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Introduction Serious bacterial neonatal infections are a major cause of global neonatal mortality. While hospitalized treatment is recommended, families cannot access inpatient treatment in low resource settings. Two parallel randomized control trials were conducted at five sites in three countries (Democratic Republic of Congo, Kenya, and Nigeria) to compare the effectiveness of treatment with experimental regimens requiring fewer injections with a reference regimen A (injection gentamicin plus injection procaine penicillin both once daily for 7 days) on the outpatient basis provided to young infants (0–59 days) with signs of possible serious bacterial infection (PSBI) when the referral was not feasible. Costs were estimated to quantify the financial implications of scaleup, and cost-effectiveness of these regimens. Methods Direct economic costs (including personnel, drugs and consumable costs) were estimated for identification, prenatal and postnatal visits, assessment, classification, treatment and follow-up. Data on time spent by providers on each activity was collected from 83% of providers. Indirect marginal financial costs were estimated for non-consumables/capital, training, transport, communication, administration and supervision by considering only a share of the total research and health system costs considered important for the program. Total economic costs (direct plus indirect) per young infant treated were estimated based on 39% of young infants enrolled in the trial during 2012 and the number of days each treated during one year. The incremental cost-effectiveness ratio was calculated using treatment failure after one week as the outcome indicator. Experimental regimens were compared to the reference regimen and pairwise comparisons were also made. Results The average costs of treating a young infant with clinical severe infection (a sub-category of PSBI) in 2012 was lowest with regimen D (injection gentamicin once daily for 2 days plus oral amoxicillin twice daily for 7 days) at US$ 20.9 (95% CI US$ 16.4–25.3) or US$ 32.5 (2018 prices). While all experimental regimens B (injection gentamicin once daily plus oral amoxicillin twice daily, both for 7 days), regimen C (once daily of injection gentamicin injection plus injection procaine penicillin for 2 days, thereafter oral amoxicillin twice daily for 5 days) and regimen D were found to be more cost-effective as compared with the reference regimen A; pairwise comparison showed regimen D was more cost-effective than B or C. For fast breathing, the average cost of treatment with regimen E (oral amoxicillin twice daily for 7 days) at US$ 18.3 (95% CI US$ 13.4–23.3) or US$ 29.0 (2018 prices) was more cost-effective than regimen A. Indirect costs were 32% of the total treatment costs. Conclusion Scaling up of outpatient treatment for PSBI when the referral is not feasible with fewer injections and oral antibiotics is cost-effective for young infants and can lead to increased access to treatment resulting in potential reductions in neonatal mortality. Clinical trial registration The trial was registered with Australian New Zealand Clinical Trials Registry under ID ACTRN 12610000286044.

Summary Background WHO recommends hospital-based treatment for young infants aged 0–59 days with clinical signs of possible serious bacterial infection, but most families in resource-poor settings cannot accept referral. We aimed to assess whether use of simplified antibiotic regimens to treat young infants with clinical signs of severe infection was as efficacious as an injectable procaine benzylpenicillin–gentamicin combination for 7 days for situations in which hospital referral was not possible. Methods In a multisite open-label equivalence trial in DR Congo, Kenya, and Nigeria, community health workers visited all newborn babies at home, identifying and referring unwell young infants to a study nurse. We stratified young infants with clinical signs of severe infection whose parents did not accept referral to hospital by age (0–6 days and 7–59 days), and randomly assigned each individual within these strata to receive one of the four treatment regimens. Randomisation was stratified by age group of infants. An age-stratified randomisation scheme with block size of eight was computer-generated off-site at WHO. The outcome assessor was masked. We randomly allocated infants to receive injectable procaine benzylpenicillin–gentamicin for 7 days (group A, reference group); injectable gentamicin and oral amoxicillin for 7 days (group B); injectable procaine benzylpenicillin–gentamicin for 2 days, then oral amoxicillin for 5 days (group C); or injectable gentamicin for 2 days and oral amoxicillin for 7 days (group D). Trained health professionals gave daily injections and the first dose of oral amoxicillin. Our primary outcome was treatment failure by day 8 after enrolment, defined as clinical deterioration, development of a serious adverse event (including death), no improvement by day 4, or not cured by day 8. Independent outcome assessors, who did not know the infant's treatment regimen, assessed study outcomes on days 4, 8, 11, and 15. Primary analysis was per protocol. 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 In Kenya and Nigeria, we started enrolment on April 4, 2011, and we enrolled the necessary number of young infants aged 7 days or older from Oct 17, 2011, to April 30, 2012. At these sites, we continued to enrol infants younger than 7 days until March 29, 2013. In DR Congo, we started enrolment on Sept 17, 2012, and continued until June 28, 2013. We randomly assigned 3564 young infants to either group A (n=894), group B (n=884), group C (n=896), or group D (n=890). We excluded 200 randomly assigned infants, who did not fulfil the predefined criteria of adherence to treatment and adequate follow-up. In the per-protocol analysis, 828 infants were included in group A, 826 in group B, 862 in group C, and 848 in group D. 67 (8%) infants failed treatment in group A compared with 51 (6%) infants in group B (risk difference −1·9%, 95% CI −4·4 to 0·1), 65 (8%) in group C (−0·6%, −3·1 to 2·0), and 46 (5%) in group D (−2·7%, −5·1 to 0·3). Treatment failure in groups B, C, and D was within the similarity margin compared with group A. During the 15 days after random allocation, 12 (1%) infants died in group A, compared with ten (1%) infants in group B, 20 (2%) infants in group C, and 11 (1%) infants in group D. An infant in group A had a serious adverse event other than death (injection abscess). Interpretation The three simplified regimens were as effective as injectable procaine benzylpenicillin–gentamicin for 7 days on an outpatient basis in young infants with clinical signs of severe infection, without signs of critical illness, and whose caregivers did not accept referral for hospital admission. Funding Bill & Melinda Gates Foundation grant to WHO.

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.