Oral amoxicillin versus benzyl penicillin for severe pneumonia among kenyan children: a pragmatic randomized controlled noninferiority trial

Abstract

Background: There are concerns that the evidence from studies showing noninferiority of oral amoxicillin to benzyl penicillin for severe pneumonia may not be generalizable to high-mortality settings.

Methods: An open-label, multicenter, randomized controlled noninferiority trial was conducted at 6 Kenyan hospitals. Eligible children aged 2-59 months were randomized to receive amoxicillin or benzyl penicillin and followed up for the primary outcome of treatment failure at 48 hours. A noninferiority margin of risk difference between amoxicillin and benzyl penicillin groups was prespecified at 7%.

Results: We recruited 527 children, including 302 (57.3%) with comorbidity. Treatment failure was observed in 20 of 260 (7.7%) and 21 of 261 (8.0%) of patients in the amoxicillin and benzyl penicillin arms, respectively (risk difference, -0.3% [95% confidence interval, -5.0% to 4.3%]) in per-protocol analyses. These findings were supported by the results of intention-to-treat analyses. Treatment failure by day 5 postenrollment was 11.4% and 11.0% and rising to 13.5% and 16.8% by day 14 in the amoxicillin vs benzyl penicillin groups, respectively. The most frequent cause of cumulative treatment failure at day 14 was clinical deterioration within 48 hours of enrollment (33/59 [55.9%]). Four patients died (overall mortality 0.8%) during the study, 3 of whom were allocated to the benzyl penicillin group. The presence of wheeze was independently associated with less frequent treatment failure.

Conclusions: Our findings confirm noninferiority of amoxicillin to benzyl penicillin, provide estimates of risk of treatment failure in Kenya, and offer important additional evidence for policy making in sub-Saharan Africa.

Clinical trial registration: NCT01399723.

Keywords: World Health Organization; amoxicillin; childhood pneumonia; sub-Saharan Africa; treatment failure.

Figure 1.

Kenyan Ministry of Health classification of pneumonia for children aged 2–59 months with cough and/or difficulty breathing (without stridor, severe malnutrition, or signs of meningitis). Abbreviation: RR, respiratory rate.

Figure 2.

Criteria for treatment failure. Abbreviation: bpm, breaths per minute.

Figure 3.

Screening allocation and follow-up of study participants.

Figure 4.

Intention-to-treat and per-protocol analyses for treatment failure at 48 hours.

Figure 5.

Outcome of recruited patients on day 14 postenrollment.