Elsevier

The Lancet

Volume 385, Issue 9979, 2–8 May 2015, Pages 1758-1766
The Lancet

Articles
Oral amoxicillin compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with fast breathing when referral is not possible: a randomised, open-label, equivalence trial

https://doi.org/10.1016/S0140-6736(14)62285-6Get rights and content

Summary

Background

WHO recommends referral to hospital for possible serious bacterial infection in young infants aged 0–59 days. We aimed to assess whether oral amoxicillin treatment for fast breathing, in the absence of other signs, is as efficacious as the combination of injectable procaine benzylpenicillin–gentamicin.

Methods

In a randomised, open-label, equivalence trial at five sites in DR Congo, Kenya, and Nigeria, community health workers followed up all births in the community, identified unwell young infants, and referred them to study nurses. We randomly assigned infants with fast breathing as a single sign of illness or possible serious bacterial infection, whose parents did not accept referral to hospital, to receive either injectable procaine benzylpenicillin–gentamicin once per day or oral amoxicillin treatment twice per day for 7 days. A person who was off-site generated randomisation lists using computer software. Trained health professionals gave injections, but outcome assessors were masked to group allocations. The primary outcome was treatment failure by day 8 after enrolment, defined as clinical deterioration, development of a serious adverse event including death, persistence of fast breathing on day 4, or recurrence up to day 8. The primary analysis was per protocol and we used a prespecified similarity margin of 5% to assess equivalence between regimens. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000286044.

Findings

From April 4, 2011, to March 29, 2013, we enrolled 2333 infants aged 0–59 days with fast breathing as the only sign of possible serious bacterial infection at the five study sites. We assigned 1170 infants to receive injectable procaine benzylpenicillin–gentamicin and 1163 infants to receive oral amoxicillin. In the per-protocol analysis, from which 137 infants were excluded, we included 1061 (91%) infants who fulfilled predefined criteria of adherence to treatment and adequate follow-up in the injectable procaine benzylpenicillin–gentamicin group and 1145 (98%) infants in the oral amoxicillin group. In the procaine benzylpenicillin–gentamicin group, 234 infants (22%) failed treatment, compared with 221 (19%) infants in the oral amoxicillin group (risk difference −2·6%, 95% CI −6·0 to 0·8). Four infants died within 15 days of follow-up in each group. We detected no drug-related serious adverse events.

Interpretation

Young infants with fast breathing alone can be effectively treated with oral amoxicillin on an outpatient basis when referral to a hospital is not possible.

Funding

Bill & Melinda Gates Foundation grant to WHO.

Introduction

Together, pneumonia, sepsis, and meningitis cause about 700 000 deaths in neonates every year.1 Differentiation of these conditions on the basis of clinical presentation is difficult, so WHO recommends referral to hospital for neonates and young infants aged 1 month or older with clinical signs of possible serious bacterial infection, including fever (≥37·5°C), low body temperature (≤35·5°C), fast breathing (≥60 breaths per min), severe chest indrawing, inability to feed well, convulsions, and movement only when stimulated or no movement at all.2 The recommended hospital treatment consists of intramuscular or intravenous antibiotic therapy with a combination of gentamicin and benzylpenicillin or ampicillin for at least 7–10 days.3 In many low-income and middle-income countries, such treatment might only be available at tertiary care hospitals and access to such treatment is limited by transportation, financial, or cultural reasons. Even when these constraints have been addressed in previous studies, a substantial proportion of families (60%) still refuse referral to hospital for young infants with possible serious bacterial infection.4, 5, 6

Of the signs of possible serious bacterial infection, fast breathing, which suggests pneumonia, is one of the most common, but probably least severe sign.7 Fast breathing is associated with a lower risk of death in neonates and young infants than are other more serious signs, such as lethargy or unconsciousness, convulsions, inability to feed well, hypothermia, and chest indrawing.8, 9, 10 A meta-analysis11 of four studies in Asia and one in Africa showed that community-based oral antibiotic treatment for neonates and young infants with fast breathing reduces neonatal and infant mortality. However, oral antibiotics to treat fast breathing in young infants have not been directly compared with injectable antibiotics in randomised controlled trials in neonates and young infants.11, 12, 13 We aimed to test the hypothesis that an oral antibiotic regimen is as safe and effective as treatment with intramuscular antibiotics for treatment of neonates and young infants with fast breathing, by doing a trial in three African countries. The results of this trial, the AFRINEST study, will inform policy for the management of fast breathing in neonates and young infants in Africa and worldwide.

Section snippets

Study design

The methods of this study have been described in detail previously.14, 15 The study was an individually randomised, multicentre, open-label, community-based equivalence trial, in which all sites followed the same protocol and contributed to the overall results. We did the study at five sites: one each in DR Congo and Kenya, and three in Nigeria (Ibadan, Ile-Ife, and Zaria sites). The sites in Kenya and DR Congo were both rural and had similar models of care, whereby a lay community health

Results

At the five study sites, from April 4, 2011, to March 29, 2013, we enrolled 2333 infants aged 0–59 days with fast breathing as the only sign of possible serious bacterial infection (figure 1). We assigned 1170 infants to receive injectable procaine benzylpenicillin–gentamicin and 1163 infants to receive oral amoxicillin. The two groups had similar baseline characteristics (table 1). 882 (38%) infants were younger than 7 days. 183 (8%) infants had weight for age Z scores of −2 or less. Most

Discussion

We report that, for the treatment of neonates and young infants with fast breathing alone, oral amoxicillin twice per day for 7 days is as effective as intramuscular procaine benzylpenicillin plus gentamicin once per day for 7 days. The most common reason for treatment failure in both groups was persistent fast breathing at day 4. Very few enrolled infants died, and we saw no serious adverse effects deemed to be related to the study treatment. Fast breathing alone represents a mild form of the

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