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EFFICACY OF SHORT COURSE EFFICACY OF SHORT COURSE AMOXICILLIN FOR NON-SEVERE AMOXICILLIN FOR NON-SEVERE

PNEUMONIA IN CHILDRENPNEUMONIA IN CHILDREN(Hazir T*, Latif E*, Qazi S** AND MASCOT (Hazir T*, Latif E*, Qazi S** AND MASCOT

Study Group) Study Group) *Children’s Hospital, Pakistan Institute of *Children’s Hospital, Pakistan Institute of Medical Sciences, Islamabad, Pakistan and Medical Sciences, Islamabad, Pakistan and

**WHO Geneva**WHO Geneva

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Efficacy of Short-Course Oral Amoxicillin Therapy for Non-Severe Pneumonia in Children

Hazir T, Latif E, Qazi S, and the Multicentre Amoxicillin Short Course Therapy (MASCOT) Pneumonia Study Group

Children Hospital, Pakistan Institute of Medical Sciences, Islamabad, Pakistan

Problem Statement: The optimal duration of therapy for most infections, especially acute respiratory infections, is not based on strong scientific evidence. Conventionally, antibiotics are used until the patient is afebrile or laboratory parameters are normal. Use of antibiotics contributes to development of antimicrobial resistance. If a shorter course is found to be effective for treatment of pneumonia, it would reduce the cost of treatment, enhance patient compliance, and contribute toward containment of antimicrobial resistance.

Objective: The clinical efficacy of three days versus five days of oral amoxicillin was compared for treatment of non-severe pneumonia in children.

Design: Multicenter, double blind, randomized, controlled trial.

Setting and Population: We recruited 1,953 children, aged 2–59 months, with non-severe pneumonia (World Health Organization criteria) diagnosed in the outpatient departments of seven hospitals in five cities of Pakistan.

Intervention: Patients were randomly assigned on a 1:1 basis to either three days or five days of amoxicillin therapy. Oral amoxicillin was given at doses of 15 mg/kg three times a day.

Outcome Measures: The primary outcome was treatment failure, which included change of antibiotic therapy or death.

Results: 980 children were randomized to three days and 973 to five days of amoxicillin therapy. Five days after enrollment, the treatment failure in the three-days group was 18.1%, compared to 16.5% in the five-days group. No significant differences were found in the two therapeutic groups. Chest radiographs were obtained in 1,847 children, of whom 259 had radiological pneumonia. Of the 475 nasopharangeal aspirates obtained, 99 were positive for respiratory syncytial virus. The treatment failure rate was higher in infants (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.12–1.18), those who had a respiratory rate of more than 60 breaths per minute (OR, 1.44; 95% CI, 1.01–2.06), and those who had been ill relatively longer before presentation (OR, 1.59; 95% CI, 1.20–2.11).

Conclusions: Three days’ duration of therapy with oral amoxicillin was as effective as five days of therapy for treatment of non-severe pneumonia in children 2–59 months old. Because of the high therapy failure rate in both groups, the treatment guidelines need to be reviewed.

Study Funding: World Health Organization, Geneva

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BACKGROUNDBACKGROUND

1.1. ARI is the leading cause of under 5 mortality in ARI is the leading cause of under 5 mortality in

the developing world.the developing world.

2.2. To reduce ARI mortality WHO introduced To reduce ARI mortality WHO introduced

standardised case management guidelines.standardised case management guidelines.

3.3. The duration of therapy for non-severe The duration of therapy for non-severe

pneumonia is 5 days. pneumonia is 5 days.

4.4. This recommendation is not based on strong This recommendation is not based on strong

scientific evidence.scientific evidence.

5. Shorter course antibiotic therapy for non-severe 5. Shorter course antibiotic therapy for non-severe

pneumonia would have many advantages:pneumonia would have many advantages:

a. Reduce the cost of treatmenta. Reduce the cost of treatment

b. Enhance patient compliance.b. Enhance patient compliance.

c. Contribute towards containment of c. Contribute towards containment of

antimicrobial antimicrobial

resistance.resistance.

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OBJECTIVESOBJECTIVES

Primary Objective:Primary Objective:

To compare the proportion of children 2-59 To compare the proportion of children 2-59

months of age presenting with non-severe months of age presenting with non-severe

pneumonia, who achieve clinical cure on day 6 pneumonia, who achieve clinical cure on day 6

with 3 day versus 5 day of oral amoxicillin with 3 day versus 5 day of oral amoxicillin

therapy.therapy.

Secondary Objectives:Secondary Objectives:

1.1. To assess the proportion of children who have To assess the proportion of children who have

nasopharyngeal aspirates positive for RSV at the nasopharyngeal aspirates positive for RSV at the

time of enrolment in 3 versus 5 days oral time of enrolment in 3 versus 5 days oral

amoxicillin therapy groups. amoxicillin therapy groups.

2. To compare the proportion of enrolled children 2. To compare the proportion of enrolled children

who are judged to be clinically cured at day 6 of who are judged to be clinically cured at day 6 of

enrolment, but relapse within the next 7 days of enrolment, but relapse within the next 7 days of

observation with 3 versus 5 days oral amoxicillin observation with 3 versus 5 days oral amoxicillin

therapy.therapy.

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SUBJECTS AND METHODSSUBJECTS AND METHODS

• Each of the study patients received two medicine Each of the study patients received two medicine

bottles, labeled ‘Green’ containing active drug for first bottles, labeled ‘Green’ containing active drug for first

3 days and ‘Red’ containing either placebo or active 3 days and ‘Red’ containing either placebo or active

drug for next 2 days.drug for next 2 days.

• Follow-ups were done on day 3, 6, and 14.Follow-ups were done on day 3, 6, and 14.

• Antibiotic was changed to oral Chloramphenicol in Antibiotic was changed to oral Chloramphenicol in

children who did not show improvement.children who did not show improvement.

• Children who showed deterioration at any stage were Children who showed deterioration at any stage were

admitted for injectable antibiotics.admitted for injectable antibiotics.

• All children were followed up by study physicians till All children were followed up by study physicians till

they were cured.they were cured.

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INCLUSION CRITERIAINCLUSION CRITERIA

• Age 2-59 months.Age 2-59 months.

• History of cough and/or difficult breathing.History of cough and/or difficult breathing.

• Diagnosis of WHO defined non - severe pneumonia:Diagnosis of WHO defined non - severe pneumonia:

Respiratory Rate Respiratory Rate >> 50/min (infants 2-11months). 50/min (infants 2-11months).

Respiratory rate Respiratory rate >> 40/min (children 12-59 months). 40/min (children 12-59 months).

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SAMPLE SIZESAMPLE SIZE

• Sample size was calculated to show a point estimate of Sample size was calculated to show a point estimate of

clinical failure rate.clinical failure rate.

• We assume the two modes of therapy to be equal, if the We assume the two modes of therapy to be equal, if the

failure rate between the two regimens is within 5%.failure rate between the two regimens is within 5%.

• For an alpha of 0.03 and a power of 90% the required For an alpha of 0.03 and a power of 90% the required

sample size was 845 in each group. sample size was 845 in each group.

• With inclusion of 15% loss to follow-up the total With inclusion of 15% loss to follow-up the total

estimated sample size was 1954.estimated sample size was 1954.

• A randomization scheme was developed at WHO, Geneva A randomization scheme was developed at WHO, Geneva

for each site using uneven blocks of 2, 4, 6 for both for each site using uneven blocks of 2, 4, 6 for both

groups in ratio of 1:1.groups in ratio of 1:1.

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TRIAL PROFILETRIAL PROFILEFigure: 1Figure: 1

Randomized Patients n = 1997

3 days = 999

5 days = 998

Excluded from

Analysis n = 19

Excluded from

Analysisn = 24

Incorrect enrolment = 3

Lost to Follow-up = 13

Therapy changed on their own = 3

Incorrect enrolment = 1

Lost to Follow-up = 19

Therapy changed on their own = 4

Analyzed n = 980

Analyzed n = 974

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RESULTSRESULTSn = 1954n = 1954

DEMOGRAPHIC INDICATORSDEMOGRAPHIC INDICATORS3 days3 days 5 days5 days n = 980n = 980 n = 974n = 974

MaleMale 628 (64.0%)628 (64.0%) 597 (61.2%)597 (61.2%)

Age (in months)Age (in months)

2 - 112 - 11 537 (54.7%)537 (54.7%) 515 515 (52.8%)(52.8%)

Median Median 6.006.00 5.005.00

12 – 5912 – 59 443 (45.3%)443 (45.3%) 459 (47.2%)459 (47.2%)

Median Median 21.0021.00 22.0022.00

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3 days3 daysn = 980n = 980

5 days5 daysn = 974n = 974

CoughCough

Difficult BreathingDifficult Breathing

FeverFever

VomitingVomiting

Diarrhoea Diarrhoea

WheezingWheezing

Mean Respiratory Mean Respiratory

raterate

Breast FeedingBreast Feeding

2 – 11 months 2 – 11 months

12 – 59 months12 – 59 months

970 (98.9%)970 (98.9%)

860 (87.7%) 860 (87.7%)

914 (93.2%)914 (93.2%)

140 (14.2%)140 (14.2%)

111 (11.3%)111 (11.3%)

211 (21.5%)211 (21.5%)

54.5 54.5 ++ 6.71 6.71

471/537 471/537

(87.7%)(87.7%)

124/443 124/443

(28.0%)(28.0%)

960 (98.5%)960 (98.5%)

848 (87.0%) 848 (87.0%)

920 (94.4%)920 (94.4%)

123 (12.6%)123 (12.6%)

110 (11.2%)110 (11.2%)

226 (23.2%)226 (23.2%)

54.2 54.2 ++ 6.75 6.75

465/515 465/515

(90.2%)(90.2%)

117/459 117/459

(25.4%)(25.4%)

RESULTSRESULTSn = 1954n = 1954

CLINICAL SIGNSCLINICAL SIGNS

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FINAL OUTCOMEFINAL OUTCOMEFigure: 2Figure: 2

3 days = 980

5 days = 974

Failure = 127

Resolved = 853

Failure = 116

Resolved = 858

Failure = 50

Resolved = 803

Failure = 45

Resolved = 812

Relapse = 12

Cured = 791

Relapse = 13

Cured = 799

  

* Day of enrollment taken as day 0

† ‡

i) Cured on Chloramphenicol = 63 i) Cured on Chloramphenicol = 50

ii) Cured on injectible antibiotics = 24 ii) Cured on injectible antibiotics = 23

iii) Cured on third generation cefixime = 36 iii) Cured on third generation cefixime = 43

iv) Lost to follow-up = 4 iv) Lost to follow-up = 0

* *

† ‡

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3 DAYS

n = 980

5 DAYS

n = 974p-value

Treatment

success

Failure on day 3

Failure on day 5

Relapse on day 14

Death

791 (81.0%)

127 (12.9%)

50 (5.1%)

12 (1.2%)

799 (82.0%)

116 (11.9%)

45 (4.6%)

13 (1.3%)

1 (0.10%)

0.83

0.58

0.71

0.98

RESULTSRESULTSn = 1954n = 1954

FINAL OUTCOMEFINAL OUTCOME

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CONCLUSIONCONCLUSION

Oral amoxicillin for 3 days is as effective clinicallyOral amoxicillin for 3 days is as effective clinically

as 5 days in the treatment of children 2-59 months old as 5 days in the treatment of children 2-59 months old

suffering from non severe pneumonia.suffering from non severe pneumonia.

1. Similar multi-centre trials replicated in India, 1. Similar multi-centre trials replicated in India,

Bangladesh and Indonesia show same results. Bangladesh and Indonesia show same results.

2. WHO guidelines for the duration of treatment of 2. WHO guidelines for the duration of treatment of

non-severe pneumonia should be changed to 3 non-severe pneumonia should be changed to 3

instead of 5 days.instead of 5 days.

3. The causes of high treatment failure in non-3. The causes of high treatment failure in non-

severe pneumonia should be studied in greater severe pneumonia should be studied in greater

detail. detail.

4. There is a need to carry out etiological studies in 4. There is a need to carry out etiological studies in

non-severe pneumonia.non-severe pneumonia.

RECOMMENDATIONSRECOMMENDATIONS