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

2. 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.

3. 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.

4. Study design
Double blind, Randomized, Placebo-controlled equivalence trial.
Study was conducted from July 2001 to May 2003.
Ethical clearance was obtained from the ERC of Bangladesh Institute of Child Health and Hasan Sadikin General Hospital.

5. Sample Size Calculation
Sample size was calculated to compare the clinical failure and/or success in two treatment groups.
Expecting 12% treatment failure rate in 5 days group.
Based on previous finding of 9-13% failure
With a sample size of 887 in each group calculated to give 90% power to reject the null hypothesis: 3 day and 5-day treatment are not equal.

6. Screening of Patients Exclusion criteria Inclusion 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
Inclusion criteria
Age 2-59 months
WHO defined non-severe pneumonia with or without wheezing.
Consent given

7. 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.

8. Study Medicine Two bottles for each patients Blue cap – 1st three days
Contained cotrimoxazole
1st dose given at health care
The cup was marked for the respective patient
to prevent possible mistakes.
White Cap – Last two days
Contained either
contrimoxazole (5 days group) or placebo (3 days group). X X

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

10. Outcome of treatment
Treatment failure on day 3 (any two of the following)
RR is not reduced by 5
Temp not reduced by 10C
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

11. Analysis
Study Population: 2022 under five non severe pneumonia cases were enrolled.
Data were entered in duplicate and verified in EPI Info 6.
Final analysis was done using EPI Info 6 and SPSS 11.0

12. Demographic Indicators and Clinical Signs
5 days (n=852)
3 days (n=851)
Male
Age (in months)
2 – 11
Median
12 – 59
Duration of illness
Cough
Difficult Breathing
Fever
Vomiting
Diarrhoea
Breast Feeding
2 – 11 months
12 – 59 months
Wheezing
Mean Respiratory rate
520 (51.28)
472 (46.55)
6.00
542 (53.5%)
19.50 3
1006 (99.21%)
551 (54.34%)
870 (85.80)
338 (33.33%)
163 (16.07%)
325 (83.8%)
334 (72.0%)
171 (16.86%)
547 (54.27)
493 (48.91)
515 (51.09
20.00
1002 (99.40%)
553 (54.86%)
860 (85.32%)
315(31.25%)
133 (13.19%)
341(83.2%)
301 (68.3%)
200 (19.84%) p=
p= 0.389 p= p= p= p=
p=0.8809
p=0.5583
p= 0.595

13. 18/0 64/1 Number randomized (2022) Day 5 N= 1014 Day 3 N= 1008
Intention to treat analysis
Number excluded :
-          Lost to follow up D5 (LFU) (82)
-          Protocol violation (PV) (44)
-          Combination LFU and PV ( 16)
Number excluded :
-        Lost to follow up D5 (LFU) (63)
-        Protocol violation (PV) (44)
Combination LFU and PV (22)
Day 3 Followup
Number futher analyzed
(872)
Number futher analyzed
(879)
Per Protocol analysis
Number failed therapy/died
18/0
Number failed therapy/died
12/0
Day 5 Followup
Number improved
(854)
Number improved
(867)
Number failed therapy/died
64/1
Number failed therapy/died
68/0
Day 15 Follow-up
Number resolved
(790)
Number resolved
(799)
Number relapsed
(55)
Number relapsed
(62)
Number cured
(735)
Number cured
(737)

14. Summary Results: Per Protocol Analysis
LFU+Protocol Violation +Combination
Treatment failure
Relapsed
3 days
N=1008
5 days
N=1014
N=879
N=872
N=799
N=790
129
( )
142
( ) 80
(9.1%) 83
(9.5%)
62 (7.8%) 55
(7.0%)

15. Impact of treatment on carriage organisms
0 day
15th day
Difference
Non-susceptible S.
pneumoniae
5 day
59.6% (345/579)
69.8% (261/374)
10.2
3 day
58.9% (337/572)
68.4% (277/405)
9.5 H.
influenzae
5 day
44.0% (187/425)
64.5% (156/242)
20.5
3 day
40.3% (183/454)
55.7% (146/262)
15.4

16. Impact of in vitro resistance on nasal carriage eradication.
S. pneumoniae
Eradicated
0 day+; 15 day--
Persisted?**
0 day+; 15 day+
Non-susceptible
Susceptible
46.9%
323/688
53.2%
324/609
38.5%
265/688
46.8%
285/609
MIC Values
µg/ml
Range
Median
Range
Median- 0.50
**100 pairs (persisted) strains were serotyped 85 were found to be identical.

17. Impact of in vitro resistance on nasal carriage eradication.
H. influenzae
Non-susceptible
Susceptible
Eradicated
0 day+; 15 day--
58.4%
251/430
61.2%
347/567
Persisted?
0 day+; 15 day+
41.6%
179/430
38.8%
220/567
MIC values
µg/ml
Range
Median 0.250

18. 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 is proportionate with the duration of therapy.
As a whole, short course cotrimoxazole is effective in a population with high rate of in vitro non susceptible Spn and Hi with reduced impact on carriage strains.

20. Impact of treatment on nasal isolates perprotocol cases: S. pneumoniae

21. Impact of treatment on nasal isolates perprotocol cases: H. influenzae

22. INDONESIA BANGLADESH CONSULTANTS Eric Simoes, MD. Shamim Qazi, WHO
COTRIMOXAZOLE STUDY GROUP MEMBERS
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
CONSULTANTS
Eric Simoes, MD.
Shamim Qazi, WHO