regimen.
Children who were BACTEC blood culture positive were
evaluated on day 10 also for repeat blood culture. A window period of
±2days was admissible for each visit. If the temperature increased or the
clinical condition of the patient worsened or there was a serious drug
reaction, patient was taken off from the study and treated with ofloxacin
(15mg/kg/day oral) or intravenous ceftriaxone (100mg/kg/day). All follow
ups were carried out in the out-patient department of the hospital.
Primary efficacy end-point was clinical cure rate at
day 10 and bacteriological cure rate in children who were initially
bacteriological positive. Clinical cure was defined as defervescence/fever
clearance and subsidence of clinical symptoms. Fever clearance/defervescence
was considered as sustained period of 72 hours with axillary temperature
less than 37ºC (98.6ºF). Secondary efficacy end points were (i)
clinical improvement rates at second follow up visit i.e. day 7 in
percentage of subjects who do not achieve fever clearance but who show
signs and symptoms of improvement (ii) tolerability/global
assessment of well being assessed by the clinician at second follow up
visit (day 7) to be measured on a 4 point Likert Scale (excellent=3,
good=2, fair=1, poor=0) as assessed by the investigator and as reported
by the patient or his guardian.
Results
A total of 117 children were enrolled, but 8 were lost
to follow up and 109 (93.5%) 68 males completed the study. Mean (SD) age
was 7.5 (2.81) years. Only 22 subjects had prior history of typhoid
vaccination (duration from receiving vaccine was less than 3 years in 9).
Mean (SD) of duration of fever at presentation was 9.1 (4.5) days, of
which 51 (46.7) presented within 7 days, 35 (32.1%) within 8-10 days and
23 ( 21.1%) of more than 11 days duration.
Only 23 (21.1%) children had received antibiotics
(amoxicillin) before presentation. Table 1 shows the
baseline clinical characteristics and that on follow up. Treatment failure
was noticed in 7 (6.4%) patients by day 10. These were withdrawn from the
study. Three of them received intravenous ceftriaxone and 4 received oral
ofloxacin as an add-on therapy and all improved by day 7-15 of enrollment.
All the patients had more than 80% compliance. Mean day of response to
fever was 3.4 (1.9) days.
Table I
Clinical Characteristics of Study Children at Baseline and Follow Up
Clinical findings |
Visit 1 (Day 0) |
Visit 2 (Day 4) |
Visit 3 (Day 7) |
Visit 4 (Day 10) |
|
n |
% |
n |
% |
n |
% |
n |
% |
Fever >38.4ºC |
109 |
100 |
29 |
26.6 |
12 |
11 |
7 |
6.4 |
Headache |
74 |
67.8 |
17 |
15.5 |
2 |
1.8 |
0 |
0.0 |
Constipation/diarrhea |
61 |
55.9 |
8 |
7.3 |
0 |
0.0 |
0 |
0.0 |
Poor appetite |
39 |
35.7 |
32 |
29.3 |
6 |
5.5 |
3 |
2.7 |
Abdominal pain |
69 |
63.3 |
15 |
13.7 |
2 |
1.8 |
0 |
0.0 |
Splenomegaly |
27 |
24.7 |
22 |
20.1 |
16 |
14.6 |
7 |
6.4 |
Hepatomegaly |
73 |
66.9 |
56 |
51.3 |
35 |
32.1 |
15 |
13.7 |
BACTEC blood culture was positive in 17 (15.5%)
patients, of which one patient did not complete the study. Hence, 16/109
were BACTEC blood culture positive (Table II). All of these
patients achieved bacteriological cure at 10th day. Five of these subjects
required add on antibiotics. We did not have any case of multidrug
resistant typhoid. Resistance to quinolones including ciprofloxacin was
significantly high. Clinical characteristics and response rates were
similar in BACTEC blood culture positive and BACTEC blood culture negative
cases. No serious adverse effects were observed except worsening of
diarrhea in two subjects.
Table II
In Vitro Susceptibility of S.typhi Isolates From Bactec Culture Positive Subjects (N=17)
Drug |
Susceptible (%) |
Amoxicillin |
100 |
Cefixime |
100 |
Ceftriaxone |
100 |
Chloramphenicol |
100 |
Cotrimoxazole |
94.4 |
Ofloxacin |
83.3 |
Ciprofloxacin |
77.7 |
Azithromycin |
77.7 |
Nalidixic Acid |
16.6 |
Clinical improvement on day 7 was seen in 92 (84.4%)
subjects. Global well being assessed by the investigator on day 10 was
excellent in 54.6%, good in 37.9%, fair in 4.62% and poor in 0.92%. Global
well-being as assessed by the subjects was excellent 44.2%, good in 47.2%,
fair in 3.7% and poor in 1.8%.
Discussion
Azithromycin appears to be an effective drug for
treating uncomplicated typhoid fever in children with efficacy rate of
more than 90%. Treatment failure rates of 9.3% have been observed in
earlier studies on azithromycin [4]. Two other studies have reported a
clinical cure rate of 82% and 92% [5,7]. Sensitivity pattern seen in our
study is also similar to other Indian study demonstrating a nalidixic acid
resistance of 88% [8], hence the importance of azithromycin.
This study was not a randomized controlled trial or a
comparative trial which is one of the limitations of the study. Of the
subjects studied, 21.1% received amoxicillin before enrollment, this
could have influenced the BACTEC blood culture results, though culture
positivity was similar in those received antibiotics and those who did
not.
Acknowledgments: Prof M Pal and Dr P Bharati of
Indian Statistical Institute, Kolkata for statistical analysis of the
study.
Contributors: All authors contributed to design and
conduct of the study and drafting the paper.
Funding: Alembic Limited.
Competing interests: AOP is Associate Vice
President of Alembic Ltd, which manufactures azithromycin.
What This Study Adds?
• Azithromycin as a single daily dose therapy for
6 days was safe and efficacious for clinically diagnosed
uncomplicated typhoid fever.
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