Three days vs five days oral cotrimoxazole therapy in non-severe pneumonia Kartasasmita C, Samir K. Saha * and Cotrimoxazole Study Group Indonesia and Bangladesh.

Back ground WHO recommendation for Non-Severe pneumonia. –Cotrimoxazole or Amoxicillin for 5 days Attention to shorter course of therapy –Better understanding about the role of antibiotic –ICDDR,B experience with drop-outs –Pakistan experience with Short course amoxicillin therapy. Implications on Compliance, Cost and Microbial resistance.

Aims To determine the equivalence of 3 and 5 days of oral Cotrimoxazole for the treatment of non severe pneumonia. To study the impact of cotrimoxazole treatment on carriage strains of Streptococcus pneumoniae and Haemophilus influenzae.

Study design Double blind, Randomized, Placebo- controlled equivalence trial. Study was conducted form July 2001 to May Ethical clearance was obtained from the ERC of Bangladesh Institute of Child Health and Hasan Sadikin General Hospital.

Screening of Patients Inclusion criteria –Age 2-59 months –WHO defined non-severe pneumonia with or without wheezing. –Consent given Exclusion criteria –Having severe pneumonia or other very severe disease –Allergic to cotrimoxazole –Acute Asthma –Prior enrollment in the study. –Required antibiotic for any other disease(s) –Previous hospitalization in last two weeks. –Prior antibiotic –Weight <4.0 kg

Enrollment of patients Baseline assessment –Demographic information –Clinical examination Randomization –Done in 3 unequal blocks of 4, 6 & 8 in a larger block of 18. Provided with unique ID NP swab to isolate Spn and Hi.

Study Medicine Two bottles for each patients Blue cap – 1 st three days –Contained cotrimoxazole –1 st dose given at health care White Cap – Last two days –Contained either contrimoxazole (5 days group) or placebo (3 days group).

Follow up Follow up on day 3, and 5 & 15. –Children were assessed clinically –Compliance to therapy was recorded. Drug consumption >80% Not missed >1 dose –Outcome recorded Resolved – on day 3 & 5 Failed – day 3 & 5 Relapsed – day 15 2 nd NP swab was collected on day 15.

Outcome of treatment Treatment failure on day 3 (any two of the following) –RR is not reduced by  5 –Temp not reduced by  1 0 C –Mother/caregiver mentioned that baby has deteriorated. Treatment failure on day 5 –RR is fast –Chest in-drawing –Other danger sign(s) Relapse: Day 15 –Development of pneumonia again by 15 day. Clinically resolved –RR  age specific cut offs –No danger sign

Analysis Sample size: 1000 under five non severe pneumonia cases at each site. Data were double entered and verified in EPI Info 6. Final analysis was done using EPI Info 6 and SPSS 11.0

5 days (n=852)3 days (n=851) Male Age (in months) 2 – 11 Median 12 – 59 Median Cough Difficult Breathing Fever Vomiting Diarrhoea Breast Feeding 2 – 11 months 12 – 59 months Wheezing Mean Respiratory rate 425 (49.9%) 388 (45.5%) (54.5%) (99.2%) 455 (53.4%) 726 (85.2%) 273 (32.0%) 135 (15.9%) 325 (83.8%) 334 (72.0%) 250 (29.3%) (54.2%) 410 (48.2%) (51.8%) (99.4%) 463 (54.4%) 721 (84.7%) 261(30.7%) 111 (13.0%) 341(83.2%) 301 (68.3%) 266 (31.3%) Demographic Indicators and Clinical Signs

Number randomized (2022) Number excluded : - Lost to follow up D5 (LFU) only (82) - Protocol violation (PV) only (44) - Combination LFU and PV ( 16) Number excluded : - Lost to follow up D5 (LFU) only (63) - Protocol violation (PV) only (44) Combination LFU and PV (22) Number failed therapy/died 12/0 Number failed therapy/died 18/0 Number failed therapy/died 68/0 Number failed therapy/died 64/1 Number relapsed (62) Number relapsed (55) Day 5 N= 1014 Day 3 N= 1008 Intention to treat analysis Number futher analyzed (879) Number futher analyzed (872) Per Protocol analysis Number improved (867) Number improved (854) Day 3 Followup Number cured (737) Number cured (735) Day 15 Follow-up Number resolved (799) Number resolved (790) Day 5 Followup

Summary Results: Per Protocol Analysis LFU+Protocol Violation +Combination Treatment failureRelapsed 3 days N= days N= days N=879 5 days N=872 3 days N=799 5 days N= ( ) 142 ( ) 80 (9.1%) 83 (9.5%) 62 (7.8%) 55 (7.0%)

Impact of treatment: Per protocol 0 day15 th day Difference Non-susceptible S. pneumoniae 5 day 59.6% (345/579) 69.8% (261/374) day 58.9% (337/572) 68.4% (277/405 ) 9.5 H. influenzae 5 day 44.0% (187/425) 64.5% (156/242) day 40.3% (183/454) 55.7% (146/262) 15.4

Conclusions Cotrimoxazole therapy for 3 and 5 days are equivalent. Treatment with cotrimoxazole increases the nonsusceptibility of NP carriage strains. Impact of treatment on carriage strains are similar in both the groups. As a whole, short course cotrimoxazole is effective in a population with high rate of in vitro cotrimoxazole non susceptible Spn and Hi.

COTRIMOXAZOLE STUDY GROUP MEMBERS CONSULTANTS Eric Simoes, MD. Shamim Qazi, WHO INDONESIA Cissy B. K Dwi Agustian Chrysanti Ni Sayu Dewi Maula Rifada Anglita Vidi Permatagalih Sri Yusnita BANGLADESH Samir K. Saha Nawshad M. Hanif M. Ruhulamin Billal Hossain Rafeza Khanam Tanima Sharmin Maksuda Islam Abdullah-Al-Mahin Masoodul Haque Shams-el Arifeen