Treatment of fast breathing in neonates and young infants with oral amoxicillin compared with penicillin-gentamicin combination: study protocol for a randomized, open-label equivalence trial

Background: The World Health Organization recommends hospitalization and injectable antibiotic treatment for young infants (0–59 days old), who present with signs of possible serious bacterial infection. Fast breathing alone is not associated with a high mortality risk for young infants and has been treated with oral antibiotics in some settings. This trial was designed to examine the safety and efficacy of oral amoxicillin for young infants with fast breathing compared with that of an injectable penicillin–gentamicin combination. The study is currently being conducted in the Democratic Republic of Congo, Kenya and Nigeria Methods/Design: This is a randomized, open-label equivalence trial. All births in the community are visited at home by trained community health workers to identify sick infants who are then referred to a trial study nurse for assessment. The primary outcome is treatment failure by day 8 after enrollment, defined as clinical deterioration, development of a serious adverse event including death, persistence of fast breathing by day 4 or recurrence up to day 8. Secondary outcomes include adherence to study therapy, relapse, death between days 9 and 15 and adverse effects associated with the study drugs. Study outcomes are assessed on days 4, 8, 11 and 15 after randomization by an independent outcome assessor who is blinded to the treatment being given. Discussion: The results of this study will help inform the development of policies for the treatment of fast breathing among neonates and young infants in resource-limited settings

Simplified Regimens for Management of Neonates and Young Infants With Severe Infection When Hospital Admission Is Not Possible

Background: In resource-limited settings, most young infants with signs of severe infection do not receive the recommended inpatient treatment with intravenous broad spectrum antibiotics for 10 days or more because such treatment is not accessible, acceptable or affordable to families. This trial was initiated in the Democratic Republic of Congo, Kenya and Nigeria to assess the safety and efficacy of simplified treatment regimens for the young infants with signs of severe infection who cannot receive hospital care. Methods: This is a randomized, open-label equivalence trial in which 3600 young infants with signs of clinical severe infection will be enrolled. The primary outcome is treatment failure in 7 days after enrollment, which includes death or worsening of the clinical condition on any day, or no improvement in the clinical condition by day 4 of treatment. Secondary outcomes include compliance with study therapy, adverse effects due to the study drugs and relapse or death during the week after completion of treatment. Discussion: The results of this study, along with ongoing studies in Pakistan and Bangladesh, will inform the development of global policy for treatment of severe neonatal infections in resource-limited settings

Scientific rationale for study design of community-based simplified antibiotic therapy trials in newborns and young infants with clinically diagnosed severe infections or fast breathing in South Asia and sub-Saharan Africa.

Background: Newborns and young infants suffer high rates of infections in South Asia and sub-Saharan Africa. Timely access to appropriate antibiotic therapy is essential for reducing mortality. In an effort to develop community case management guidelines for young infants, 0–59 days old, with clinically diagnosed severe infections, or with fast breathing, 4 trials of simplified antibiotic therapy delivered in primary care clinics (Pakistan, Democratic Republic of Congo, Kenya and Nigeria) or at home (Bangladesh and Nigeria) are being conducted. Methods: This article describes the scientific rationale for these trials, which share major elements of trial design. All the trials are in settings of high neonatal mortality, where hospitalization is not feasible or frequently refused. All use procaine penicillin and gentamicin intramuscular injections for 7 days as reference therapy and compare this to various experimental arms utilizing comparatively simpler combination regimens with fewer injections and oral amoxicillin. Conclusion: The results of these trials will inform World Health Organization policy regarding community case management of young infants with clinical severe infections or with fast breathing

Pneumonia hospitalizations and mortality in children 3 – 24-month-old in Nigeria from 2013 to 2020: Impact of pneumococcal conjugate vaccine ten valent (PHiD-CV-10)

Pneumococcal conjugate vaccine ten valent (PCV 10) was introduced into Nigeria in three phases. Phase 3 introduction started in August 2016. However, its impact on pneumonia admissions and mortality among vaccinated Nigerian children has not been determined. Data in the period before PCV-10 introduction (3 August 2013–2 August 2016), and after (3 August 2017–2 August 2020) were retrospectively extracted from the medical charts of eligible patients aged 3–24 months with hospitalized radiological pneumonia at the University College Hospital (UCH), Ibadan; National Hospital (NH), Abuja; and Federal Teaching Hospital (FTH), Gombe, allowing for an intervening period of 1 year. Proportions of the patients with hospitalized pneumonia and case fatality rates were determined during both periods. The results were compared using z-test, multiple logistic regression analysis and p < .05 was considered significant. Adjusted pneumonia hospitalization rates between the two periods increased at the NH Abuja (10.7% vs 14.6%); decreased at the UCH, Ibadan (8.7% vs 6.9%); and decreased at the FTH, Gombe (28.5% vs 18.9%). Case fatality rates decreased across all the sites during the post-PCV introduction period: NH Abuja, from 6.6% to 4.4% (p = .106); FTH, Gombe, 11.7% to 7.7% (p = .477); and UCH, Ibadan, 2.0% to 0% (p = .045); but only significant at Ibadan. Overall, proportion of hospitalized pneumonia cases decreased after 3 years of PCV 10 introduction into the National Immunization Programme in Nigeria. The case fatality rate during post-PCV 10 introduction decreased at all the three sites, but this difference was significant at the UCH, Ibadan

Simplified antibiotic regimens compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with clinical signs of possible serious bacterial infection when referral is not possible: a randomised, open-label, equivalence trial

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\u27s 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 WH

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

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 WH