1. 1 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

2. 2 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. Because of the high therapy failure rate in both groups, the treatment guidelines need to be reviewed. Study Funding: World Health Organization, Geneva

3. 3 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 a. Reduce the cost of treatment b. Enhance patient compliance. b. Enhance patient compliance. c. Contribute towards containment of antimicrobial c. Contribute towards containment of antimicrobial resistance. resistance.

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 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.

5. 5 SUBJECTS AND METHODS Each of the study patients received two medicine Each of the study patients received two medicine bottles, labeled ‘Green’ containing active drug for first bottles, labeled ‘Green’ containing active drug for first 3 days and ‘Red’ containing either placebo or active 3 days and ‘Red’ containing either placebo or active drug for next 2 days. drug for next 2 days. Follow-ups were done on day 3, 6, and 14. Follow-ups were done on day 3, 6, and 14. Antibiotic was changed to oral Chloramphenicol in Antibiotic was changed to oral Chloramphenicol in children who did not show improvement. children who did not show improvement. Children who showed deterioration at any stage were Children who showed deterioration at any stage were admitted for injectable antibiotics. admitted for injectable antibiotics. All children were followed up by study physicians till All children were followed up by study physicians till they were cured. they were cured.

6. 6 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).

7. 7 SAMPLE SIZE Sample size was calculated to show a point estimate of Sample size was calculated to show a point estimate of clinical failure rate. clinical failure rate. We assume the two modes of therapy to be equal, if the We assume the two modes of therapy to be equal, if the failure rate between the two regimens is within 5%. 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. 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 With inclusion of 15% loss to follow-up the total estimated sample size was 1954. estimated sample size was 1954. A randomization scheme was developed at WHO, Geneva A randomization scheme was developed at WHO, Geneva for each site using uneven blocks of 2, 4, 6 for both for each site using uneven blocks of 2, 4, 6 for both groups in ratio of 1:1. groups in ratio of 1:1.

8. 8 TRIAL PROFILE Figure: 1 Randomized Patients n = 1997 3 days = 999 5 days = 998 Excluded from Analysis n = 19 Excluded from Analysis n = 24 Incorrect enrolment = 3 Lost to Follow-up = 13 Therapy changed on their own = 3 Incorrect enrolment = 1 Lost to Follow-up = 19 Therapy changed on their own = 4 Analyzed n = 980 Analyzed n = 974

9. 9 RESULTS n = 1954 DEMOGRAPHIC INDICATORS DEMOGRAPHIC INDICATORS 3 days5 days n = 980n = 974 n = 980n = 974 Male628 (64.0%)597 (61.2%) Age (in months) 2 - 11537 (54.7%)515 (52.8%) 2 - 11537 (54.7%)515 (52.8%) Median 6.005.00 Median 6.005.00 12 – 59443 (45.3%)459 (47.2%) 12 – 59443 (45.3%)459 (47.2%) Median 21.0022.00 Median 21.0022.00

10. 10 3 days n = 980 5 days n = 974 Cough Difficult Breathing FeverVomitingDiarrhoeaWheezing Mean Respiratory rate Breast Feeding 2 – 11 months 2 – 11 months 12 – 59 months 12 – 59 months 970 (98.9%) 860 (87.7%) 914 (93.2%) 140 (14.2%) 111 (11.3%) 211 (21.5%) 54.5 + 6.71 471/537 (87.7%) 124/443 (28.0%) 960 (98.5%) 848 (87.0%) 920 (94.4%) 123 (12.6%) 110 (11.2%) 226 (23.2%) 54.2 + 6.75 465/515 (90.2%) 117/459 (25.4%) RESULTS n = 1954 CLINICAL SIGNS

11. 11 FINAL OUTCOME Figure: 2 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 * 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 * * † ‡

12. 12 3 DAYS n = 980 5 DAYS n = 974 p-value Treatment success Failure on day 3 Failure on day 5 Relapse on day 14 Death 791 (81.0%) 127 (12.9%) 50 (5.1%) 12 (1.2%) 799 (82.0%) 116 (11.9%) 45 (4.6%) 13 (1.3%) 1 (0.10%) 0.83 0.58 0.71 0.98 RESULTS n = 1954 FINAL OUTCOME

13. 13 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. 1. Similar multi-centre trials replicated in India, Bangladesh and Indonesia show same results. 2. WHO guidelines for the duration of treatment of non- severe 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 non- severe pneumonia. RECOMMENDATIONS