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.

Predictive value of pulse oximetry for mortality in infants and children presenting to primary care with clinical pneumonia in rural Malawi: A data linkage study.

BACKGROUND: The mortality impact of pulse oximetry use during infant and childhood pneumonia management at the primary healthcare level in low-income countries is unknown. We sought to determine mortality outcomes of infants and children diagnosed and referred using clinical guidelines with or without pulse oximetry in Malawi. METHODS AND FINDINGS: We conducted a data linkage study of prospective health facility and community case and mortality data. We matched prospectively collected community health worker (CHW) and health centre (HC) outpatient data to prospectively collected hospital and community-based mortality surveillance outcome data, including episodes followed up to and deaths within 30 days of pneumonia diagnosis amongst children 0-59 months old. All data were collected in Lilongwe and Mchinji districts, Malawi, from January 2012 to June 2014. We determined differences in mortality rates using <90% and <93% oxygen saturation (SpO2) thresholds and World Health Organization (WHO) and Malawi clinical guidelines for referral. We used unadjusted and adjusted (for age, sex, respiratory rate, and, in analyses of HC data only, Weight for Age Z-score [WAZ]) regression to account for interaction between SpO2 threshold (pulse oximetry) and clinical guidelines, clustering by child, and CHW or HC catchment area. We matched CHW and HC outpatient data to hospital inpatient records to explore roles of pulse oximetry and clinical guidelines on hospital attendance after referral. From 7,358 CHW and 6,546 HC pneumonia episodes, we linked 417 CHW and 695 HC pneumonia episodes to 30-day mortality outcomes: 16 (3.8%) CHW and 13 (1.9%) HC patients died. SpO2 thresholds of <90% and <93% identified 1 (6%) of the 16 CHW deaths that were unidentified by integrated community case management (iCCM) WHO referral protocol and 3 (23%) and 4 (31%) of the 13 HC deaths, respectively, that were unidentified by the integrated management of childhood illness (IMCI) WHO protocol. Malawi IMCI referral protocol, which differs from WHO protocol at the HC level and includes chest indrawing, identified all but one of these deaths. SpO2 < 90% predicted death independently of WHO danger signs compared with SpO2 ≥ 90%: HC Risk Ratio (RR), 9.37 (95% CI: 2.17-40.4, p = 0.003); CHW RR, 6.85 (1.15-40.9, p = 0.035). SpO2 < 93% was also predictive versus SpO2 ≥ 93% at HC level: RR, 6.68 (1.52-29.4, p = 0.012). Hospital referrals and outpatient episodes with referral decision indications were associated with mortality. A substantial proportion of those referred were not found admitted in the inpatients within 7 days of referral advice. All 12 deaths in 73 hospitalised children occurred within 24 hours of arrival in the hospital, which highlights delay in appropriate care seeking. The main limitation of our study was our ability to only match 6% of CHW episodes and 11% of HC episodes to mortality outcome data. CONCLUSIONS: Pulse oximetry identified fatal pneumonia episodes at HCs in Malawi that would otherwise have been missed by WHO referral guidelines alone. Our findings suggest that pulse oximetry could be beneficial in supplementing clinical signs to identify children with pneumonia at high risk of mortality in the outpatient setting in health centres for referral to a hospital for appropriate management.

Care-seeking patterns amongst suspected paediatric pneumonia deaths in rural Malawi.

Background: Pneumonia remains a leading cause of paediatric deaths. To understand contextual challenges in care pathways, we explored patterns in care-seeking amongst children who died of pneumonia in Malawi. Methods: We conducted a mixed-methods analysis of verbal autopsies (VA) amongst deaths in children aged 1-59 months from 10/2011 to 06/2016 in Mchinji district, Malawi. Suspected pneumonia deaths were defined as: 1. caregiver reported cough and fast breathing in the 2-weeks prior to death; or, 2. the caregiver specifically stated the child died of pneumonia; or 3. cause of death assigned as 'acute respiratory infection' using InterVA-4. Data were extracted from free-text narratives based on domains in the 'Pathways to Survival' framework, and described using proportions. Qualitative analysis used a framework approach, with pre-specified themes. Results: We analysed 171 suspected pneumonia deaths. In total, 86% of children were taken to a healthcare facility during their final illness episode, and 44% sought care more than once.  Of children who went to hospital (n=119), 70% were admitted, and 25% received oxygen. Half of the children died within a healthcare setting (43% hospital, 5% health centre and 2% private clinics), 64 (37%) at home, and 22 (13%) in transit. Challenges in delayed care, transport and quality of care (including oxygen), were reported. Conclusions: Healthcare was frequently sought for children who died of suspected pneumonia, however several missed opportunities for care were seen. Sustained investment in timely appropriate care seeking, quick transportation to hospital and improved case management at all levels of the system is needed.

Antenatal iron-folic acid supplementation reduces risk of low birthweight in Pakistan: secondary analysis of Demographic and Health Survey 2006-2007.

The aim of the current study was to examine the impact of antenatal iron-folic acid (IFA) supplementation on perceived birth size and birthweight in Pakistan over a 5-year period from 2002 to 2006. The data source was the Pakistan Demographic and Health Survey (PDHS) 2006-2007. Information from 5692 most recent live-born infants within 5 years prior to the survey was examined. The primary outcomes were maternal perception of birth size and birthweight, and the main exposure was any use of antenatal IFA supplements. Birthweight was reported for only 10% of the live births in the PDHS 2006-2007. Multivariate logistic regression analysis was adjusted for the cluster sampling design and for 13 potential confounders. The risk of having smaller than average birth size newborn was significantly reduced by 18% (adjusted odds ratio 0.82, 95% confidence interval 0.71, 0.96) for mothers who used any IFA supplements compared with those who did not. A similar (18%), but non-significant reduction in the risk of low birthweight, was found with the maternal use of IFA supplements. The risk of having smaller than average birth size babies was significantly reduced by 19% in those women who started IFA in the first trimester of pregnancy. About 11% of babies with smaller than average birth size were attributed to non-use of antenatal IFA supplements. Antenatal IFA supplementation significantly reduces the risk of a newborn of smaller than average birth size in Pakistan. Universal coverage of supplementation would improve birth size.

Low rates of treatment failure in children aged 2-59 months treated for severe pneumonia: a multisite pooled analysis.

BACKGROUND: Despite advances in childhood pneumonia management, it remains a major killer of children worldwide. We sought to estimate global treatment failure rates in children aged 2-59 months with World Health Organization-defined severe pneumonia. METHODS: We pooled data from 4 severe pneumonia studies conducted during 1999-2009 using similar methodologies. We defined treatment failure by day 6 as death, danger signs (inability to drink, convulsions, abnormally sleepy), fever (≥38°C) and lower chest indrawing (LCI; days 2-3), LCI (day 6), or antibiotic change. RESULTS: Among 6398 cases of severe pneumonia from 10 countries, 564 (cluster adjusted: 8.5%; 95% confidence interval [CI], 5.9%-11.5%) failed treatment by day 6. The most common reasons for clinical failure were persistence of fever and LCI or LCI or fever alone (75% of failures). Seventeen (0.3%) children died. Danger signs were uncommon (<1%). Infants 6-11 months and 2-5 months were 2- and 3.5-fold more likely, respectively, to fail treatment (adjusted OR [AOR], 1.8 [95% CI, 1.4-2.3] and AOR, 3.5 [95% CI, 2.8-4.3]) as children aged 12-59 months. Failure was increased 7-fold (AOR, 7.2 [95% CI, 5.0-10.5]) when comparing infants 2-5 months with very fast breathing to children 12-59 months with normal breathing. CONCLUSIONS: Our findings demonstrate that severe pneumonia case management with antibiotics at health facilities or in the community is associated with few serious morbidities or deaths across diverse geographic settings and support moves to shift management of severe pneumonia with oral antibiotics to outpatients in the community.

Impact of essential surgical skills with an emphasis on emergency maternal, neonatal and child health training on the practice of doctors: a cluster randomised controlled trial in Pakistan.

INTRODUCTION: Majority of studies on evaluation of emergency management courses have focused on outcomes such as knowledge and skills demonstrated in non-clinical or traditional testing manner. Such surrogate outcomes may not necessarily reflect vital changes in practice. The aim of this study was to determine if and to what extent, specific training in the management of life threatening emergencies resulted in an increased in compliance with established care guidelines of doctors working in the emergency departments of public sector hospitals in Pakistan. METHODS: A cluster randomised controlled trial was conducted in three districts hospitals in three cities (Khairpur, Vehari and Peshawar) of Pakistan. Thirty-six doctors, 18 in intervention (trained in ESS-EMNCH training) and 18 in control (untrained), were enrolled and 248 life threatening emergency events, 124 in each group, were observed for the correct use of the Airway, Breathing, Circulation (ABC) structured approach. The outcome measure was structured approach defined a priori. Data was analysed by using STATA software. RESULTS: At individual level, 79 (63.7%) life threatening episodes were managed according to the structured approach in the intervention group and 46 (37.1%) were managed according to the structured approach in controls (OR 2.98, 95%CI 1.78-4.99, p-value=0.0001). At cluster level, the mean percentage (95% CI) of the structured approach used by doctors in the intervention group [62.9% (50.4-75.3%)], was significantly higher than those in the control group, [36.3% (26.3-46.4)] (p-value=0.001). CONCLUSIONS: 5-day training of ESS-EMNCH significantly increased the compliance with established care guidelines of doctors during their management of life threatening emergency episodes in the public sector hospitals in Pakistan.

Comparison of standard versus double dose of amoxicillin in the treatment of non-severe pneumonia in children aged 2-59 months: a multi-centre, double blind, randomised controlled trial in Pakistan.

INTRODUCTION: WHO pneumonia case management guidelines recommend oral amoxicillin as first line treatment for non-severe pneumonia. Increasing treatment failure rates have been reported over a period of time, which could possibly be due to increasing minimum inhibitory concentrations of Streptococcus pneumoniae and Haemophilus influenzae for amoxicillin. Microbiological data show that this resistance can be overcome by increasing amoxicillin dosage. Based on this data, we examined whether we can improve the clinical outcome in non-severe pneumonia by doubling the dose of amoxicillin. METHODS: A double blind randomised controlled trial was conducted in the outpatient departments of four large hospitals in Pakistan. Children aged 2-59 months with non-severe pneumonia were randomised to receive either standard (45 mg/kg/day) or double dose (90 mg/kg/day) oral amoxicillin for 3 days and then followed up for 14 days. Final outcome was treatment failure by day 5. RESULTS: From September 2003 to June 2004, 876 children completed the study. 437 were randomised to standard and 439 to double dose oral amoxicillin. 20 (4.5%) children in the standard and 25 (5.7%) in the double dose group had therapy failure by day 5. Including the relapses, by day 14 there were 26 (5.9%) cumulative therapy failures with standard and 35 (7.9%) with double dose amoxicillin. These differences were not statistically significant (p = 0.55 and p = 0.29, respectively). CONCLUSION: Clinical outcome in children aged 2-59 months with non-severe pneumonia is the same with standard and double dose oral amoxicillin. Non-severe pneumonia can be treated effectively and safely with a 3 day course of a standard dose.