David Paul Moore

Background: Severe community-acquired pneumonia (CAP) remains a leading cause of mortality in children under five. The PediCAP trial evaluated oral step-down therapy using dispersible amoxicillin or amoxicillin/clavulanate tablets in African children hospitalised with severe CAP. Dispersible tablet formulations are preferred in children; however, pharmacokinetic data for oral amoxicillin/clavulanate in paediatric populations remain limited. We characterised the pharmacokinetics of 4:1, 7:1, and 14:1 dispersible amoxicillin/clavulanate tablets in children enrolled in the PediCAP trial and predicted target attainment under different dosing schemes. Methods: Children were randomised within 24 hours of starting intravenous antibiotics to oral step-down therapy with weight-banded dosing of twice-daily amoxicillin/clavulanate (4:1, 7:1, or 14:1). Plasma concentrations were quantified following intensive sampling and analysed using nonlinear mixed-effects modelling with allometric scaling and postmenstrual age-dependent clearance maturation. Pharmacodynamic indices included %fT>MIC for amoxicillin and %fT>C _t for clavulanate. Results: A total of 157 children (median [range] age, 12 [2–70] months; weight, 8.4 [4.0-22.0] kg) contributed 707 paired concentrations. Amoxicillin was described by a two-compartment model and clavulanate by a one-compartment model, both with sequential zero-and first-order absorption. Typical clearance for an 8-kg individual at full maturation was 11.8L/h for amoxicillin and 6.1L/h for clavulanate. Pharmacokinetics were similar between the formulation ratios. Weight-banded dosing achieved balanced exposures across weight groups. Amoxicillin achieved 40%fT>MIC for MICs≤2mg/L. A proposed clavulanate target of 20%fT>0.5mg/L was achieved in most children even at the lowest amoxicillin/clavulanate ratio. Conclusion: Weight-banded dosing using dispersible amoxicillin/clavulanate tablets provide consistent exposure profiles in African children with severe CAP. SUMMARY: Population pharmacokinetic modelling of dispersible amoxicillin/clavulanate tablets (4:1, 7:1, 14:1) in 157 African children with severe pneumonia showed weight-banded dosing achieved consistent and adequate amoxicillin and clavulanate exposures across formulations.

Objectives: Risk stratification tools for childhood pneumonia may improve identification of children at highest risk of death in low-resource settings. However, added value over the WHO Integrated Management of Childhood Illness (IMCI) criteria and danger signs remains uncertain. We compared the performance of published paediatric pneumonia risk scores with WHO-IMCI criteria and WHO danger signs. Design: Secondary analysis of a multi-country randomised controlled trial Setting: Thirteen hospitals in Mozambique, South Africa, Uganda, Zambia, and Zimbabwe. Participants: Children aged 2-59 months without HIV hospitalised with WHO-defined severe community-acquired pneumonia in the PediCAP trial. Children requiring intensive care or invasive ventilation were excluded. Primary and secondary outcome measures: The primary outcome was in-hospital mortality. The exploratory outcome was readmission or death by day 28. Discrimination was assessed using area under the receiver operating characteristic curve (ROC-AUC). Results: Among 1052 children, 18 (1.7%) died in hospital and 22 (2.1%) died in hospital or within 7 days of discharge. Among 1010 children with day-28 follow-up, 63 (6.2%) died or were readmitted by day 28. ROC-AUC point estimates for in-hospital mortality ranged from approximately 0.73 to 0.87. WHO danger signs had lower point estimate than the other scores, although confidence intervals overlapped substantially and no score demonstrated clear superiority. In contrast, all approaches showed limited discrimination for the exploratory outcome of 28-day readmission or death (ROC-AUC approximately 0.54-0.57). Conclusions: In this multi-country cohort of children hospitalised with severe pneumonia, no score demonstrated clear superiority for mortality prediction, although point estimates of AUC-ROC scores ranged from 0.75 (Danger signs) to 0.87 (RISC-MGMU). Published risk scores and WHO-IMCI criteria showed broadly similar performance. These findings suggest that opportunities to improve risk stratification in low-resource settings may lie not only in developing new tools, but also in optimising the delivery and use of existing WHO IMCI-based assessment. Trial Registration: ISRCTN63115131 What is already known on this topic: Several clinical risk scores have been developed to predict mortality in childhood pneumonia, with some validation studies in low-resource settings, although direct comparisons across multiple risk stratification tools within the same population are limited. WHO IMCI criteria are widely used in many low-resource settings, but performance relative to published risk stratification tools remains uncertain. What this study adds: In a multi-country African cohort of children hospitalised with severe pneumonia, published paediatric pneumonia risk scores and WHO IMCI criteria showed broadly similar point estimates for mortality prediction, with no score demonstrating clear superiority. WHO danger signs generally had lower point estimates than the published risk scores and WHO IMCI criteria, although confidence intervals overlapped substantially. How this study might affect research, practice, or policy: These findings suggest that opportunities to improve risk stratification in low-resource settings may lie not only in developing new tools, but also in optimising the delivery and use of existing WHO IMCI-based assessment.

Coronavirus disease 2019 (COVID-19) following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection caused a 41-month global public health emergency (January 2020–May 2023). Although the pandemic has subsided, there is ongoing concern about emerging viral variants [1]. Furthermore, knowledge gaps persist regarding paediatric COVID-19 clinical presentation, treatment and outcomes in high HIV prevalence settings, with […]

Antimicrobial resistance (AMR) poses a global threat, partly fueled by antimicrobial overuse. Paediatric inpatients are particularly vulnerable to infections, leading to high antimicrobial consumption. In low-to-middle income countries (LMICs) like South Africa, research on antimicrobial usage for neonatal and paediatric healthcare-associated infections (HAI) is limited. This cross-sectional study evaluated antimicrobial usage in three academic public sector hospitals in South Africa to improve appropriateness. 22.9% of hospitalised children received at least one prescribed antimicrobial, with neonates, infants, and adolescents having higher prescription rates for HAIs. Common antimicrobials prescribed included beta-lactamase sensitive penicillin, aminoglycosides, and carbapenems. Antimicrobial selection aligned with the WHO AWaRe classification system. HIV infection did not emerge as a risk factor for HAIs or excessive antimicrobial usage. The policy brief recommends several strategies, summarized by the acronym 'PRACTICE,' to optimize antimicrobial prescribing practices. These include implementing standardized policies for empiric antimicrobial use, routine review of antimicrobial therapy, age-specific antimicrobial stewardship programs, and continued collaborative efforts and research. Individualized treatment plans, improved infection prevention and control measures, ongoing surveillance, and exploring electronic technology for antimicrobial stewardship are also crucial. Addressing antimicrobial usage is imperative to combat the growing threat of AMR and improve patient outcomes in LMICs like South Africa.

Endemic human coronaviruses (HCoV) are capable of causing a range of diseases from the common cold to pneumonia. We evaluated the epidemiology and seasonality of endemic HCoVs in children hospitalized with clinical pneumonia and among community controls living in countries with a high HIV burden, namely South Africa and Zambia, between August 2011 to October 2013. Nasopharyngeal/oropharyngeal swabs were collected from all cases and controls and tested for endemic HCoV species and 12 other respiratory viruses using a multiplex real-time PCR assay. We found that the likelihood of detecting endemic HCoV species was higher among asymptomatic controls than cases (11% vs. 7.2%; 95% CI: 1.2–2.0). This was however only observed among children > 6 months and was mainly driven by the Betacoronavirus endemic species (HCoV-OC43 and –HKU1). Endemic HCoV species were detected through the year; however, in Zambia, the endemic Betacoronavirus species tended to peak during the winter months (May–August). There was no association between HIV status and endemic HCoV detection.

Rhinovirus (RV) is commonly detected in asymptomatic children; hence, its pathogenicity during childhood pneumonia remains controversial. We evaluated RV epidemiology in HIV-uninfected children hospitalized with clinical pneumonia and among community controls. PERCH was a case-control study that enrolled children (1–59 months) hospitalized with severe and very severe pneumonia per World Health Organization clinical criteria and age-frequency-matched community controls in seven countries. Nasopharyngeal/oropharyngeal swabs were collected for all participants, combined, and tested for RV and 18 other respiratory viruses using the Fast Track multiplex real-time PCR assay. RV detection was more common among cases (24%) than controls (21%) (aOR = 1.5, 95%CI:1.3–1.6). This association was driven by the children aged 12–59 months, where 28% of cases vs. 18% of controls were RV-positive (aOR = 2.1, 95%CI:1.8–2.5). Wheezing was 1.8-fold (aOR 95%CI:1.4–2.2) more prevalent among pneumonia cases who were RV-positive vs. RV-negative. Of the RV-positive cases, 13% had a higher probability (>75%) that RV was the cause of their pneumonia based on the PERCH integrated etiology analysis; 99% of these cases occurred in children over 12 months in Bangladesh. RV was commonly identified in both cases and controls and was significantly associated with severe pneumonia status among children over 12 months of age, particularly those in Bangladesh. RV-positive pneumonia was associated with wheezing.

Diagnosis and management of community-acquired pneumonia in children: South African Thoracic Society guidelines