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

Ambrose Agweyu, David Gathara, Jacquie Oliwa, Naomi Muinga, Tansy Edwards, Elizabeth Allen, Elizabeth Maleche-Obimbo, Mike English, Severe Pneumonia Study Group, Florence Aweyo, Bernard Awuonda, Martin Chabi, Newton Isika, Mary Kariuki, Magdalene Kuria, Polycarp Mandi, Leah Masibo, Thaddeus Massawa, Wycliffe Mogoa, Beatrice Mutai, Gatwiri Muriithi, Samuel Ng'arng'ar, Rachel Nyamai, Dorothy Okello, Wilson Oywer, Lordin Wanjala, Ambrose Agweyu, David Gathara, Jacquie Oliwa, Naomi Muinga, Tansy Edwards, Elizabeth Allen, Elizabeth Maleche-Obimbo, Mike English, Severe Pneumonia Study Group, Florence Aweyo, Bernard Awuonda, Martin Chabi, Newton Isika, Mary Kariuki, Magdalene Kuria, Polycarp Mandi, Leah Masibo, Thaddeus Massawa, Wycliffe Mogoa, Beatrice Mutai, Gatwiri Muriithi, Samuel Ng'arng'ar, Rachel Nyamai, Dorothy Okello, Wilson Oywer, Lordin Wanjala

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.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Figures

Figure 1.
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.
Figure 2.
Criteria for treatment failure. Abbreviation: bpm, breaths per minute.
Figure 3.
Figure 3.
Screening allocation and follow-up of study participants.
Figure 4.
Figure 4.
Intention-to-treat and per-protocol analyses for treatment failure at 48 hours.
Figure 5.
Figure 5.
Outcome of recruited patients on day 14 postenrollment.

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Source: PubMed

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