Tackling the threat of antimicrobial resistance in neonates and children: outcomes from the first WHO-convened Paediatric Drug Optimisation exercise for antibiotics.

Children and neonates are highly vulnerable to the impact of antimicrobial resistance. Substantial barriers are faced in relation to research and development of antibacterial agents for use in neonates, children, and adolescents aged yonger than 19 years, and focusing finite resources on the most appropriate agents for development and paediatric optimisation is urgently needed. In November and December, 2022, following the successes of previous similar disease-focused exercises, WHO convened the first Paediatric Drug Optimisation (PADO) exercise for antibiotics, aiming to provide a shortlist of antibiotics to be prioritised for paediatric research and development, especially for use in regions with the highest burden of disease attributable to serious bacterial infection. A range of antibiotics with either existing license for children or in clinical development in adults but with little paediatric data were considered, and PADO priority and PADO watch lists were formulated. This Review provides the background and overview of the exercise processes and its outcomes as well as a concise review of the literature supporting decision making. Follow-up actions to implement the outcomes from the PADO for antibiotics process are also summarised. This Review highlights the major beneficial influence the collaborative PADO process can have, both for therapeutic drug class and disease-specific themes, in uniting efforts to ensure children have access to essential medicines across the world.

Optimizing integration of community-based management of possible serious bacterial infection (PSBI) in young infants into primary healthcare systems in Ethiopia and Kenya: successes and challenges.

BACKGROUND: Ethiopia and Kenya have adopted the community-based integrated community case management (iCCM) of common childhood illnesses and newborn care strategy to improve access to treatment of infections in newborns and young infants since 2012 and 2018, respectively. However, the iCCM strategy implementation has not been fully integrated into the health system in both countries. This paper describes the extent of integration of iCCM program at the district/county health system level, related barriers to optimal integration and implementation of strategies. METHODS: From November 2020 to August 2021, Ethiopia and Kenya implemented the community-based treatment of possible serious bacterial infection (PSBI) when referral to a higher facility is not possible using embedded implementation research (eIR) to mitigate the impact of COVID-19 on the delivery of this life-saving intervention. Both projects conducted mixed methods research from April-May 2021 to identify barriers and facilitators and inform strategies and summative evaluations from June-July 2022 to monitor the effectiveness of implementation outcomes including integration of strategies. RESULTS: Strategies identified as needed for successful implementation and sustainability of the management of PSBI integrated at the primary care level included continued coaching and support systems for frontline health workers, technical oversight from the district/county health system, and ensuring adequate supply of commodities. As a result, support and technical oversight capacity and collaborative learning were strengthened between primary care facilities and community health workers, resulting in improved bidirectional linkages. Improvement of PSBI treatment was seen with over 85% and 81% of estimated sick young infants identified and treated in Ethiopia and Kenya, respectively. However, perceived low quality of service, lack of community trust, and shortage of supplies remained barriers impeding optimal PSBI services access and delivery. CONCLUSION: Pragmatic eIR identified shared and unique contextual challenges between and across the two countries which informed the design and implementation of strategies to optimize the integration of PSBI management into the health system during the COVID-19 pandemic. The eIR participatory design also strengthened ownership to operationalize the implementation of identified strategies needed to improve the health system's capacity for PSBI treatment.

Incidence of possible serious bacterial infection in young infants in the three high-burden countries of the Democratic Republic of the Congo, Kenya, and Nigeria: A secondary analysis of a large, multi-country, multi-centre clinical trial.

Background: Neonatal infections are a major public health concern worldwide, particularly in low- and middle-income countries, where most of the infection-related deaths in under-five children occur. Sub-Saharan Africa has the highest mortality rates, but there is a lack of data on the incidence of sepsis from this region, hindering efforts to improve child survival. We aimed to determine the incidence of possible serious bacterial infection (PSBI) in young infants in three high-burden countries in Africa. Methods: This is a secondary analysis of data from the African Neonatal Sepsis (AFRINEST) trial, conducted in the Democratic Republic of the Congo (DRC), Kenya, and Nigeria between 15 March 2012 and 15 July 2013. We recorded baseline characteristics, the incidence of PSBI (as defined by the World Health Organization), and the incidence of local infections among infants from 0-59 days after birth. We report descriptive statistics. Results: The incidence of PSBI among 0-59-day-old infants across all three countries was 11.2% (95% confidence interval (CI) = 11.0-11.4). The DRC had the highest incidence of PSBI (19.0%; 95% CI = 18.2-19.8). Likewise, PSBI rates were higher in low birth weight infants (24.5%; 95% CI = 23.1-26.0) and infants born to mothers aged <20 years (14.1%; 95% CI = 13.4-14.8). The incidence of PSBI was higher among infants delivered at home (11.7%; 95% CI = 11.4-12.0). Conclusions: The high burden of PSBI among young infants in DRC, Kenya, and Nigeria demonstrates the importance of addressing PSBI in improving child survival in sub-Saharan Africa to reach the Sustainable Development Goals (SDGs). These data can support government authorities, policymakers, programme implementers, non-governmental organisations, and international partners in reducing preventable under-five deaths. Registration: Australian New Zealand Clinical Trials Registry: ACTRN12610000286044.

Cost of treating sick young infants (0-59 days) with Possible Serious Bacterial Infection in resource-constrained outpatient primary care facilities: An insight from implementation research in two districts of Haryana and Uttar Pradesh (India).

Background: Information on the average and incremental costs of implementing alternative strategies for treating young infants 0-59 days old in primary health facilities with signs of possible serious bacterial infection (PSBI) when a referral is not feasible is limited but valuable for policymakers. Methods: Direct activity costs were calculated for outpatient treatment of PSBI and pneumonia in two districts of India: Palwal, Haryana and Lucknow, Uttar Pradesh. These included costs of staff time and consumables for initial assessment, classification, and referrals; recommended treatment of fast breathing (oral amoxicillin for seven days) and PSBI (injection gentamicin and oral amoxicillin for seven days); and daily assessments. Indirect operational costs included staff training; staff time cost for general management, supervision, and coordination; referral transport; and communication. Results: The average cost per young infant treated for recommended and acceptable treatment for PSBI was 16 US dollars (US$) (95% CI = US$15.4-16.3) in 2018-19 and US$18.5 in 2022 (adjusted for inflation) when all direct and indirect operational costs were considered. The average cost of recommended treatment for pneumonia was US$10.1 (95% CI = US$9.7-10.6) or US$11.7 in 2022, per treated young infant. The incremental cost 2018-2019 for supplies, medicines, and operations (excluding staff time costs) per infant treated for PSBI was US$6.1 and US$4.3 and for pneumonia was US$3.5 and US$2.2 in Palwal and Lucknow, respectively. Operation and administrative costs were 25% in Palwal and 12% in Lucknow of the total PSBI treatment costs. The average cost per live birth for treating PSBI in each population was US$5 in Palwal and US$3 in Lucknow. Higher operation costs for social mobilisation activities in Palwal led to the empowerment of families and timely care-seeking. Conclusions: Costs of treatment of PSBI with the recommended regimen in an outpatient setting, when a referral is not feasible, are under US$20 per treated child and must be budgeted to reduce deaths from neonatal sepsis. The investment must be made in activities that lead to successful identification, prompt care seeking, timely initiation of treatment and follow-up.

Antibiotic resistance trends for common bacterial aetiologies of childhood diarrhoea in low- and middle-income countries: A systematic review.

Background: Diarrhoea is the second most common cause of death among children under the age of five worldwide. The World Health Organization (WHO) recommends treating diarrhoea with oral rehydration therapy, intravenous fluids for severe dehydration, and zinc supplements. Antibiotics are only recommended to treat acute, invasive diarrhoea. Rising antibiotic resistance has led to a decrease in the effectiveness of treatments for diarrhoea. Methods: A systematic literature review in PubMed, Web of Science, and EMBASE was conducted to identify articles relevant to antibiotic-resistant childhood diarrhoea. Articles in English published between 1990 to 2020 that described antibiotic resistance patterns of common pathogens causing childhood diarrhoea in low- and middle-income countries were included. The studies were limited to papers that categorized children as 0-5 years or 0-10 years old. The proportion of isolates with resistance to major classes of antibiotics stratified by major WHO global regions and time was determined. Results: Quantitative data were extracted from 44 articles that met screening criteria; most focused on children under five years. Escherichia coli isolates had relatively high resistance rates to ampicillin and tetracycline in the African (AFR), American (AMR), and Eastern Mediterranean Regions (EMR). There was moderate to high resistance to ampicillin and third generation cephalosporins among Salmonella spp in the AFR, EMR, and the Western Pacific Region (WPR). Resistance rates for ampicillin, co-trimoxazole, and chloramphenicol for Shigella in the AFR started at an alarmingly high rate ( ~ 90%) in 2006 and fluctuated over time. There were limited antibiotic resistance data for Aeromonas, Yersinia, and V. cholerae. The 161 isolates of Campylobacter analysed showed initially low rates of fluoroquinolone resistance with high rates of resistance in recent years, especially in the Southeast Asian Region. Conclusions: Resistance to inexpensive antibiotics for treatment of invasive diarrhoea in children under ten years is widespread (although data on 6- to 10-year-old children are limited), and resistance rates to fluoroquinolones and later-generation cephalosporins are increasing. A strong regional surveillance system is needed to carefully monitor trends in antibiotic resistance, future studies should include school-aged children, and interventions are needed to reduce inappropriate use of antibiotics for the treatment of community-acquired, non-invasive diarrhoea. Registration: This systematic review was registered in Prospero (registration number CRD42020204004) in August 2020.

Implementation research to increase treatment coverage of possible serious bacterial infections in young infants when a referral is not feasible: lessons learnt.

BACKGROUND: The objective was to achieve high coverage of possible serious bacterial infections (PSBI) treatment using the World Health Organization (WHO) guideline for managing it on an outpatient basis when referral to a hospital is not feasible. METHODS: We implemented this guideline in the programme settings at 10 Basic Health Units (BHU) in two rural districts of Sindh in Pakistan using implementation research. A Technical Support Unit supported the programme to operationalize guidelines, built capacity of health workers through training, monitored their clinical skills, mentored them and assured quality. The community-based health workers visited households to identify sick infants and referred them to the nearest BHU for further management. The research team collected data. RESULTS: Of 17 600 identified livebirths, 1860 young infants with any sign of PSBI sought care at BHUs and 1113 (59.8%) were brought by families. We achieved treatment coverage of 95%, assuming an estimated 10% incidence of PSBI in the first 2 months of life and that 10% of young infants came from outside the study catchment area. All 923 infants (49%; 923/1860) 7-59 days old with only fast breathing (pneumonia) treated with outpatient oral amoxicillin were cured. Hospital referral was refused by 83.4% (781/937) families who accepted outpatient treatment; 92.2% (720/781) were cured and 0.8% (6/781) died. Twelve (7.6%; 12/156) died among those treated in a hospital. CONCLUSION: It is feasible to achieve high coverage by implementing WHO PSBI management guidelines in a programmatic setting when a referral is not feasible.

Importance of breastfeeding and complementary feeding for management and prevention of childhood diarrhoea in low- and middle-income countries.

Background: Early and exclusive breastfeeding have been shown to protect young infants from all-cause and diarrhoea-related mortality. Ideally breastfeeding should be initiated within the first hour of birth. Despite efforts to increase rates of early and exclusive breastfeeding in low- and middle-income countries (LMICs), challenges with uptake remain. This analysis reviews trends in early and exclusive breastfeeding, and the impact of infant feeding interventions in reducing childhood diarrhoea. Methods: We conducted a detailed review of articles written in English between 1990 and 2020 on the impact and efficacy of breastfeeding and complementary feeding on diarrhoea in children aged 0-2 years in LMICs. Using data from 86 countries and all WHO global regions collected from the mid-1980s through 2018 obtained from publicly available Demographic Health Surveys, we assessed trends in five-year intervals of timing of breastfeeding initiation, exclusive breastfeeding, median and mean duration of exclusive breastfeeding, and complementary feeding. Results: The literature search identified ten articles that described variable rates of early initiation of breastfeeding from 20% in Pakistan to 76% in Egypt. An analysis of 288 DHS studies found that the proportion of women who reported initiating breastfeeding within an hour of birth increased from 32% in the early 1990s to 55% between 2016 and 2020. Exclusive breastfeeding increased from 20% in the late 1980s to 48% between 2016 and 2020 and the mean duration of exclusive breastfeeding of 2-to-4-month-old infants doubled. Early initiation of breastfeeding and exclusive breastfeeding was associated with reductions in diarrhoea prevalence in the South East Asian, Western Pacific, Eastern Mediterranean, and African regions. Eight studies evaluating the effectiveness of different maternal education interventions, health care worker training, and media campaigns demonstrated improvements in exclusive breastfeeding, and most resulted in reductions in the incidence or duration of diarrhoea. Conclusions: During the last two decades, early and exclusive breastfeeding have increased. Nevertheless, the uptake of this basic, low-cost intervention remains suboptimal across all global regions. Given the potential benefits the in reduction of diarrhoea and diarrhoea-associated mortality, interventions for improving the uptake of early and exclusive breastfeeding in different sociological contexts need to be designed, implemented, and evaluated.

A multi-country implementation research initiative to jump-start scale-up of outpatient management of possible serious bacterial infections (PSBI) when a referral is not feasible: Summary findings and implications for programs.

INTRODUCTION: Research on simplified antibiotic regimens for outpatient treatment of 'Possible Serious Bacterial Infection' (PSBI) and the subsequent World Health Organization (WHO) guidelines provide an opportunity to increase treatment coverage. This multi-country implementation research initiative aimed to learn how to implement the WHO guideline in diverse contexts. These experiences have been individually published; this overview paper provides a summary of results and lessons learned across sites. METHODS SUMMARY: A common mixed qualitative and quantitative methods protocol for implementation research was used in eleven sites in the Democratic Republic of Congo (Equateur province), Ethiopia (Tigray and Oromia regions), India (Haryana, Himachal Pradesh, Maharashtra, and Uttar Pradesh states), Malawi (Central Region), Nigeria (Kaduna and Oyo states), and Pakistan (Sindh province). Key steps in implementation research were: i) policy dialogue with the national government and key stakeholders, ii) the establishment of a 'Technical Support Unit' with the research team and district level managers, and iii) development of an implementation strategy and its refinement using an iterative process of implementation, programme learning and evaluation. RESULTS SUMMARY: All sites successfully developed and evaluated an implementation strategy to increase coverage of PSBI treatment. During the study period, a total of 6677 young infants from the study catchment area were identified and treated at health facilities in the study area as inpatients or outpatients among 88179 live births identified. The estimated coverage of PSBI treatment was 75.7% (95% CI 74.8% to 78.6%), assuming a 10% incidence of PSBI among all live births. The treatment coverage was variable, ranging from 53.3% in Lucknow, India to 97.3% in Ibadan, Nigeria. The coverage of inpatient treatment ranged from 1.9% in Zaria, Nigeria, to 33.9% in Tigray, Ethiopia. The outpatient treatment coverage ranged from 30.6% in Pune, India, to 93.6% in Zaria, Nigeria. Overall, the case fatality rate (CFR) was 14.6% (95% CI 11.5% to 18.2%) for 0-59-day old infants with critical illness, 1.9% (95% CI 1.5% to 2.4%) for 0-59-day old infants with clinical severe infection and 0.1% for fast breathing in 7-59 days old. Among infants treated as outpatients, CFR was 13.7% (95% CI 8.7% to 20.2%) for 0-59-day old infants with critical illness, 0.9% (95% CI 0.6% to 1.2%) for 0-59-day old infants with clinical severe infection, and 0.1% for infants 7-59 days old with fast breathing. CONCLUSION: Important lessons on how to conduct each step of implementation research, and the challenges and facilitators for implementation of PSBI management guideline in routine health systems are summarised and discussed. These lessons will be used to introduce and scale-up implementation in relevant Low- and middle-income countries.

Simplified antibiotic regimens for young infants with possible serious bacterial infection when the referral is not feasible in the Democratic Republic of the Congo.

INTRODUCTION: Neonates with serious bacterial infections should be treated with injectable antibiotics after hospitalization, which may not be feasible in many low resource settings. In 2015, the World Health Organization (WHO) launched a guideline for the management of young infants (0-59 days old) with possible serious bacterial infection (PSBI) when referral for hospital treatment is not feasible. We evaluated the feasibility of the WHO guideline implementation in the Democratic Republic of the Congo (DRC) to achieve high coverage of PSBI treatment. METHODS: From April 2016 to March 2017, in a longitudinal, descriptive, mixed methods implementation research study, we implemented WHO PSBI guideline for sick young infants (0-59 dyas of age) in the public health programme setting in five health areas of North and South Ubangi Provinces with an overall population of about 60,000. We conducted policy dialogue with national and sub-national level government planners, decision-makers, academics and other stakeholders. We established a Technical Support Unit to provide implementation support. We built the capacity of health workers and managers and ensured the availability of necessary medicines and commodities. We followed infants with PSBI signs up to 14 days. The research team systematically collected data on adherence to treatment and outcomes. RESULTS: We identified 3050 live births and 285 (9.3%) young infants with signs of PSBI in the study area, of whom 256 were treated. Published data have reported 10% PSBI incidence rate in young infants. Therefore, the estimated coverage of treatment was 83.9% (256/305). Another 426 from outside the study catchment area were also identified with PSBI signs by the nurses of a health centre within the study area. Thus, a total of 711 young infants with PSBI were identified, 285 (40%) 7-59 days old infants had fast breathing (pneumonia), 141 (20%) 0-6 days old had fast breathing (severe pneumonia), 233 (33%) had signs of clinical severe infection (CSI), and 52 (7%) had signs of critical illness. Referral to a hospital was advised to 426 (60%) infants with CSI, critical illness or severe pneumonia. The referral was refused by 282 families who accepted simplified antibiotic treatment on an outpatient basis at the health centres. Treatment failure among those who received outpatient treatment occurred in 10/128 (8%) with severe pneumonia, 25/147 (17%) with CSI, including one death, and 2/7 (29%) young infants with a critical illness. Among 285 infants with pneumonia, 257 (90%) received oral amoxicillin treatment, and 8 (3%) failed treatment. Adherence to outpatient treatment was 98% to 100% for various PSBI sub-categories. Among 144 infants treated in a hospital, 8% (1/13) with severe pneumonia, 23% (20/86) with CSI and 40% (18/45) with critical illness died. CONCLUSION: Implementation of the WHO PSBI guideline when a referral was not possible was feasible in our context with high coverage. Without financial and technical input to strengthen the health system at all levels, including the community and the referral level, it may not be possible to achieve and sustain the same high treatment coverage.

Prospective cohort study of referred Malawian children and their survival by hypoxaemia and hypoglycaemia status.

Objective: To investigate survival in children referred from primary care in Malawi, with a focus on hypoglycaemia and hypoxaemia progression. Methods: The study involved a prospective cohort of children aged 12 years or under referred from primary health-care facilities in Mchinji district, Malawi in 2019 and 2020. Peripheral blood oxygen saturation (SpO2) and blood glucose were measured at recruitment and on arrival at a subsequent health-care facility (i.e. four hospitals and 14 primary health-care facilities). Children were followed up 2 weeks after discharge or their last clinical visit. The primary study outcome was the case fatality ratio at 2 weeks. Associations between SpO2 and blood glucose levels and death were evaluated using Cox proportional hazards models and the treatment effect of hospitalization was assessed using propensity score matching. Findings: Of 826 children recruited, 784 (94.9%) completed follow-up. At presentation, hypoxaemia was moderate (SpO2: 90-93%) in 13.1% (108/826) and severe (SpO2: < 90%) in 8.6% (71/826) and hypoglycaemia was moderate (blood glucose: 2.5-4.0 mmol/L) in 9.0% (74/826) and severe (blood glucose: < 2.5 mmol/L) in 2.3% (19/826). The case fatality ratio was 3.7% (29/784) overall but 26.3% (5/19) in severely hypoglycaemic children and 12.7% (9/71) in severely hypoxaemic children. Neither moderate hypoglycaemia nor moderate hypoxaemia was associated with mortality. Conclusion: Presumptive pre-referral glucose treatment and better management of hypoglycaemia could reduce the high case fatality ratio observed in children with severe hypoglycaemia. The morbidity and mortality burden of severe hypoxaemia was high; ways of improving hypoxaemia identification and management are needed.

Measuring coverage and quality of supportive care for inpatient neonatal infections: EN-BIRTH multi-country validation study.

Background: An estimated 7 million episodes of severe newborn infections occur annually worldwide, with half a million newborn deaths, most occurring in low- and middle-income countries. Whilst injectable antibiotics are necessary to treat the infection, supportive care is also crucial in ending preventable mortality and morbidity. This study uses multi-country data to assess gaps in coverage, quality, and documentation of supportive care, considering implications for measurement. Methods: The EN-BIRTH study was conducted in five hospitals in Bangladesh, Nepal, and Tanzania (July 2017-July 2018). Newborns with an admission diagnosis of clinically-defined infection (sepsis, meningitis, and/or pneumonia) were included. Researchers extracted data from inpatient case notes and interviews with women (usually the mothers) as the primary family caretakers after discharge. The interviews were conducted using a structured survey questionnaire. We used descriptive statistics to report coverage of newborn supportive care components such as oxygen use, phototherapy, and appropriate feeding, and we assessed the validity of measurement through survey-reports using a random-effects model to generate pooled estimates. In this study, key supportive care components were assessment and correction of hypoxaemia, hyperbilirubinemia, and hypoglycaemia. Results: Among 1015 neonates who met the inclusion criteria, 89% had an admission clinical diagnosis of sepsis. Major gaps in documentation and care practices related to supportive care varied substantially across the participating hospitals. The pooled sensitivity was low for the survey-reported oxygen use (47%; 95% confidence interval (CI) = 30%-64%) and moderate for phototherapy (60%; 95% CI = 44%-75%). The pooled specificity was high for both the survey-reported oxygen use (85%; 95% CI = 80%-89%) and phototherapy (91%; 95% CI = 82%-97%). Conclusions: The women's reports during the exit survey consistently underestimated the coverage of supportive care components for managing infection. We have observed high variability in the inpatient documents across facilities. A standardised ward register for inpatient small and sick newborn care may capture selected supportive care data. However, tracking the detailed care will require standardised individual-level data sets linked to newborn case notes. We recommend investments in assessing the implementation aspects of a standardised inpatient register in resource-poor settings.

Prospective cohort study of referred Malawian children and their survival by hypoxaemia and hypoglycaemia status

Objective To investigate survival in children referred from primary care in Malawi, with a focus on hypoglycaemia and hypoxaemia progression. Methods The study involved a prospective cohort of children aged 12 years or under referred from primary health-care facilities in Mchinji district, Malawi in 2019 and 2020. Peripheral blood oxygen saturation (SpO2) and blood glucose were measured at recruitment and on arrival at a subsequent health-care facility (i.e. four hospitals and 14 primary health-care facilities). Children were followed up 2 weeks after discharge or their last clinical visit. The primary study outcome was the case fatality ratio at 2 weeks. Associations between SpO2 and blood glucose levels and death were evaluated using Cox proportional hazards models and the treatment effect of hospitalization was assessed using propensity score matching. Findings Of 826 children recruited, 784 (94.9%) completed follow-up. At presentation, hypoxaemia was moderate (SpO2: 90­93%) in 13.1% (108/826) and severe (SpO2: < 90%) in 8.6% (71/826) and hypoglycaemia was moderate (blood glucose: 2.5­4.0 mmol/L) in 9.0% (74/826) and severe (blood glucose: < 2.5 mmol/L) in 2.3% (19/826). The case fatality ratio was 3.7% (29/784) overall but 26.3% (5/19) in severely hypoglycaemic children and 12.7% (9/71) in severely hypoxaemic children. Neither moderate hypoglycaemia nor moderate hypoxaemia was associated with mortality. Conclusion Presumptive pre-referral glucose treatment and better management of hypoglycaemia could reduce the high case fatality ratio observed in children with severe hypoglycaemia. The morbidity and mortality burden of severe hypoxaemia was high; ways of improving hypoxaemia identification and management are needed.

Implementation research on management of sick young infants with possible serious bacterial infection when referral is not possible in Jimma Zone, Ethiopia: Challenges and solutions.

INTRODUCTION: Of 2.5 million newborn deaths each year, serious neonatal infections are a leading cause of neonatal death for which inpatient treatment is recommended. However, manysick newborns in sub-Saharan Africa and south Asia do not have access to inpatientcare. A World Health Organization (WHO) guideline recommends simplified antibiotic treatment atan outpatient level for young infants up to two months of age with possible serious bacterial infection (PSBI), when referral is not feasible.We implemented this guidelinein Ethiopia to increase coverage of treatment and to learn about potential facilitating factors and barriers for implementation. METHODS: We conducted implementation research in two districts (Tiro Afata and Gera) in Jimma Zone, Ethiopia, to learn about the feasibility of implementing the WHO PSBI guideline within a programme setting using the existing health care structure. We conducted orientation meetings and policy dialogue with key stakeholders and trained health extension workers and health centre staff to identify and manage sick young infants with PSBI signs at a primary health care unit. We established a Technical Support Unit (TSU) to facilitate programme learning, built health workers' capacity and provided support for quality control, monitoring and data collection.We sensitized the community to appropriate care-seeking and supported the health care system in implementation. The research team collected data using structured case recording forms. RESULTS: From September 2016 to August 2017, 6185 live births and 601 sick young infants 0-59 days of age with signs of PSBI were identified. Assuming that 25% of births were missed (total births 7731) and 10% of births had an episode of PSBI in the first two months of life, the coverage of appropriate treatment for PSBI was 77.7% (601/773). Of 601 infants with PSBI, fast breathing only (pneumonia) was recorded in 432 (71.9%) infants 7-59 days of age; signs of clinical severe infection (CSI) in 155 (25.8%) and critical illnessin 14 (2.3%). Of the 432 pneumonia cases who received oral amoxicillin treatment without referral, 419 (97.0%) were successfully treated without any deaths. Of 169 sick young infants with either CSI or critical illness, only 110 were referred to a hospital; 83 did not accept referral advice and received outpatient injectable gentamicin plus oral amoxicillin treatment either at a health post or health centre. Additionally, 59 infants who should have been referred, but were not received injectable gentamicin plus oral amoxicillin outpatient treatment. Of infants with CSI, 129 (82.2%) were successfully treated as outpatients, while two died (1.3%). Of 14 infants with critical illness, the caregivers of five accepted referral to a hospital, and nine were treated with simplified antibiotics on an outpatient basis. Two of 14 (14.3%) infants with critical illness died within 14 days of initial presentation. CONCLUSION: In settings where referral to a hospital is not feasible, young infants with PSBI can be treated on an outpatient basis at either a health post or health centre, which can contribute to saving many lives. Scaling-up will require health system strengthening including community mobilization. REGISTRATION: Trial is registered on Australian New Zealand Clinical Trials registry (ANZCTR) ACTRN12617001373369.

Community-based amoxicillin treatment for fast breathing pneumonia in young infants 7-59 days old: a cluster randomised trial in rural Bangladesh, Ethiopia, India and Malawi.

INTRODUCTION: Young infants 7-59 days old with fast breathing pneumonia presented to a primary level health facility receive a 7-day course of amoxicillin as per the WHO guideline. However, community-level health workers (CLHW) are not allowed to treat these infants. This trial evaluated the community level treatment of non-hypoxaemic young infants with fast breathing pneumonia by CLHWs. METHODS: This cluster-randomised, open-label, non-inferiority trial was conducted in rural areas of Bangladesh, Ethiopia, India and Malawi. We randomly allocated clusters (first-level health facility) 1:1, stratified by the population size, to an intervention group (enhanced community case management) or control group (standard community case management). Infants aged 7-59 days with a respiratory rate of ≥60 breaths/min and oxygen saturation (SpO2) ≥90% were enrolled. In the intervention clusters, these infants were treated with a 7-day course of oral amoxicillin (according to WHO weight bands) and were regularly followed up by CLHWs. In the control clusters, CLHWs continued the standard management (assess and refer after pre-referral antibiotic dose) and followed up according to the national programme guideline. The primary outcome of treatment failure was assessed in both groups by independent outcome assessors on days 6 and 14 after enrolment. Secondary outcomes (accuracy and impact of pulse oximetry) were also assessed. RESULTS: Between September 2016 and December 2018, we enrolled 2334 infants (1168 in intervention and 1166 in control clusters) from 208 clusters (104 intervention and 104 control). Of 2334, 22 infants with fast breathing were excluded from analysis, leaving 2312 (1155 in intervention clusters and 1157 in control clusters) for intention-to-treat analysis. The proportion of treatment failure was 5.4% (63/1155) in intervention and 6.3% (73/1157) in the control clusters, including two deaths (0.2%) in each group. The adjusted risk difference for treatment failure between the two groups was -1.0% (95% CI -3.0% to 1.1%). The secondary outcome showed that CLHWs in the intervention clusters performed all recommended steps of pulse oximetry assessment in 94% (1050/1115) of enrolled patients. CONCLUSIONS: The 7-day amoxicillin treatment for 7-59 days old non-hypoxaemic infants with fast breathing pneumonia by CLHWs was non-inferior to the currently recommended referral strategy. TRIAL REGISTRATION NUMBERS: CTRI/2017/02/007761 and ACTRN12617000857303.

Improving quality of care for pregnancy, perinatal and newborn care at district and sub-district public health facilities in three districts of Haryana, India: An Implementation study.

INTRODUCTION: Improving quality of care (QoC) for childbirth and sick newborns is critical for maternal and neonatal mortality reduction. Information on the process and impact of quality improvement at district and sub-district hospitals in India is limited. This implementation research was prioritized by the Haryana State (India) to improve the QoC for maternal and newborn care at the busy hospitals in districts. METHODS: This study at nine district and sub-district referral hospitals in three districts (Faridabad, Rewari and Jhajjar) during April 2017-March 2019 adopted pre-post, quasi-experimental study design and plan-do-study-act quality improvement method. During the six quarterly plan-do-study-act cycles, the facility and district quality improvement teams led the gap identification, solution planning and implementation with external facilitation. The external facilitators monitored and collected data on indicators related to maternal and newborn service availability, patient satisfaction, case record quality, provider's knowledge and skills during the cycles. These indicators were compared between baseline (pre-intervention) and endline (post-intervention) cycles for documenting impact. RESULTS: The interventions closed 50% of gaps identified, increased the number of deliveries (1562 to 1631 monthly), improved care of pregnant women in labour with hypertension (1.2% to 3.9%, p<0.01) and essential newborn care services at birth (achieved ≥90% at most facilities). Antenatal identification of high-risk pregnancies increased from 4.1% to 8.8% (p<0.01). Hand hygiene practices improved from 35.7% to 58.7% (p<0.01). The case record completeness improved from 66% to 87% (p<0.01). The time spent in antenatal clinics declined by 19-42 minutes (p<0.01). The pooled patient satisfaction scores improved from 82.5% to 95.5% (p<0.01). Key challenges included manpower shortage, staff transfers, leadership change and limited orientation for QoC. CONCLUSION: This multipronged quality improvement strategy improved the maternal and newborn services, case documentation and patient satisfaction at district and sub-district hospitals. The processes and lessons learned shall be useful for replicating and scaling up.

Lessons from implementation research on community management of Possible Serious Bacterial Infection (PSBI) in young infants (0-59 days), when the referral is not feasible in Palwal district of Haryana, India.

BACKGROUND: Neonatal sepsis is a major cause of death in India, which needs hospital management but many families cannot access hospitals. The World Health Organization and the Government of India developed a guideline to manage possible serious bacterial infection (PSBI) when a referral is not feasible. We implemented this guideline to achieve high coverage of treatment of PSBI with low mortality. METHODOLOGY: The implementation research study was conducted in over 50 villages of Palwal district, Haryana during August 2017-March 2019 and covered a population of 199143. Policy dialogue with central, state and district health authorities was held before initiation of the study. A baseline assessment of the barriers in the implementation of the PSBI intervention was conducted. The intervention was implemented in the program setting. The research team collected data throughout and also co-participated in the implementation of the intervention for the first six months to identify bottlenecks in the health system and at the community level. RE-AIM framework was utilized to document implementation strategies of PSBI management guideline. Implementation strategies by the district technical support unit (TSU) included: (i) empower mothers and families through social mobilization to improve care-seeking of sick young infants 0-59 days of age, (ii) build capacity through training and build confidence through technical support of health staff at primary health centers (PHC), community health centers (CHC) and sub-centers to manage young infants with PSBI signs and (iii) improve performance of accredited social health activists (ASHAs). FINDINGS: A total of 370 young infants with signs of PSBI were identified and managed in 5270 live births. Treatment coverage was 70% assuming that 10% of live births would have PSBI within the first two months of life. Mothers identified 87.6% (324/370) of PSBI cases. PHCs and CHCs became functional and managed 150 (40%) sick young infants with PSBI. Twenty four young infants (7-59days) who had only fast breathing were treated with oral amoxicillin without a referral. Referral to a hospital was refused by 126 (84%); 119 had clinical severe infection (CSI), one 0-6 days old had fast breathing and six had critical illness (CI). Of 119 CSI cases managed on outpatient injection gentamicin and oral amoxicillin, 116 (96.7%) recovered, 55 (45.8%) received all seven gentamicin injections and only one died. All 7-59 day old infants with fast breathing recovered, 23 on outpatient oral amoxicillin treatment; and 19 (79%) received all doses. Of 65 infants managed at either district or tertiary hospital, two (3.1%) died, rest recovered. Private providers managed 155 (41.9%) PSBI cases, all except one recovered, but sub-classification and treatment were unknown. Sub-centers could not be activated to manage PSBI. CONCLUSION: The study demonstrated resolution of implementation bottlenecks with existing resources, activated PHCs and CHCs to manage CSI and fast breathers (7-59 day old) on an outpatient basis with low mortality when a referral was not feasible. TSU was instrumental in these achievements. We established the effectiveness of oral amoxicillin alone in 7-59 days old fast breathers and recommend a review of the current national policy.

Clinical signs of possible serious infection and associated mortality among young infants presenting at first-level health facilities.

BACKGROUND: The World Health Organization recommends inpatient hospital treatment of young infants up to two months old with any sign of possible serious infection. However, each sign may have a different risk of death. The current study aims to calculate the case fatality ratio for infants with individual or combined signs of possible serious infection, stratified by inpatient or outpatient treatment. METHODS: We analysed data from the African Neonatal Sepsis Trial conducted in five sites in the Democratic Republic of the Congo, Kenya and Nigeria. Trained study nurses classified sick infants as pneumonia (fast breathing in 7-59 days old), severe pneumonia (fast breathing in 0-6 days old), clinical severe infection [severe chest indrawing, high (> = 38°C) or low body temperature (<35.5°C), stopped feeding well, or movement only when stimulated] or critical illness (convulsions, not able to feed at all, or no movement at all), and referred them to a hospital for inpatient treatment. Infants whose caregivers refused referral received outpatient treatment. The case fatality ratio by day 15 was calculated for individual and combined clinical signs and stratified by place of treatment. An infant with signs of clinical severe infection or severe pneumonia was recategorised as having low- (case fatality ratio ≤2%) or moderate- (case fatality ratio >2%) mortality risk. RESULTS: Of 7129 young infants with a possible serious infection, fast breathing (in 7-59 days old) was the most prevalent sign (26%), followed by high body temperature (20%) and severe chest indrawing (19%). Infants with pneumonia had the lowest case fatality ratio (0.2%), followed by severe pneumonia (2.0%), clinical severe infection (2.3%) and critical illness (16.9%). Infants with clinical severe infection had a wide range of case fatality ratios for individual signs (from 0.8% to 11.0%). Infants with pneumonia had similar case fatality ratio for outpatient and inpatient treatment (0.2% vs. 0.3%, p = 0.74). Infants with clinical severe infection or severe pneumonia had a lower case fatality ratio among those who received outpatient treatment compared to inpatient treatment (1.9% vs. 6.5%, p<0.0001). We recategorised infants into low-mortality risk signs (case fatality ratio ≤2%) of clinical severe infection (high body temperature, or severe chest indrawing) or severe pneumonia and moderate-mortality risk signs (case fatality ratio >2%) (stopped feeding well, movement only when stimulated, low body temperature or multiple signs of clinical severe infection). We found that both categories had four times lower case fatality ratio when treated as outpatient than inpatient treatment, i.e., 1.0% vs. 4.0% (p<0.0001) and 5.3% vs. 22.4% (p<0.0001), respectively. In contrast, infants with signs of critical illness had nearly two times higher case fatality ratio when treated as outpatient versus inpatient treatment (21.7% vs. 12.1%, p = 0.097). CONCLUSIONS: The mortality risk differs with clinical signs. Young infants with a possible serious infection can be grouped into those with low-mortality risk signs (high body temperature, or severe chest indrawing or severe pneumonia); moderate-mortality risk signs (stopped feeding well, movement only when stimulated, low body temperature or multiple signs of clinical severe infection), or high-mortality risk signs (signs of critical illness). New treatment strategies that consider differential mortality risks for the place of treatment and duration of inpatient treatment could be developed and evaluated based on these findings. CLINICAL TRIAL REGISTRATION: This trial was registered with the Australian New Zealand Clinical Trials Registry under ID ACTRN 12610000286044.

Management of possible serious bacterial infection in young infants where referral is not possible in the context of existing health system structure in Ibadan, South-west Nigeria.

INTRODUCTION: Neonatal infections contribute substantially to infant mortality in Nigeria and globally. Management requires hospitalization, which is not accessible to many in low resource settings. World Health Organization developed a guideline to manage possible serious bacterial infection (PSBI) in young infants up to two months of age when a referral is not feasible. We evaluated the feasibility of implementing this guideline to achieve high coverage of treatment. METHODS: This implementation research was conducted in out-patient settings of eight primary health care centres (PHC) in Lagelu Local Government Area (LGA) of Ibadan, Oyo State, Nigeria. We conducted policy dialogue with the Federal and State officials to adopt the WHO guideline within the existing programme setting and held orientation and sensitization meetings with communities. We established a Technical Support Unit (TSU), built the capacity of health care providers, supervised and mentored them, monitored the quality of services and collected data for management and outcomes of sick young infants with PSBI signs. The Primary Health Care Directorate of the state ministry and the local government led the implementation and provided technical support. The enablers and barriers to implementation were documented. RESULTS: From 1 April 2016 to 31 July 2017 we identified 5278 live births and of these, 1214 had a sign of PSBI. Assuming 30% of births were missed due to temporary migration to maternal homes for delivery care and approximately 45% cases came from outside the catchment area due to free availability of medicines, the treatment coverage was 97.3% (668 cases/6861 expected births) with an expected 10% PSBI prevalence within the first 2 months of life. Of 1214 infants with PSBI, 392 (32%) infants 7-59 days had only fast breathing (pneumonia), 338 (27.8%) infants 0-6 days had only fast breathing (severe pneumonia), 462 (38%) presented with signs of clinical severe infection (CSI) and 22 (1.8%) with signs of critical illness. All but two, 7-59 days old infants with pneumonia were treated with oral amoxicillin without a referral; 80% (312/390) adhered to full treatment; 97.7% (381/390) were cured, and no deaths were reported. Referral to the hospital was not accepted by 87.7% (721/822) families of infants presenting with signs of PSBI needing hospitalization (critical illness 5/22; clinical severe infection; 399/462 and severe pneumonia 317/338). They were treated on an outpatient basis with two days of injectable gentamicin and seven days of oral amoxicillin. Among these 81% (584/721) completed treatment; 97% (700/721) were cured, and three deaths were reported (two with critical illness and one with clinical severe infection). We identified health system gaps including lack of staff motivation and work strikes, medicines stockouts, sub-optimal home visits that affected implementation. CONCLUSIONS: When a referral is not feasible, outpatient treatment for young infants with signs of PSBI is possible within existing programme structures in Nigeria with high coverage and low case fatality. To scale up this intervention successfully, government commitment is needed to strengthen the health system, motivate and train health workers, provide necessary commodities, establish technical support for implementation and strengthen linkages with communities. REGISTRATION: Trial is registered on Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12617001373369.