Transcript Oral Presentation 1

Recent Advances in Provision of Primary Care
in the Public Sector: Is 3 Days of Oral
Antibiotic Therapy Enough for Treatment
of Ambulatory Pneumonia?
Dr. Tabish Hazir
MASCOT Study Group, Pakistan
ISCAP Study Group, India
2nd ICIUM Conference 2004
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BACKGROUND
 ARI is the leading cause of under 5 mortality in the developing
world.
 To reduce ARI mortality WHO introduced standardised case
management guidelines.
 Amoxicillin and cotrimoxazole are recommended as first line
treatment for non-severe pneumonia.
 The currently recommended duration of therapy is 5 days.
 This recommendation is not based on strong scientific evidence.
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BACKGROUND
Contd.
 Patients tend to stop treatment once they are better which
results in non-adherence.
 Shorter antibiotic courses have shown to be effective in the
treatment of otitis media, sinusitis and tonsillopharyngitis.
 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.
 If effective, shorter antibiotic course for treatment of
pneumonia will have important policy implications.
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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 5 with 3 day versus 5 day of oral amoxicillin therapy.
Secondary Objectives:
1. To compare the proportion of enrolled children who are judged
to be clinically cured at day 5 of enrolment, but relapse within the
next 7 days of observation with 3 days versus 5 days oral
amoxicillin therapy.
2. To compare the proportions who had resistant strains of S.
pneumoniae or H. influenzae in NP cultures on day 0 and 14. 4
DEFINITIONS
Clinical cure:
Return of respiratory rate to age specific WHO cut off.
Clinical Failure:
Development of chest indrawing with danger signs or
persistence of fast breathing at day 3 or later leading to
therapy change.
Relapse:
Development of signs of pneumonia between day 6 -14.
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METHODS
PAKISTAN (250 mg/5 ml)
• Green labeled bottle with active medicine for 3 days
• Red labeled bottle with active or placebo for day 4 and 5
INDIA (dispersible tablets 125 mg/tab)
• Blue envelope with active medicine for 3 days
• Green envelope with active/placebo for day 4 and 5.
Dose used approx 45-50 mg/kg/day
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METHODS
• Follow-ups were done on day 3, 5-6, and 12-14. Home visits
done within 24 hours if child did not come.
• Antibiotic was changed to oral Chloramphenicol in children
who did not show improvement.
• Children showing deterioration at any stage were hospitalized.
• All children were followed up till they were cured.
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The study was conducted at 6 sites in Pakistan and 7 sites in India. It
was a multi-centre, randomized, double blind, placebo controlled trial
* Gilgit
* *Rawalpindi
* Multan
*
* Chandigarh
*
*
*
* Mumbai
* Trivandrum
* Vellore
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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).
• Written informed consent.
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EXCLUSION CRITERIA
• WHO defined severe pneumonia or very severe disease.
• Severe malnutrition.
• Known penicillin allergy.
• Clinically recognized congenital heart disease.
• Complicating acute non-pulmonary or chronic illness.
• Taken appropriate doses of 48 hours prior to presentation.
• Prior history of wheezing or bronchial asthma
• Hospitalization in past two weeks.
• Previously enrolled patient.
• Living outside the municipal limits and refusal to give consent.
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SAMPLE SIZE
Using standard formula for equivalence study. Sample size 1:1
for each regimen was calculated. Expected amoxicillin failure
12% with 5% acceptable difference.
Pakistan n = 1954
India
n = 1900
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LABORATORY PROCEDURES

Nasopharyngeal aspirate for RSV detection at the time
of enrollment.

Nasopharyngeal swab for culture and sensitivity of
S. pneumoniae and H. influenzae at enrollment and at
day 12-14 follow up.

In Pakistan chest radiographs were also done.
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TRIAL PROFILE
Pakistan
India
n = 1997
3 day
n = 980
n = 2188
5 day
n = 974
3 day
n = 1095
5 day
n = 1093
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RESULTS
DEMOGRAPHIC INDICATORS
Pakistan n = 1954
India n = 2198
3 days
5 days
3 days
5 days
n = 980
n = 974
n = 1095
n = 1093
628 (64.0%)
597 (61.2%)
685 (62.5%)
676 (61.8%)
2 - 11
537 (54.7%)
515 (52.8%)
479 (43.7%)
475 (43.5%)
Median
6.00
5.00
12 – 59
443 (45.3%)
459 (47.2%)
616 (56.3%)
618 (56.5%)
Median
21.00
22.00
Sex
Male
Age (in months)
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RESULTS
CLINICAL SIGNS
Pakistan n = 1954
India n = 2198
3 days
5 days
3 days
5 days
n = 980
n = 974
n = 1095
n = 1093
Cough
970 (98.9%)
960 (98.5%)
1938 (98.7%)
221 (98.2%)
Difficult Breathing
860 (87.7%)
848 (87.0%)
726 (37.0%)
78 (34.7%)
Fever
914 (93.2%)
920 (94.4%)
1518 (77.3%)
165 (73.3%)
Vomiting
140 (14.2%)
123 (12.6%)
246 (12.5%)
30 (13.3%)
Wheezing
211 (21.5%)
226 (23.2%)
211 (21.5%)
226 (23.2%)
Mean Resp. rate +S.D
54.5 + 6.71
54.2 + 6.75
54.5 + 6.71
54.2 + 6.75
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FINAL OUTCOME
Figure: 3 (Pakistan)
3 days = 980
5 days = 974
1st follow-up
Failure = 127
Failure = 116
Resolved = 853
Resolved = 858
2nd follow-up
Failure = 50
Resolved = 803
Failure = 45
Resolved = 812
Relapse = 13
Cured = 799
3rd follow-up
Relapse = 12
Cured = 791
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FINAL OUTCOME
Figure: 4 (India)
3 days = 1095
5 days = 1093
1st follow-up
Failure = 0
Failure = 0
Resolved = 0
Resolved = 0
2nd follow-up
Failure = 0
Resolved = 0
Failure = 0
Resolved = 0
Relapse = 0
Cured = 0
3rd follow-up
Relapse = 0
Cured = 0
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RESULTS
FINAL OUTCOME
Pakistan n = 1954
India n = 2198
3 DAYS
n = 980
5 DAYS
n = 974
3 DAYS
N = 1095
5 DAYS
N = 1093
Overall treatment success
791 (81.0%)
799 (82.0%)
948 (86.6%)
954 (87.3%)
Therapy failure on day 5
177 (18.0%)
161(16.5%)
115 (10.5%)
110 (10.1%)
12 (1.2%)
13 (1.3%)
32 (2.9%)
29 (2.6%)
Relapse on day 14
Death
1 (0.10%)
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RESULTS
MICROBIOLOGY
Pakistan n = 566
India n = 2188*
3 Days
n= 281
5 Days
n = 285
3 day
n= 1095
5 day
n= 1093
Positive NP swabs
25 (8.9%)
19 (6.7%)
421 (38.4%)
419 (38.3%)
Positive RSV
44 (15.7%)
50 (17.5%)
252 (23.0%)
261 (23.9%)
* For s. pneumoniae only.
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RESULTS
Relationship of Treatment Failure with
Radio Positive x-rays
n = 259/1843 (14.0%)
3 DAYS
5 DAYS
n = 927
n = 916
133 (14.3%)
126 (13.7%)
Success Group
106/791 (13.4%)
97/799 (12.1%)
0.55
Treatment Failure Group
27/189 (14.2%)
29/175 (16.5%)
0.70
Positive Chest radiographs
p - value
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Antimicrobial resistance of Strep. pneumoniae in two treatment
arms at the time of enrollment (Day 0) and at the time of third
follow up (Day 14) (India)
S. pneumoniae
(1204 isolates)
3 day amoxicillin
Day 0
Isolates/Total
tested(%)
Day 14
Isolates/Total
tested (%)
Cotrimoxazole
253/380 (66.6)
106/159 (66.7)
Chloramphenicol
21/418(5.0)
Oxacillin
Erythromycin
X2,
p-value
5 day amoxicillin
X2,
p-value
Day 0
Isolates/Total
tested (%)
Day 14
Isolates/Total
tested (%)
.0004, 0.98
252381(66.1)
111/142(78.2)
7.0, 0.008
9/163(5.5)
0.06, 0.81
14/419(3.3)
6/142(4.2)
0.24, 0.62
67/408(16.4)
17/160 (10.6)
3.1, 0.08
64/413(15.5
17/142(4.2)
1.0, 0.32
15/421(3.6)
2/161(1.2)
2.2, 0.14
9/418(2.2)
4/142(2.8)
0.2, 0.65
Relative risk of developing resistance to co-trimoxazole in s. pneumoniae with 5 day treatment with
amoxicillin 1.7 (95% CI: 1.02-1.35)
Strep. pneumoniae resistant to Oxacillin (<20); Chloramphenicol (< 20), erythromycin (< 15); cotrimoxazole (< 15)
Footnote: Definition of antimicrobial resistance based on zone of inhibition in mm.
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CONCLUSIONS
1. In both studies 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.
2. In S. pneumoniae on day 12 – 14 an increased in-vitro resistance
to cotrimoxazole with 5 day treatment seen.
3. Over all high treatment failure with amoxicillin.
4. Higher risk of treatment failure:
 With radiological positive pneumonia?
 With age < 1 year?
 With duration of illness > 48 hours?
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RECOMMENDATIONS
For the treatment of non-severe pneumonia in children
< 5 years of age:
1. National ARI Control Programmes already using amoxicillin as
first line drug should consider 3 day antibiotic therapy.
2. Considering the high clinical failure with amoxicillin, the Pakistan
ARI Control Programme should not switch over to amoxicillin as
first line drug.
3. Other potential antibiotics for treatment of pneumonia should be
identified for future.
4. WHO definition of treatment failure must be critically evaluated.
5. Large scale community based etiological studies must be carried
out to understand “non-severe pneumonia” better.
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