Transcript 708-El-Sayed-_b

Assessment of the Effectiveness and Safety of
Outpatient Treatment of Severe Pneumonia Among
Egyptian Children with Oral Amoxicillin
(MASS Study - Egypt Chapter)
Third International Conference for Improving Use of
Medicines “ICIUM 2011”
Antalya, Turkey, November 14-18th, 2011
Hesham El-Sayed,
Narendra Arora, & Ahmed El-Gohary
Faculty of Medicine
Suez Canal University, Egypt
Study Rationale
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Two million children <5Y die each year from ARI.
ARI are the major cause of OP and Emergency
Department visits and hospital admissions.
Standard ARI case management [IMCI] recommends
hospitalization of patients with sever pneumonia
(chest indrawing & rapid breathing).
APPIS study reported equivalent response of
pneumonia patients to oral amoxicillin compared to
injectable penicillin (Addo-Uobo et al, 2004).
Pharmacokinetics study showed that amoxicillin twice
daily is feasible alternative to thrice-daily dosing &
recommended by American Academy of Pediatrics
(Fonseca et al, 2003)
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Study Objectives
To assess the effectiveness and safety of
home-based, 5-day treatment with oral
amoxicillin, for curing severe pneumonia
in children
 To identify baseline clinical predictors of
treatment failure in children with severe
pneumonia
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Study Area & Population
Ismailia governorate,
Egypt, with population
of one million
inhabitants
 Seven primary health
care centers
 Children presenting to
the outpatient clinics
of participating centers
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Other study sites:
(Bangladesh, Ghana, and Vietnam)
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Ismailia
Inclusion Criteria
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Children aged 3 to 59 months.
Patients suffering from Severe
pneumonia, defined as lower chest
indrawing (LCI) with cough and/or
difficult breathing.
Patients who are able to drink and do
not have central cyanosis, regardless of
the respiratory rate.
Informed consent by a legal guardian
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Exclusion Criteria (a)
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Very severe pneumonia/disease
(central cyanosis, abnormally sleepy or difficult to wake,
inability to drink, or convulsions)
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Known prior episodes of asthma or three
or more prior episodes of wheezing
LCI that resolves after three doses of
bronchodilator therapy
Severe malnutrition (visible severe wasting
or edema)
Known anaphylactic reaction to penicillin or
amoxicillin
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Exclusion Criteria (b)
6. Hospitalization in the last two weeks
7. Other diseases requiring antibiotic therapy
at presentation (e.g., meningitis, dysentery,
osteomyelitis, evident tuberculosis, etc.)
8. Persistent vomiting (vomiting three repeated doses
of oral amoxicillin within ½ hour of administration).
9. Previous inclusion in the study or already
included in another study
10. Living outside the pre-defined study area
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Study Design
A single-arm, cohort prospective
intervention study
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Baseline Assessment
Demographic data
 History of the present illness
◦ The use of antibiotics
◦ The use of bronchodilators
◦ Immunization status
◦ Breast-feeding
 Physical examination that included:
◦ Respiratory rate
◦ Lower chest indrawing.
◦ Auscultatory wheezing, crackles (unilateral or
bilateral), bronchial breathing, diminished or
absent breath sounds.
 Urine Antibacterial Activity
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Ambulatory Management
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Assessing eligibility for enrollment in the study
Amoxicillin provided as suspension in a total dose of
80-90mg/kg per day for 5 days in 12 hourly doses
The first dose administered by the caretaker under
supervision in the health facility
No other antibiotics were allowed while the child
enrolled in the study
Study patients who require additional antibiotics
subsequent to enrollment, were declared treatment
failures and withdrawn from the study, but follow-up
of these patients continued until resolution of the
morbid episode.
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INTERVENTIONS
Patient assessment data were collected on standard data
collection forms at enrollment and Day 14 in the health
centers by physicians, and at days 1,2,3,6 at home by
trained nurse.
 Collected data included clinical assessment, adherence to
therapy and adverse events occurrence.
 If the patient was well on Day 14, the patient was deemed
cured and no further follow-up was done.
 Children who did not show up for their clinic appointment
on Day 14 were actively traced for evaluation at home.
 If the patient is unwell at any time during the 14 days the
patient was managed according to the standard clinic or
hospital practices.
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Study Outcome (a)
Clinical deterioration occurring at any
time after enrollment.
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(Developing any sign of very severe disease such as
central cyanosis, abnormally sleepy or difficult to wake,
inability to drink, convulsions, or death)
Inability to take oral medication due to
persistent vomiting.
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(Vomiting three repeated doses of oral amoxicillin
within ½ hour of administration)
Change or addition of antibiotics due to:
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Developing a co-morbid condition.
Persistence of fever > 38oC with lower chest
indrawing on day 3 (after 72 hours).
Either Fever or lower chest indrawing alone at day 6.
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Study Outcome (b)
4. Hospitalization related to pneumonia or
therapy with amoxicillin.
5. Serious adverse event considered possibly
or probably related to amoxicillin
6. Loss to follow up
7. Treatment failure between day 6 and 14
(relapse)
8.Voluntary withdrawal of consent from the
study
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STUDY RESULTS
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Study Results
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The study included 237 children (3-59 mo.)
Mean age of recruited children (12.42+10.05)
months.
Over 95% of children adhered to the treatment
Clinical Cure rate with 5 days Amoxicillin
therapy at Day 6 was 90.7%.
Relapses occurred in 3.4% of the patients at
Day 14, with Clinical Cure rate of 87.3%
Loss to follow up of 3 patients (1.3%), 3
hospitalizations (1.3%) and no deaths
Adverse events occurred in 14 children (5.9%)
in the form of mild diarrhea and/or vomiting
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Failure Rate of Treated Patients
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Comparison of Baseline Characteristics of
Cured vs. failed Treated Patients at Day 6
Characteristic Cured at Day 6 Failure at Day 6
-Age (months)
12.81+10.45
13.73+6.34
-Weight (Kg.)
9.47+4.86
7.86+2.33 *
-Length (Cm.)
71.26+10.91
67.88+10.79
-Temperature ©
37.56+1.34
37.66+0.51
-Respiratory rate
49.62+9.99
58.98+8.74 *
(per minute)
* Statistically Significant Difference (P <0.05)
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Comparison of Clinical Baseline Characteristics
of Cured vs. failed
Treated Patients at Day 6
Clinical Finding Cured at Day 6 Failure at Day 6
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Fever
Cough
Difficult breathing
Vomiting
Diarrhea
74.9%
96.7%
62.3%
15.3%
5.6%
63.3%
95.5%
63.6%
13.6%
9.1%
N.B.: No statistical difference between the two groups
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Conclusions
Oral amoxicillin is effective and safe in treating
pneumonia in children in ambulatory setting,
when given for 5 days in a dose of 80-90
mg/kg/day in 2 divided doses.
 Minor adverse effects occurred in small
proportion of treated patients and did not
affect cure rate.
 Failure of therapy occurred more frequently in
patients of low weight and in those with rapid
respiratory rate (>50/minute) at recruitment.
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Potential Study Limitations
It is an observational study, which did not have control arm
to compare outcomes, however we compared our findings
with prior studies conducted with similar protocols.
 We must be cautious in treating these children as they do
need to be monitored for clinical deterioration through
follow-up visits.
 We could only test 42% of patients’ urine for antibacterial
activity that decreased our power to assess the effect that
prior antibiotic use had on treatment failure
 The multicenter study did not include any area with high
HIV prevalence or any sites from Latin America, where the
population characteristics or disease ecology may differ
from the included study sites, which may effect
generalizability of our results.
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Mutlicenter Study Strengths
Large sample size provided good precision to our estimates
of treatment failure rates
 The diversity of geographic settings, study implementation
staff and prevalence of co-morbid conditions demonstrates
that home-based therapy is applicable to a variety of public
health settings
 Over 95% of children adhered to the treatment, while
fewer than 5% of subjects were lost to follow-up.
 There were no deaths, and none had a serious adverse
event related to study drug
 The study findings have important policy and programmatic
implications for the treatment of pneumonia by reducing
hospital referrals and admissions, which will reduce health
care costs and hospital-acquired infections
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Acknowledgement
The study was supported by grant from
INCLEN Inc., USAID,
Johns Hopkins University
& WHO Technical support
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