Recent Advances in Provision of Primary Care in the Public Sector: Is 3 Days of Oral

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

2. 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.

3. 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.

4. 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.

5. 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.

6. 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

7. 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.

8. 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

9. 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.

10. 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.

11. 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

12. 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.

13. TRIAL PROFILE Pakistan India n = 1997 n = 2188 3 day n = 980 5 day n = 974 3 day n = 1095 5 day n = 1093

14. RESULTS DEMOGRAPHIC INDICATORS

15. RESULTS CLINICAL SIGNS

16. 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

17. 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

18. RESULTS FINAL OUTCOME

19. RESULTS MICROBIOLOGY * For s. pneumoniae only.

20. RESULTS Relationship of Treatment Failure with Radio Positive x-rays n = 259/1843 (14.0%)

21. 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 (<20); Chloramphenicol (< 20), erythromycin (< 15); cotrimoxazole (< 15) Footnote: Definition of antimicrobial resistance based on zone of inhibition in mm.

22. 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?

23. 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.