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, 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.

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

• 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 – 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

X X

X X X

X X X

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.

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

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

5 days (n=852)

3 days (n=851)

MaleAge (in months) 2 – 11 Median 12 – 59 MedianDuration of illnessCough Difficult BreathingFeverVomitingDiarrhoea Breast Feeding 2 – 11 months 12 – 59 monthsWheezingMean Respiratory rate

520 (51.28)

472 (46.55)6.00

542 (53.5%)19.50

31006

(99.21%)551 (54.34%) 870 (85.80)

338 (33.33%)163 (16.07%)

325 (83.8%)334 (72.0%)171 (16.86%)54.21 + 6.71

547 (54.27)

493 (48.91)6.00

515 (51.0920.00

31002

(99.40%)553 (54.86%) 860 (85.32%)315(31.25%)133 (13.19%)

341(83.2%)301 (68.3%)200 (19.84%)54.37 + 6.83

p= 0.2881

p= 0.2881

p= 0.389p= 0.5995 p= 0.8137p= 0.7582p= 0.0670

p=0.8809p=0.8809p=0.5583

p= 0.595

Demographic Indicators and Clinical Signs

Number randomized (2022)

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)

Number failed therapy/died12/0 

Number failed therapy/died

18/0

Number failed therapy/died68/0

Number failed therapy/died

64/1

Number relapsed(62)

Number relapsed(55)

Day 5N= 1014

Day 3N= 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 failure Relapsed

3 days

N=1008

5 days

N=1014

3 days

N=879

5 days

N=872

3 days

N=799

5 days

N=790

129

(63+44+22)

142

(82+44+16)

80

(9.1%)

83

(9.5%)

62 (7.8%)

55

(7.0%)

Impact of treatment on carriage organisms

0 day 15th day Difference

Non-susceptible 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

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- .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

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 0.01-33.0

Median 0.250

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

52

54

56

58

60

62

64

66

68

70

72

5 days 3 days

Treatment Group

No.

of

non-

susc

epti

ble

case

s

0 day

15 day

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

0

10

20

30

40

50

60

70

5 days 3 daysTreatment Group

No.

of

non-

susc

epti

ble

case

s

0 day

15 day

COTRIMOXAZOLE STUDY GROUP MEMBERS

CONSULTANTSEric 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