Three days vs five days oral cotrimoxazole therapy
- Slides: 22
Three days vs five days oral cotrimoxazole therapy in non -severe pneumonia 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, Placebocontrolled 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.
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.
Screening of Patients • Exclusion criteria • Inclusion criteria – Age 2 -59 months – WHO defined non -severe pneumonia with or without wheezing. – Consent given – 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 X X X • Two bottles for each patients • Blue cap – 1 st three days – Contained cotrimoxazole – 1 st dose given at health care – The cup was marked for the respective patient • to prevent possible mistakes. • White Cap – Last two days X X – Contained either • contrimoxazole (5 days group) or placebo (3 days group).
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 • 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 10 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 • 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
Demographic Indicators and Clinical Signs 5 days (n=852) 3 days (n=851) Male Age (in months) 2 – 11 Median 12 – 59 Median Duration of illness Cough Difficult Breathing Fever Vomiting Diarrhoea Breast Feeding 2 – 11 months 12 – 59 months Wheezing Mean Respiratory 520 (51. 28) 547 (54. 27) 472 (46. 55) 493 (48. 91) 6. 00 542 (53. 5%) 515 (51. 09 19. 50 20. 00 3 3 1006 (99. 21%) 1002 (99. 40%) 551 (54. 34%) 553 (54. 86%) 870 (85. 80) 860 (85. 32%) 338 (33. 33%) 315(31. 25%) 163 (16. 07%) 133 (13. 19%) p= 0. 2881 325 (83. 8%) 334 (72. 0%) 171 (16. 86%) 54. 21 + 6. 71 p=0. 8809 p=0. 5583 p= 0. 595 341(83. 2%) 301 (68. 3%) 200 (19. 84%) 54. 37 + 6. 83 p= 0. 2881 p= 0. 389 p= 0. 5995 p= 0. 8137 p= 0. 7582 p= 0. 0670
Number randomized (2022) Day 5 N= 1014 Number excluded : - Lost to follow up D 5 (LFU) (82) - Protocol violation (PV) (44) - Combination LFU and PV ( 16) Day 3 Followup Number futher analyzed (872) Day 3 N= 1008 Number excluded : - Lost to follow up D 5 (LFU) (63) - Protocol violation (PV) (44) Combination LFU and PV (22) Number futher analyzed (879) 18/0 Number improved (854) Number improved (867) Number failed therapy/died 68/0 64/1 Day 15 Follow-up Per Protocol analysis Number failed therapy/died 12/0 Number failed therapy/died Day 5 Followup Intention to treat analysis Number resolved (790) Number resolved (799) Number relapsed (55) Number relapsed (62) Number cured (735) Number cured (737)
Summary Results: Per Protocol Analysis LFU+Protocol Violation +Combination 3 days 5 days N=1008 N=1014 129 142 (63+44+22) (82+44+16) Treatment failure Relapsed 3 days N=879 80 (9. 1%) 5 days 3 days 5 days N=872 N=799 N=790 83 62 55 (9. 5%) (7. 8%) (7. 0%)
Impact of treatment on carriage organisms 0 day 15 th day Difference Non-susceptible S. 5 day 59. 6% (345/579) 69. 8% (261/374) 10. 2 pneumoniae 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
Impact of in vitro resistance on nasal carriage eradication. S. pneumoniae Non. Susceptible MIC Values susceptible µg/ml Eradicated 46. 9% 0 day+; 15 day-- 323/688 53. 2% Persisted? ** 38. 5% 0 day+; 15 day+ 265/688 46. 8% 324/609 285/609 Range-. 030 -33. 0 Median- 0. 750 Range-. 050 -33. 0 Median- 0. 50 **100 pairs (persisted) strains were serotyped 85 were found to be identical.
Impact of in vitro resistance on nasal carriage eradication. H. influenzae Non. Susceptible MIC values susceptible µg/ml Eradicated 58. 4% 0 day+; 15 day-- 251/430 61. 2% 347/567 Range 0. 01 -33. 0 Median 0. 250 Persisted? 41. 6% 0 day+; 15 day+ 179/430 38. 8% 220/567 Range 0. 01 -33. 0 Median 0. 250
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.
Impact of treatment on nasal isolates perprotocol cases: S. pneumoniae
Impact of treatment on nasal isolates perprotocol cases: H. influenzae
COTRIMOXAZOLE STUDY GROUP MEMBERS INDONESIA • • Cissy B. K Dwi Agustian Chrysanti Ni Sayu Dewi Maula Rifada Anglita Vidi Permatagalih Sri Yusnita CONSULTANTS Eric Simoes, MD. Shamim Qazi, WHO 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
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