Background

Parenteral antibiotic therapy for young infants (aged 0–59 days) with suspected sepsis is sometimes not available or feasible in countries with high neonatal mortality. Outpatient treatment could save lives in such settings. We aimed to assess the equivalence of two simplified antibiotic regimens, comprising fewer injections and oral rather than parenteral administration, compared with a reference treatment for young infants with clinical severe infection.

Methods

We undertook the Simplified Antibiotic Therapy Trial (SATT), a three-arm, randomised, open-label, equivalence trial in five communities in Karachi, Pakistan. We enrolled young infants (aged 0–59 days) who either presented at a primary health-care clinic or were identified by a community health worker with signs of clinical severe infection. We included infants who were not critically ill and whose family refused admission. We randomly assigned infants to either intramuscular procaine benzylpenicillin and gentamicin once a day for 7 days (reference); oral amoxicillin twice daily and intramuscular gentamicin once a day for 7 days; or intramuscular procaine benzylpenicillin and gentamicin once a day for 2 days followed by oral amoxicillin twice daily for 5 days. The primary outcome was treatment failure within 7 days of enrolment and the primary analysis was per protocol. We judged experimental treatments as efficacious as the reference if the upper bound of the 95% CI for the difference in treatment failure was less than 5·0. This trial is registered at ClinicalTrials.gov , number NCT01027429 .

Findings

Between Jan 1, 2010, and Dec 26, 2013, 2780 infants were deemed eligible for the trial, of whom 2453 (88%) were enrolled. Because of inadequate clinical follow-up or treatment adherence, 2251 infants were included in the per-protocol analysis. 820 infants (747 per protocol) were assigned the reference treatment of procaine benzylpenicillin and gentamicin, 816 (751 per protocol) were allocated amoxicillin and gentamicin, and 817 (753 per protocol) were assigned procaine benzylpenicillin, gentamicin, and amoxicillin. Treatment failure within 7 days of enrolment was reported in 90 (12%) infants who received procaine benzylpenicillin and gentamicin (reference), 76 (10%) of those given amoxicillin and gentamicin (risk difference with reference −1·9, 95% CI −5·1 to 1·3), and 99 (13%) of those treated with procaine benzylpenicillin, gentamicin, and amoxicillin (risk difference with reference 1·1, −2·3 to 4·5).

Interpretation

Two simplified antibiotic regimens requiring fewer injections are equivalent to a reference treatment for young infants with signs of clinical severe infection but without signs of critical illness. The use of these simplified regimens has the potential to increase access to treatment for sick young infants who cannot be referred to hospital.

Funding

The Saving Newborn Lives initiative of Save the Children, through support from the Bill & Melinda Gates, and by WHO and USAID.

Despite improvements in child survival over recent decades, progress in newborn survival remains slow, with 44% of all child deaths occurring in the first month of life. Of these neonatal deaths, 23–30% are due to infections. ¹

WHO recommends hospital referral and 7 days of injectable penicillin and gentamicin for neonates and young infants (aged 0–59 days) with suspected sepsis. ² However, up to three-quarters of families of sick young infants in Karachi, Pakistan, refuse hospital referrals, despite free transport and treatment, because of the substantial opportunity costs to very poor families of prolonged admissions at locations far from their place of residence. ³ Stated reasons for refusal are financial constraints, cultural beliefs, and concern about poor quality of care at hospitals. ^{3 and 4} Similar constraints to optimum care of sick newborn babies in high-mortality settings have also been noted from other low-resource settings. ⁵

An expert consultation reviewed the issue of low adherence to referral advice for sick young infants and recommended that clinical trials were needed to evaluate simplified antibiotic regimens to manage severe infections in young infants when referral was not possible, to improve access to care and newborn survival. ⁶ Thus, randomised controlled trials assessing simplified antibiotic regimens—ie, fewer injections, addition of high-dose oral amoxicillin in lieu of penicillin—for outpatient management of young infants with clinical severe infection were undertaken in several countries (Democratic Republic of Congo, Bangladesh, Kenya, Nigeria, and Pakistan) to ensure wide generalisability. ^{7 , 8 , 9 and 10} These trials were not designed to show that the simpler regimens were better than the standard regimen but rather that they had similar efficacy to the reference regimen—namely, an equivalence or non-inferiority design. ¹¹ Thus, the trials were designed to produce narrow confidence intervals when examining the difference in risk of treatment failure between the simplified regimens and the reference treatment and, hence, provide a high degree of confidence that any differences between efficacy of the treatments were small. The choice of treatment regimens followed a systematic review of pathogens causing neonatal sepsis, ¹² their antimicrobial resistance patterns, ¹³ antibiotic pharmacodynamics in neonates, ¹⁴ and existing evidence on treatment success with various oral and injectable antibiotics in young infants. ^{15 and 16}

Research in context

Evidence before the study

We searched PubMed between January, 1990, and October, 2015, with the terms “young infant”, “clinical severe infection”, and “simplified antibiotic regimens” to identify peer-reviewed publications in the English language about simplified antibiotic regimens for severe infections in neonates and young infants in the primary-care setting. We identified five reports (three protocol papers), of which two reported findings of similar trials undertaken in Africa (Kenya, Nigeria, and Democratic Republic of Congo) and Bangladesh, comparing the WHO-recommended regimen of parenteral penicillin and gentamicin with simpler antibiotic regimens.

Added value of this study

Compared with previous studies in Africa and Bangladesh, our trial from Pakistan had a higher representation of very young infants (those in the first week of life) and was enriched by the availability of bacterial aetiological data and antimicrobial susceptibility data. A pooled analysis can now be done of data from all three related trials, to support policy recommendations for this very young group of patients.

Implications of all the available evidence

The findings of our trial are consistent with those published previously, showing that simplified antibiotic regimens are as efficacious as the WHO-recommended regimen of parenteral penicillin and gentamicin for young infants with severe infection. Our study has contributed to development of new WHO guidelines for treatment of severe infection in young infants where referral is not feasible.

We targeted young infants (aged 0–59 days) with clinical severe infections because increased susceptibility to infection persists into the second month of life. ¹⁷ Additionally, the signs and management of sepsis in young infants (aged 29–59 days) are similar to those in neonates (aged 0–28 days). WHO and UNICEF's Integrated Management of Childhood Illness (IMCI) strategy addresses children aged 0–59 days as a separate group (young infants) from children aged 2–59 months. ¹⁸