ArticlesOral 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
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.
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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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2022, The Lancet Global HealthCitation Excerpt :The 2015 WHO guidelines further categorise young infants aged 0–59 days meeting the possible serious bacterial infection definition by severity, and provide treatment recommendations tailored to the severity level. Young infants aged at least 3 days with fast breathing as their only sign of illness—and thus considered to have the least severe disease—are recommended to receive oral antibiotic treatment in an outpatient setting, based on demonstrated effectiveness in this subgroup.16 Infants with clinical severe infection, which is the case definition most similar to the original 1996 of possible serious bacterial infection, are recommended to receive the simpler antibiotic regimens described above when referral is not feasible.