Recent Advances in Provision of Primary Care

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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.
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DEFINITIONS
Clinical cure Return of respiratory rate to age
specific WHO cut off. Clinical Failure Developmen
t 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 gt 50/min (infants 2-11months).
• Respiratory rate gt 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 11 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
n 2188
3 day n 980
5 day n 974
3 day n 1095
5 day n 1093
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RESULTS
DEMOGRAPHIC INDICATORS
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RESULTS
CLINICAL SIGNS
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FINAL OUTCOME Figure 3 (Pakistan)
3 days 980
5 days 974
1st follow-up
Failure 116
Resolved 858
Failure 127
Resolved 853
2nd follow-up
Failure 50
Resolved 812
Failure 45
Resolved 803
3rd follow-up
Relapse 12
Cured 791
Relapse 13
Cured 799
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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
Resolved 0
Failure 0
3rd follow-up
Relapse 0
Cured 0
Relapse 0
Cured 0
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RESULTS
FINAL OUTCOME
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RESULTS
MICROBIOLOGY
For s. pneumoniae only.
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RESULTS
Relationship of Treatment Failure with Radio
Positive x-rays n 259/1843 (14.0)
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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)
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 (lt20) Chloramphenicol (lt 20),
erythromycin (lt 15) cotrimoxazole (lt
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 lt 1 year?
• With duration of illness gt 48 hours?

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RECOMMENDATIONS
For the treatment of non-severe pneumonia in
children lt 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.