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EFFICACY OF SHORT COURSE
AMOXICILLIN FOR NON-SEVERE
PNEUMONIA IN CHILDREN
(Hazir T*, Latif E*, Qazi S** AND MASCOT
Study Group)
*Children’s Hospital, Pakistan Institute of
Medical Sciences, Islamabad, Pakistan and
**WHO Geneva
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Efficacy of Short-Course Oral Amoxicillin Therapy for Non-Severe Pneumonia in
Children
Hazir T, Latif E, Qazi S, and the Multicentre Amoxicillin Short Course Therapy
(MASCOT) Pneumonia Study Group
Children Hospital, Pakistan Institute of Medical Sciences, Islamabad, Pakistan
Problem Statement: The optimal duration of therapy for most infections, especially acute
respiratory infections, is not based on strong scientific evidence. Conventionally, antibiotics
are used until the patient is afebrile or laboratory parameters are normal. Use of antibiotics
contributes to development of antimicrobial resistance. If a shorter course is found to be
effective for treatment of pneumonia, it would reduce the cost of treatment, enhance patient
compliance, and contribute toward containment of antimicrobial resistance.
Objective: The clinical efficacy of three days versus five days of oral amoxicillin was
compared for treatment of non-severe pneumonia in children.
Design: Multicenter, double blind, randomized, controlled trial.
Setting and Population: We recruited 1,953 children, aged 2–59 months, with non-severe
pneumonia (World Health Organization criteria) diagnosed in the outpatient departments of
seven hospitals in five cities of Pakistan.
Intervention: Patients were randomly assigned on a 1:1 basis to either three days or five
days of amoxicillin therapy. Oral amoxicillin was given at doses of 15 mg/kg three times a
day.
Outcome Measures: The primary outcome was treatment failure, which included change of
antibiotic therapy or death.
Results: 980 children were randomized to three days and 973 to five days of amoxicillin
therapy. Five days after enrollment, the treatment failure in the three-days group was 18.1%,
compared to 16.5% in the five-days group. No significant differences were found in the two
therapeutic groups. Chest radiographs were obtained in 1,847 children, of whom 259 had
radiological pneumonia. Of the 475 nasopharangeal aspirates obtained, 99 were positive for
respiratory syncytial virus. The treatment failure rate was higher in infants (odds ratio [OR],
1.43; 95% confidence interval [CI], 1.12–1.18), those who had a respiratory rate of more than
60 breaths per minute (OR, 1.44; 95% CI, 1.01–2.06), and those who had been ill relatively
longer before presentation (OR, 1.59; 95% CI, 1.20–2.11).
Conclusions: Three days’ duration of therapy with oral amoxicillin was as effective as five
days of therapy for treatment of non-severe pneumonia in children 2–59 months old.2Because
of the high therapy failure rate in both groups, the treatment guidelines need to be reviewed.
Study Funding: World Health Organization, Geneva
BACKGROUND
1.
ARI is the leading cause of under 5 mortality in the
developing world.
2.
To reduce ARI mortality WHO introduced standardised
case management guidelines.
3.
The duration of therapy for non-severe pneumonia is 5
days.
4.
This recommendation is not based on strong scientific
evidence.
5. Shorter course antibiotic therapy for non-severe
pneumonia would have many advantages:
a. Reduce the cost of treatment
b. Enhance patient compliance.
c. Contribute towards containment of antimicrobial
resistance.
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OBJECTIVES
Primary Objective:
To compare the proportion of children 2-59 months of
age presenting with non-severe pneumonia, who
achieve clinical cure on day 6 with 3 day versus 5 day
of oral amoxicillin therapy.
Secondary Objectives:
1. To assess the proportion of children who have
nasopharyngeal aspirates positive for RSV at the time of
enrolment in 3 versus 5 days oral amoxicillin therapy
groups.
2. To compare the proportion of enrolled children who
are judged to be clinically cured at day 6 of enrolment,
but relapse within the next 7 days of observation with 3
versus 5 days oral amoxicillin therapy.
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SUBJECTS AND METHODS
• Each of the study patients received two medicine
bottles, labeled ‘Green’ containing active drug for first
3 days and ‘Red’ containing either placebo or active
drug for next 2 days.
• Follow-ups were done on day 3, 6, and 14.
• Antibiotic was changed to oral Chloramphenicol in
children who did not show improvement.
• Children who showed deterioration at any stage were
admitted for injectable antibiotics.
• All children were followed up by study physicians till
they were cured.
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INCLUSION CRITERIA
• Age 2-59 months.
• History of cough and/or difficult breathing.
• Diagnosis of WHO defined non - severe pneumonia:
 Respiratory Rate > 50/min (infants 2-11months).
 Respiratory rate > 40/min (children 12-59 months).
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SAMPLE SIZE
• Sample size was calculated to show a point estimate of
clinical failure rate.
• We assume the two modes of therapy to be equal, if the
failure rate between the two regimens is within 5%.
• For an alpha of 0.03 and a power of 90% the required
sample size was 845 in each group.
• With inclusion of 15% loss to follow-up the total
estimated sample size was 1954.
• A randomization scheme was developed at WHO, Geneva
for each site using uneven blocks of 2, 4, 6 for both
groups in ratio of 1:1.
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TRIAL PROFILE
Figure: 1
Randomized
Patients
n = 1997
3 days =
999
Incorrect
enrolment = 3
Lost to Follow-up
= 13
Therapy changed
on their own = 3
Excluded
from
Analysis
n = 19
Analyzed
n = 980
5 days =
998
Excluded
from
Analysis
n = 24
Incorrect
enrolment = 1
Lost to Follow-up
= 19
Therapy changed
on their own = 4
Analyzed
n = 974
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RESULTS
n = 1954
DEMOGRAPHIC INDICATORS
Male
3 days
5 days
n = 980
n = 974
628 (64.0%)
597 (61.2%)
2 - 11
537 (54.7%)
515 (52.8%)
Median
6.00
5.00
12 – 59
443 (45.3%)
459 (47.2%)
Median
21.00
22.00
Age (in months)
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RESULTS
n = 1954
CLINICAL SIGNS
3 days
n = 980
5 days
n = 974
Cough
970 (98.9%)
960 (98.5%)
Difficult Breathing
860 (87.7%)
848 (87.0%)
Fever
914 (93.2%)
920 (94.4%)
Vomiting
140 (14.2%)
123 (12.6%)
Diarrhoea
111 (11.3%)
110 (11.2%)
Wheezing
211 (21.5%)
226 (23.2%)
Mean Respiratory
54.5 + 6.71
54.2 + 6.75
471/537
465/515
2 – 11 months
(87.7%)
(90.2%)
12 – 59 months
124/443
117/459
(28.0%)
(25.4%)
rate
Breast Feeding
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FINAL OUTCOME
Figure: 2
*
†
Failure =
127
3 days =
980
Resolved =
853
Failure =
50
Resolved =
803
Relapse =
12
Cured =
791
*
*
‡
5 days =
974
Failure =
116
Failure =
45
Relapse =
13
Resolved =
858
Resolved =
812
Cured =
799
Day of enrollment taken as day 0
†
‡
i) Cured on Chloramphenicol = 63
i) Cured on Chloramphenicol = 50
ii) Cured on injectible antibiotics = 24
ii) Cured on injectible antibiotics = 23
iii) Cured on third generation cefixime = 36
iii) Cured on third generation cefixime = 43
iv) Lost to follow-up = 4
iv) Lost to follow-up = 0
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RESULTS
n = 1954
FINAL OUTCOME
3 DAYS
5 DAYS
n = 980
n = 974
Treatment success
791 (81.0%)
799 (82.0%)
0.83
Failure on day 3
127 (12.9%)
116 (11.9%)
0.58
Failure on day 5
50 (5.1%)
45 (4.6%)
0.71
Relapse on day 14
12 (1.2%)
13 (1.3%)
0.98
Death
p-value
1 (0.10%)
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CONCLUSION
Oral amoxicillin for 3 days is as effective clinically
as 5 days in the treatment of children 2-59 months old
suffering from non severe pneumonia.
RECOMMENDATIONS
1. Similar multi-centre trials replicated in India,
Bangladesh and Indonesia show same results.
2. WHO guidelines for the duration of treatment of nonsevere pneumonia should be changed to 3 instead of
5 days.
3. The causes of high treatment failure in non-severe
pneumonia should be studied in greater detail.
4. There is a need to carry out etiological studies in nonsevere pneumonia.
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