1. 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 2 nd ICIUM Conference 2004

2. 2 BACKGROUND  ARI is the leading cause of under 5 mortality in the developing world. world.  To reduce ARI mortality WHO introduced standardised case management guidelines. management guidelines.  Amoxicillin and cotrimoxazole are recommended as first line treatment for non-severe pneumonia. treatment for non-severe pneumonia.  The currently recommended duration of therapy is 5 days.  This recommendation is not based on strong scientific evidence.

3. 3  Patients tend to stop treatment once they are better which results in non-adherence. results in non-adherence.  Shorter antibiotic courses have shown to be effective in the treatment of otitis media, sinusitis and tonsillopharyngitis. treatment of otitis media, sinusitis and tonsillopharyngitis.  Shorter course antibiotic therapy for non-severe pneumonia would have many advantages: would have many advantages: a. Reduce the cost of treatment a. Reduce the cost of treatment b. Enhance patient compliance. b. Enhance patient compliance. c. Contribute towards containment of antimicrobial resistance. c. Contribute towards containment of antimicrobial resistance.  If effective, shorter antibiotic course for treatment of pneumonia will have important policy implications. pneumonia will have important policy implications. BACKGROUND Contd.

4. 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. 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. 6 METHODS PAKISTAN (250 mg/5 ml) Green labeled bottle with active medicine for 3 days Green labeled bottle with active medicine for 3 days Red labeled bottle with active or placebo for day 4 and 5 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 Blue envelope with active medicine for 3 days Green envelope with active/placebo for day 4 and 5. Green envelope with active/placebo for day 4 and 5. Dose used approx 45-50 mg/kg/day

7. 7 Follow-ups were done on day 3, 5-6, and 12-14. Home visits Follow-ups were done on day 3, 5-6, and 12-14. Home visits done within 24 hours if child did not come. done within 24 hours if child did not come. Antibiotic was changed to oral Chloramphenicol in children Antibiotic was changed to oral Chloramphenicol in children who did not show improvement. who did not show improvement. Children showing deterioration at any stage were hospitalized. Children showing deterioration at any stage were hospitalized. All children were followed up till they were cured. All children were followed up till they were cured. METHODS

8. 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 * Rawalpindi * * Multan * Gilgit * * * * * Trivandrum * Vellore * Mumbai * Chandigarh

9. 9 INCLUSION CRITERIA Age 2-59 months. Age 2-59 months. History of cough and/or difficult breathing. History of cough and/or difficult breathing. Diagnosis of WHO defined non - severe pneumonia: 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. Written informed consent.

10. 10 EXCLUSION CRITERIA WHO defined severe pneumonia or very severe disease. WHO defined severe pneumonia or very severe disease. Severe malnutrition. Severe malnutrition. Known penicillin allergy. Known penicillin allergy. Clinically recognized congenital heart disease. Clinically recognized congenital heart disease. Complicating acute non-pulmonary or chronic illness. Complicating acute non-pulmonary or chronic illness. Taken appropriate doses of 48 hours prior to presentation. Taken appropriate doses of 48 hours prior to presentation. Prior history of wheezing or bronchial asthma Prior history of wheezing or bronchial asthma Hospitalization in past two weeks. Hospitalization in past two weeks. Previously enrolled patient. Previously enrolled patient. Living outside the municipal limits and refusal to give consent. Living outside the municipal limits and refusal to give consent.

11. 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. 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. 13 TRIAL PROFILE n = 1997 3 day n = 980 5 day n = 974 Pakistan n = 2188 3 day n = 1095 5 day n = 1093 India

14. 14 RESULTS Pakistan n = 1954 India n = 2198 3 days n = 980 5 days n = 974 3 days n = 1095 5 days n = 1093 Sex Male Male Age (in months) 2 - 11 2 - 11 Median Median 12 – 59 12 – 59 Median Median 628 (64.0%) 537 (54.7%) 6.00 443 (45.3%) 21.00 597 (61.2%) 515 (52.8%) 5.00 459 (47.2%) 22.00 685 (62.5%) 479 (43.7%) 616 (56.3%) 676 (61.8%) 475 (43.5%) 618 (56.5%) DEMOGRAPHIC INDICATORS

15. 15 Pakistan n = 1954 India n = 2198 3 days n = 980 5 days n = 974 3 days n = 1095 5 days n = 1093 Cough Difficult Breathing FeverVomitingWheezing Mean Resp. rate +S.D 970 (98.9%) 860 (87.7%) 914 (93.2%) 140 (14.2%) 211 (21.5%) 54.5 + 6.71 960 (98.5%) 848 (87.0%) 920 (94.4%) 123 (12.6%) 226 (23.2%) 54.2 + 6.75 1938 (98.7%) 726 (37.0%) 1518 (77.3%) 246 (12.5%) 211 (21.5%) 54.5 + 6.71 221 (98.2%) 78 (34.7%) 165 (73.3%) 30 (13.3%) 226 (23.2%) 54.2 + 6.75 RESULTS CLINICAL SIGNS

16. 16 FINAL OUTCOME Figure: 3 (Pakistan) 3 days = 980 5 days = 974 Failure = 127 Resolved = 853 Failure = 116 Resolved = 858 Failure = 50 Resolved = 803 Failure = 45 Resolved = 812 Relapse = 12 Cured = 791 Relapse = 13 Cured = 799 1 st follow-up 2 nd follow-up 3 rd follow-up

17. 17 FINAL OUTCOME Figure: 4 (India) 3 days = 1095 5 days = 1093 Failure = 0 Resolved = 0 Failure = 0 Resolved = 0 Failure = 0 Resolved = 0 Failure = 0 Resolved = 0 Relapse = 0 Cured = 0 Relapse = 0 Cured = 0 1 st follow-up 2 nd follow-up 3 rd follow-up

18. 18 Pakistan n = 1954India n = 2198 3 DAYS n = 980 5 DAYS n = 974 3 DAYS N = 1095 5 DAYS N = 1093 Overall treatment success Therapy failure on day 5 Relapse on day 14 Death 791 (81.0%) 177 (18.0%) 12 (1.2%) 799 (82.0%) 161(16.5%) 13 (1.3%) 1 (0.10%) 948 (86.6%) 115 (10.5%) 32 (2.9%) 954 (87.3%) 110 (10.1%) 29 (2.6%) RESULTS FINAL OUTCOME

19. 19 RESULTS 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 Positive RSV 25 (8.9%) 44 (15.7%) 19 (6.7%) 50 (17.5%) 421 (38.4%) 252 (23.0%) 419 (38.3%) 261 (23.9%) MICROBIOLOGY * For s. pneumoniae only.

20. 20 RESULTS 3 DAYS n = 927 5 DAYS n = 916 p - value Positive Chest radiographs Success Group Treatment Failure Group 133 (14.3%) 106/791 (13.4%) 27/189 (14.2%) 126 (13.7%) 97/799 (12.1%) 29/175 (16.5%) 0.55 0.70 Relationship of Treatment Failure with Radio Positive x-rays n = 259/1843 (14.0%)

21. 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) S. pneumoniae (1204 isolates) 3 day amoxicillinX 2, p-value 5 day amoxicillinX 2, p-value Day 0 Isolates/Total tested(%) Day 14 Isolates/Total tested (%) Day 0 Isolates/Total tested (%) Day 14 Isolates/Total tested (%) Cotrimoxazole253/380 (66.6)106/159 (66.7).0004, 0.98252381(66.1)111/142(78.2)7.0, 0.008 Chloramphenicol21/418(5.0)9/163(5.5)0.06, 0.8114/419(3.3)6/142(4.2)0.24, 0.62 Oxacillin67/408(16.4)17/160 (10.6)3.1, 0.0864/413(15.517/142(4.2)1.0, 0.32 Erythromycin15/421(3.6)2/161(1.2)2.2, 0.149/418(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.

22. 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. 23 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. RECOMMENDATIONS