Randomized Trial of Amoxicillin for Pneumonia in Pakistan
Fyezah Jehan1, Imran Nisar1, Salima Kerai1
1From Aga Khan University, Karachi, Pakistan (F.J., I.N., S.K., B.B., N.B., N.R., A.R., Y.S., A.K.M.Z.); Uppsala University, Uppsala, Sweden (N.B.); and the Bill and Melinda Gates Foundation, Seattle (A.K.M.Z.).
Insights
In children with pneumonia, amoxicillin treatment showed a lower failure rate than placebo. However, the difference did not meet the noninferiority margin, suggesting placebo may be a viable alternative.
Area of Science:
- Pediatric infectious diseases
- Clinical trial methodology
- Global health research
Background:
- The World Health Organization (WHO) recommends amoxicillin for pediatric pneumonia with tachypnea.
- Emerging trial data suggest that withholding amoxicillin may be noninferior to its use in treating this condition.
Purpose of the Study:
- To evaluate the noninferiority of a placebo regimen compared to amoxicillin for treating nonsevere pneumonia with tachypnea in children.
- To assess treatment failure rates in a randomized, double-blind, placebo-controlled trial.
Main Methods:
- A double-blind, randomized, placebo-controlled noninferiority trial was conducted in Karachi, Pakistan.
- 4002 children aged 2-59 months with WHO-defined nonsevere pneumonia and tachypnea were randomized to a 3-day course of amoxicillin or placebo.
- The primary outcome was treatment failure during the 3-day course, with a noninferiority margin of 1.75 percentage points.
Main Results:
- Treatment failure occurred in 4.9% of the placebo group and 2.6% of the amoxicillin group (difference: 2.3 percentage points).
- The between-group difference in treatment failure did not meet the prespecified noninferiority margin for placebo.
- Fever and wheeze were predictors of treatment failure; relapse rates were similar between groups.
Conclusions:
- In children under 5 with nonsevere pneumonia, the placebo group had a higher frequency of treatment failure than the amoxicillin group.
- The observed difference did not meet the noninferiority margin, indicating amoxicillin remains the recommended treatment.
- This study provides crucial data for refining treatment guidelines for pediatric pneumonia in low-resource settings.
Background:
The World Health Organization (WHO) recommends oral amoxicillin for patients who have pneumonia with tachypnea, yet trial data indicate that not using amoxicillin to treat this condition may be noninferior to using amoxicillin.
Methods:
We conducted a double-blind, randomized, placebo-controlled noninferiority trial involving children at primary health care centers in low-income communities in Karachi, Pakistan. Children who were 2 to 59 months of age and who met WHO criteria for nonsevere pneumonia with tachypnea were randomly assigned to a 3-day course of a suspension of amoxicillin (the active control) of 50 mg per milliliter or matched volume of placebo (the test regimen), according to WHO weight bands (500 mg every 12 hours for a weight of 4 to <10 kg, 1000 mg every 12 hours for a weight of 10 to <14 kg, or 1500 mg every 12 hours for a weight of 14 to <20 kg). The primary outcome was treatment failure during the 3-day course of amoxicillin or placebo. The prespecified noninferiority margin was 1.75 percentage points.
Results:
From November 9, 2014, through November 30, 2017, a total of 4002 children underwent randomization (1999 in the placebo group and 2003 in the amoxicillin group). In the per-protocol analysis, the incidence of treatment failure was 4.9% among placebo recipients (95 of 1927 children) and 2.6% among amoxicillin recipients (51 of 1929 children) (between-group difference, 2.3 percentage points; 95% confidence interval [CI], 0.9 to 3.7). Results were similar in the intention-to-treat analysis. The presence of fever and wheeze predicted treatment failure. The number needed to treat to prevent one treatment failure was 44 (95% CI, 31 to 80). One patient (<0.1%) in each group died. Relapse occurred in 40 children (2.2%) in the placebo group and in 58 children (3.1%) in the amoxicillin group.
Conclusions:
Among children younger than 5 years of age with nonsevere pneumonia, the frequency of treatment failure was higher in the placebo group than in the amoxicillin group, a difference that did not meet the noninferiority margin for placebo. (Funded by the Joint Global Health Trials Scheme [of the Department for International Development, Medical Research Council, and Wellcome] and others; RETAPP ClinicalTrials.gov number, NCT02372461.).
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