Three days vs five days oral cotrimoxazole therapy

  • Slides: 22
Download presentation
Three days vs five days oral cotrimoxazole therapy in non -severe pneumonia Samir K.

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

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

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

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

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

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

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

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

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)

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. •

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

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

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

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.

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

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

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

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: S. pneumoniae

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

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

COTRIMOXAZOLE STUDY GROUP MEMBERS INDONESIA • • Cissy B. K Dwi Agustian Chrysanti Ni

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