Antibiotic and antifungal use in paediatric departments at three academic hospitals in South Africa.

Objectives: South Africa implemented a National Strategic Framework to optimise antimicrobial stewardship in 2014; however, there is limited data on how this has affected prescribing, especially to children treated in academic centres. Methods: We conducted a point prevalence survey using the World Health Organization (WHO) methodology to evaluate antibiotic and antifungal prescribing practices in paediatric departments at three academic hospitals in South Africa. Results: We recorded 1946 antimicrobial prescriptions in 1191 children, with 55.2% and 39.2% of the antibiotics classified as WHO AWaRe Access and Watch drugs, respectively. There were significant differences in prescription of Reserve antibiotics and antifungals between institutions. Receipt of WHO Watch and Reserve antibiotics was independently associated with infancy (<12 months) and adolescents (13-17 years) (adjusted relative risk [aRR]: 2.09-9.95); prolonged hospitalisation (aRR: 3.29-30.08); rapidly or ultimately fatal illness (aRR: 1.94 to 5.52); and blood transfusion (aRR: 3.28-5.70). Antifungal prescribing was associated with treatment of hospital-associated infection (aRR: 2.90), medical prophylaxis (aRR: 3.30), and treatment in intensive care units (aRR: 2.15-2.27). Conclusions: Guidance on optimisation of infection prevention and control practice and strengthening of antimicrobial stewardship would impact positively on the care of sick children in our setting.

Safety and Pharmacokinetics of Lopinavir/Ritonavir Oral Solution in Preterm and Term Infants Starting Before 3 Months of Age.

BACKGROUND: Study of liquid lopinavir/ritonavir (LPV/r) in young infants has been limited by concerns for its safety in neonates. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1106 was a phase IV, prospective, trial evaluating the safety and pharmacokinetics of antiretroviral medications administered according to local guidelines to South African preterm and term infants <3 months of age. Safety evaluation through 24-week follow-up included clinical, cardiac and laboratory assessments. Pharmacokinetic data from P1106 were combined with data from International Maternal Pediatric Adolescent AIDS Clinical Trials Network studies P1030 and P1083 in a population pharmacokinetics model used to simulate LPV exposures with a weight-band dosing regimen in infants through age 6 months. RESULTS: Safety and pharmacokinetics results were similar in 13/28 (46%) infants initiating LPV/r <42 weeks postmenstrual age (PMA) and in those starting ≥42 weeks PMA. LPV/r was started at a median (range) age of 47 (13-121) days. No grade 3 or higher adverse events were considered treatment related. Modeling and simulation predicted that for infants with gestational age ≥27 weeks who receive the weight-band dosing regimen, 82.6% will achieve LPV trough concentration above the target trough concentration of 1.0 µg/mL and 56.6% would exceed the observed adult lower limit of LPV exposure of 55.9 µg·h/mL through age 6 months. CONCLUSIONS: LPV/r oral solution was safely initiated in a relatively small sample size of infants ≥34 weeks PMA and >2 weeks of life. No serious drug-related safety signal was observed; however, adrenal function assessments were not performed. Weight-band dosing regimen in infants with gestational age ≥27 weeks is predicted to result in LPV exposures equivalent to those observed in other pediatric studies.

Long-term impact of serious neonatal bacterial infections on neurodevelopment.

BACKGROUND: Neonatal bacterial infections have long been recognized as an important cause of acute morbidity and mortality, but long-term neurodevelopmental consequences have not been comprehensively described and discussed. OBJECTIVES: We aimed to summarize evidence on the pathogenesis, diagnosis, and epidemiology of long-term sequelae after neonatal bacterial sepsis and meningitis. We also discuss approaches for future studies to quantify the public health impact of neonatal infection-associated neurodevelopmental impairment. SOURCES: We identified studies, both research articles and reviews, which provide mechanistic information on the long-term disease, as well as epidemiological studies that describe the frequency of neurodevelopmental impairment in children with and, for comparison, without a history of neonatal bacterial infection. Tools currently used in clinical practice and research settings to assess neurodevelopmental impairment were also reviewed. CONTENT: We first enumerate potential direct and indirect mechanisms that can lead to brain injury following neonatal infections. We then discuss summary data, either frequencies or measures of association, from epidemiological studies. Risk factors that predict long-term outcomes are also described. Finally, we describe clinical approaches for identifying children with neurodevelopmental impairment and provide an overview of common diagnostic tools. IMPLICATIONS: The limited number of studies that describe the long-term consequences of neonatal infections, often undertaken in high-income settings and using variable designs and diagnostic tools, are not sufficient to inform clinical practice and policy prioritization. Multi-country studies with follow-up into adolescence, standardized diagnostic approaches, and local comparator groups are needed, especially in low and middle-income countries where the incidence of neonatal sepsis is high.

A multicentre neonatal interventional randomised controlled trial of nebulized surfactant for preterm infants with respiratory distress: Neo-INSPIRe trial protocol.

INTRODUCTION: Respiratory distress syndrome in preterm infants is an important cause of morbidity and mortality. Less invasive methods of surfactant administration, along with the use of continuous positive airway pressure (CPAP), have improved outcomes of preterm infants. Aerosolized surfactant can be given without the need for airway instrumentation and may be employed in areas where these skills are scarce. Recent trials from high-resourced countries utilising aerosolized surfactant have had a low quality of evidence and varying outcomes. METHODS AND ANALYSIS: The Neo-INSPIRe trial is an unblinded, multicentre, randomised trial of a novel aerosolized surfactant drug/device combination. Inclusion criteria include preterm infants of 27-34+6 weeks' gestational age who weigh 900-1999g and who require CPAP with a fraction of inspired oxygen (FiO2) of 0.25-0.35 in the first 2-24 h of age. Infants are randomised 1:1 to control (CPAP alone) or intervention (CPAP with aerosolized surfactant). The primary outcome is the need for intratracheal bolus surfactant instillation within 72 h of age. Secondary outcomes include the incidence of reaching failure criteria (persistent FiO2 of > 0.40, severe apnoea or severe work of breathing), the need for and duration of ventilation and respiratory support, bronchopulmonary dysplasia and selected co-morbidities of prematurity. Assuming a 40% relative risk reduction to reduce the proportion of infants requiring intratracheal bolus surfactant from 45 to 27%, the study will aim to enrol 232 infants for the study to have a power of 80% to detect a significant difference with a type 1 error of 0.05. ETHICS AND DISSEMINATION: Ethical approval has been granted by the relevant human research ethics committees at University of Cape Town (HREC 681/2022), University of the Witwatersrand HREC (221112) and Stellenbosch University (M23/02/004). TRIAL REGISTRATION: PACTR202307490670785.

Candida auris Clinical Isolates Associated with Outbreak in Neonatal Unit of Tertiary Academic Hospital, South Africa.

Candida auris was first detected at a university-affiliated hospital in Johannesburg, South Africa, in 2009. We used whole-genome sequencing to describe the molecular epidemiology of C. auris in the same hospital during 2016-2020; the neonatal unit had a persistent outbreak beginning in June 2019. Of 287 cases with culture-confirmed C. auris infection identified through laboratory surveillance, 207 (72%) had viable isolates and 188 (66%) were processed for whole-genome sequencing. Clade III (118/188, 63%) and IV (70/188, 37%) isolates co-circulated in the hospital. All 181/188 isolates that had a fluconazole MIC >32 µg/mL had ERG11 mutations; clade III isolates had VF125AL substitutions, and clade IV isolates had K177R/N335S/E343D substitutions. Dominated by clade III, the neonatal unit outbreak accounted for 32% (91/287) of all cases during the study period. The outbreak may have originated through transmission from infected or colonized patients, colonized healthcare workers, or contaminated equipment/environment.

High Prevalence of Candida auris Colonization during Protracted Neonatal Unit Outbreak, South Africa.

One third of patients were colonized by Candida auris during a point-prevalence survey in a neonatal unit during an outbreak in South Africa. The sensitivity of a direct PCR for rapid colonization detection was 44% compared with culture. The infection incidence rate decreased by 85% after the survey and implementation of isolation/cohorting.

Single surgeon case series of myelomeningocele repairs in a developing world setting: Challenges and lessons.

Purpose: Neural Tube Defects are the second most common group of birth malformations following congenital heart anomalies, with myelomeningoceles being the most severe manifestation (MMC). They require expedited surgical repair, preferably within 72 â€‹h of birth. In low- and middle-income countries (LMIC) where resources are limited, timing to MMC repair is not optimal and leads to undesirable outcomes. The purpose of this study was to determine whether a proactive approach in a setting from a LMIC could achieve repair within 72 â€‹h. Methods: A concerted effort to expedite repair of all neonates referred with a MMC was undertaken from 01 January 2014 to 1 August 2015. A consensus was reached between neonatologists and neurosurgeons that neonates born or admitted with a MMC are referred immediately to surgeons and that repair will be performed within 72 â€‹h of birth. Hospital records of neonates who had MMC repaired during this period were reviewed for infant characteristics and hospital outcomes. Results: 24 patients with a MMC were operated upon by the senior author (CP) during the study period. Only 13 of these patients were born at the treating institution and 11 were referred from outside hospitals. Most MMCs were in the lumbosacral region and mean MMC surface area was 19.4 â€‹cm2. Mean time to repair for the entire series was 13.6 days. Patients born at the treating institution has a mean time to repair of 10.5 days and patients referred from outside had a mean time to repair of 17.3 days. Series wide, only 21% of neonates were operated upon in less than 72 â€‹h. Conclusion: Despite a pro-active commitment to repairing MMCs within 72 â€‹h for the duration of this series, satisfactory time to repair was not achieved. Late referral, referral from outside hospitals and operating theatre availability were the predominant factors leading to delay in MMC repair. Nevertheless, time to repair in our series was significantly shorter than that reported in MMC repair series based in similar environments. This suggests that even if the gold-standard of a 72-h window cannot be achieved, neonates benefit from much quicker repair when a concerted effort to minimise repair time is employed. This study also highlights the urgent need to address health care constraints in LMIC to improve outcomes for this vulnerable group.

Healthcare-associated Infections Drive Antimicrobial Prescribing in Pediatric Departments at Three Academic Hospitals in South Africa.

BACKGROUND: The prevalence of antimicrobial prescriptions for healthcare-associated infections (HAI) in South Africa is largely unknown. This study aimed to estimate the point prevalence of pediatric antibiotic and antifungal usage in 3 South African academic hospitals. METHODS: This cross-sectional study included hospitalized neonates and children (0-15 years). We used the World Health Organization methodology for antimicrobial point prevalence studies, with weekly surveys to achieve a sample size of ~400 at each site. RESULTS: Overall, 1,946 antimicrobials were prescribed to 1,191 patients. At least 1 antimicrobial was prescribed for 22.9% [95% confidence interval (CI): 15.5-32.5%] of patients. The prevalence of antimicrobial prescribing for HAI was 45.6%. In the multivariable analysis, relative to children 6-12 years, neonates [adjusted relative risk (aRR): 1.64; 95% CI: 1.06-2.53], infants (aRR: 1.57; 95% CI: 1.12-2.21) and adolescents (aRR: 2.18; 95% CI: 1.45-3.29) had significantly increased risk of prescriptions for HAI. Being preterm (aRR: 1.33; 95% CI: 1.04-1.70) and underweight (aRR: 1.25; 95% CI: 1.01-1.54) was predictive of antimicrobial usage for HAI. Having an indwelling device, surgery since admission, blood transfusions and classification as rapidly fatal on McCabe score also increased the risk of prescriptions for HAI. CONCLUSIONS: The high prevalence of antimicrobial prescribing for HAI to treat children with recognized risk factors in academic hospitals in South Africa is concerning. Concerted efforts need to be made to strengthen hospital-level infection prevention and control measures, with a critical review of antimicrobial usage through functional antibiotic stewardship programs to preserve the available antimicrobial armamentarium at the hospital level.

Challenges in the Implementation of the NeoOBS Study, a Global Pragmatic Observational Cohort Study, to Investigate the Aetiology and Management of Neonatal Sepsis in the Hospital Setting.

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

Characteristics and outcomes of neonates with intrapartum asphyxia managed with therapeutic hypothermia in a public tertiary hospital in South Africa.

BACKGROUND: In randomized clinical trials, therapeutic hypothermia (TH) has been shown to reduce death and/or moderate-to-severe disability in neonates with hypoxic ischemic encephalopathy (HIE) in high-income countries, while this has not consistently been the case in low-and middle-income countries (LMICs). Many studies reporting on outcomes of neonates with HIE managed with TH are those conducted under controlled study conditions, and few reporting in settings where this intervention is offered as part of standard of care, especially from LMICs. In this study we report on short-term outcomes of neonates with moderate-to-severe HIE where TH was offered as part of standard of care. OBJECTIVE: To determine characteristics and mortality rate at hospital discharge in neonates with moderate-to-severe HIE. METHODS: Hospital records of neonates with intrapartum asphyxia were reviewed for clinical findings, management with TH (cooled or non-cooled) and mortality at hospital discharge. Inclusion criteria were birthweight ≥ 1800 g, gestational age ≥ 36 weeks and moderate-to-severe HIE. Comparisons were made between survivors and non-survivors in cooled and/or non-cooled neonates. RESULTS: Intrapartum asphyxia was diagnosed in 856 neonates, with three having no recorded HIE status; 30% (258/853) had mild HIE, and 595/853 (69%) with moderate-to-severe HIE. The overall incidence of intrapartum asphyxia was 8.8/1000 live births. Of the 595 with moderate-to-severe HIE, three had no records on cooling and 67% (399/592) were cooled. Amongst 193 non-cooled neonates, 126 (67%) had documented reasons for not being cooled with common reasons being a moribund neonate (54.0%), equipment unavailability (11.1%), pulmonary hypertension (9.5%), postnatal age > 6 h on admission (8.7%), and improvement in severity of encephalopathy (8.7%). Overall mortality was 29.0%, being 17.0% and 53.4% in cooled and non-cooled infants respectively. On multivariate analysis, the only factor associated with mortality was severe encephalopathy. CONCLUSION: Overall mortality in neonates with moderate-to-severe HIE was 29.0% and 17.0% in those who were cooled. Cooling was not offered to all neonates mainly because of severe clinical illness, equipment unavailability and delayed presentation, making it difficult to assess overall impact of this intervention. Prospective clinical studies need to be conducted in LMIC to further assess effect of TH in short and long-term outcomes.

Hypothermia in neonates born by caesarean section at a tertiary hospital in South Africa.

Introduction: neonatal hypothermia has previously been noted in a large proportion of neonates born through Caesarean section at Chris Hani Baragwanath Hospital (CHBAH), yet no study in South Africa specifically explores the extent and severity of the threat of hypothermia to this population of neonates. Objectives: to describe the proportion and severity of neonatal hypothermia in infants born via Caesarean section at CHBAH as well as to document and describe possible contributing factors to neonatal hypothermia in this population. Methods: A neonatal unit's database records were reviewed for demographic information of patients and their mothers, clinical characteristics, body temperature and outcomes. Comparisons between normothermic and hypothermic neonates were performed. Results: Forty-one percent of neonates born via Caesarean section had hypothermia at birth, of whom 71%, 27% and 2% had mild, moderate and severe hypothermia, respectively. Prevalence of admission hypothermia was 42%. On average, neonates were born at term and were of normal birth weight. No maternal factors were found to be statistically significant. Bag-mask ventilation (BMV) and cardiopulmonary resuscitation (CPR) [3.4% vs. 0.7%, p-0.033; OR 2.67 (95% CI: 1.06-6.77)] and an elevated lactate [13.25 vs. 3.2 mmol/l, p-0.032; OR 1.13 (95% CI: 1.01-1.26)] were associated with hypothermia. In the multivariable logistic regression analysis hypothermia in neonates was associated with an elevated lactate. Conclusions: Prevalence of hypothermia in neonates born by Caesarean section is high and further prospective studies are required to elucidate the factors contributing to this.

A comparison of weight gain between HIV exposed uninfected and HIV unexposed uninfected infants who received KMC at Chris Hani Baragwanath Academic Hospital.

Introduction: Kangaroo Mother Care (KMC) has been associated with improved growth in low birthweight infants and reduction in hypothermia, hypoglycaemia, apnoeas, sepsis, hospital stay, and mortality. The growth of HIV-infected children is poorer than those who are HIV-uninfected. There is paucity of data on weight gain in the HIV-exposed uninfected (HEU) infants compared to HIV-unexposed uninfected (HUU) infants receiving KMC. Aim: This study compared the weight gain of HEU and infants HUU from admission to the KMC ward until 12 months corrected age (CA) follow-up visit. Methods: Retrospective record review of the neonates admitted in KMC at Chris Hani Baragwanath Hospital over a 2-year period (2012-2013). The weight gain was assessed via weight velocity using the formula; weight/kg/day from admission to KMC to discharge, and g/ week at term, 3, 6 and 9- and 12-months (CA). The demographics were collected and analyzed using Statistica. Results: Seventy-seven (129/166) percent of the mothers were HIV negative. HIV negative mothers were younger (25.9 vs. 31.6 years; p = 0.000) and had fewer pregnancies (p = 0.02). There was no difference between the gestational age (30.3 ± 2.53 vs. 30.8 ± 2.88 weeks; p = 0.35) and birthweight (1,345 g ± 234 vs. 1,314 g ± 209; p = 0.47) between HEU and HUU. There were no differences in the weight gain (23.83 g ± 12.2 vs. 23.22 g ± 15.2; p = 0.83) in KMC. There was no differences in weight gain at the different follow-up time points between the two groups. Conclusion: Both HEU and HUU groups of infants showed reasonable weight gain despite maternal HIV status.

An outbreak of infection due to severe acute respiratory corona virus-2 in a neonatal unit from a low and middle income setting.

Introduction: The provision of kangaroo mother care (KMC) involving continuous skin-to-skin care (SSC) is an important intervention in neonatal care, which is recommended even when women are infected with severe acute respiratory syndrome coronavirus (SARS-CoV-2). We report on a nosocomial outbreak of SARS-CoV-2 infections in a KMC ward. Methods: Contact tracing was conducted following the diagnosis of SARS-CoV-2 in a mother lodging in the KMC ward. All mother-newborn dyads in the KMC and healthcare workers (HCW) were tested for SARS-CoV-2 within 24-72 h of diagnosing the index case. Nasopharyngeal swab samples were obtained and tested from contacts, with a nucleic acid amplification test (NAAT) assay. Next-generation sequencing was done on positive samples. The secondary attack rate (SAR) was calculated assuming that the mother who presented with symptoms was the source of infection. Results: Twelve (70.6%) of 17 mothers and 8 (42.1%) of 19 neonates who were in the KMC ward with the index case were found to be positive with SARS-CoV-2. Seven (87.5%) of the 8 neonates who tested positive had mothers who also tested positive. Seventy-five percent (9/12) of the mothers and 62.5% (5/8) of the neonates who tested positive were asymptomatic. Eight (27.6%) of 29 HCW were found to be positive and were all asymptomatic. One neonate died from Acinetobacter baumannii sepsis, and his post-mortem lung histopathology showed features compatible with SARS-CoV-2 pneumonia. The sequencing of 13 specimens, which included 1 mother-newborn dyad, indicated clustering to the same phylogenetic lineage with identical mutations. In assessing for factors contributing to this outbreak, it was found that spaces between beds were less than 1 m and mothers had their meals around the same table at the same time. Conclusion: We report on a nosocomial outbreak of SARS-CoV-2 in a KMC ward, affecting a high number of mothers and neonates, and to a lesser extent HCWs. Although it is difficult to point to the index case as the source of this outbreak, as asymptomatic individuals can spread infection, the inadequate adherence to non-pharmaceutical interventions was assessed to have contributed to the spread of infection. This highlights the need for awareness and adherence to mitigation strategies to avoid SARS-CoV-2 outbreaks.

Prediction of Retinopathy of Prematurity Using the WINROP (Weight, IGF-1, Neonatal Retinopathy of Prematurity) Algorithm in a South African Population.

Aim: This study aimed to assess the efficacy of the WINROP (Weight, IGF-1, Neonatal Retinopathy of Prematurity) screening algorithm in a South African population. Methods: A retrospective record review included infants born between 1 January 2013 and 1 December 2014 who underwent ROP (retinopathy of prematurity) screening. Outcomes of ophthalmology examinations were compared to alarms triggered on WINROP after gestational age, date of birth, and weekly weights were entered. Sensitivity, specificity, positive predictive, and negative predictive values and mean time of alarm were calculated. Results: Rates of ROP were 5.9% for all stages of ROP and 2.3% for severe ROP in the 220 infants included. Mean gestation age was 29.1 ± 1.3 weeks and mean birth weight 1,115.5 ± 201 g. WINROP triggered high-risk alarms in 70.5% of infants at a mean of 30.7 weeks of gestational age. Sensitivity for severe ROP was 100 and 76.9% for all stages of ROP. Specificity was low for both severe ROP and all stages of ROP at 30.2 and 30.0%, respectively. Conclusion: Rates of ROP are low in this population. The high number of alarms with a low negative predictive value would reduce the number of screens by 29.5%. Alarms were triggered before scheduled screening, possibly helpful in planning discharges and follow-up visits.

The association between early-onset sepsis and neonatal encephalopathy.

OBJECTIVE: We evaluated the association between early-onset sepsis and neonatal encephalopathy in a low-middle-income setting. METHODS: We undertook a retrospective study in newborns with gestational age ≥35 weeks and/or birth weight ≥2500 grams, diagnosed with neonatal encephalopathy. Early-onset sepsis was defined as culture-confirmed sepsis or probable sepsis. RESULTS: Of 10,182 hospitalised newborns, 1027 (10.1%) were diagnosed with neonatal encephalopathy, of whom 52 (5.1%) had culture-confirmed and 129 (12.5%) probable sepsis. The case fatality rate for culture-confirmed sepsis associated neonatal encephalopathy was threefold higher compared to neonatal encephalopathy without sepsis (30.8% vs. 10.5%, p < 0.001). Predictors of mortality for culture-confirmed sepsis associated neonatal encephalopathy included severe neonatal encephalopathy (aOR 6.51, 95%CI: 1.03-41.44) and seizures (aOR 10.64, 95%CI: 1.05-107.39). CONCLUSION: In this setting, 5% of neonatal encephalopathy cases was associated with culture-confirmed sepsis and a high case fatality rate.

Abacavir dosing in neonates from birth to 3 months of life: a population pharmacokinetic modelling and simulation study.

BACKGROUND: No evidence-based optimal dosing guidance is available for abacavir liquid formulation use from birth. We used abacavir pharmacokinetic data from neonates and infants to determine an exact abacavir dosing strategy (mg/kg) for infants aged 0-3 months and to propose dosing by WHO weight band for neonates. METHODS: Abacavir pharmacokinetic and safety data were pooled from three completed studies (1997-2020): PACTG 321 (USA), the Tygerberg Cohort (South Africa), and IMPAACT P1106 (South Africa). PACTG 321 and the Tygerberg Cohort were performed in neonates exposed to HIV receiving a single dose of abacavir. IMPAACT P1106 included predominantly low birthweight (<2500 g) infants on antiretroviral therapy enrolled when they were younger than 3 months. We developed a population pharmacokinetic model and performed simulations to achieve abacavir exposures (area under the curve for 0-12 h) within the target range of 3·2-25·2 µg·h/mL, previously reported in older children. FINDINGS: 45 infants contributed 308 abacavir concentrations; 21 neonates were younger than 15 days. At first pharmacokinetic assessment, median postnatal age for PACTG 321 was 1 day and median bodyweight was 3·1 kg; for the Tygerberg Cohort it was 10 days and 3·3 kg; and for IMPAACT P1106 it was 73 days and 3·8 kg. Our model predicted a slow abacavir clearance of 2·51 mL/min per kg at birth, which doubled by 4 weeks of age. Therapeutic targets were achieved with exact abacavir doses of 2·0 mg/kg twice daily from 0 weeks to 4 weeks and 4·0 mg/kg twice daily from 4 weeks to 12 weeks. A fixed weight-band dosing strategy of 8 mg (for 2-3 kg), 10 mg (3-4 kg), and 12 mg (4-5 kg) abacavir twice daily achieved target exposures throughout the first 4 weeks of life without the need for dose adjustment due to age or bodyweight changes. No adverse events of grade 3 or higher were related to abacavir. INTERPRETATION: Integration of these dosing strategies into national and international guidelines for the abacavir liquid formulation will expand antiretroviral options from birth and simplify the clinical management of neonates with HIV. FUNDING: National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Mental Health, and the Collaborative Initiative for Paediatric HIV Education and Research Programme.

Clinical Characteristics and Histopathology of Coronavirus Disease 2019-Related Deaths in African Children.

BACKGROUND: Globally, very few childhood deaths have been attributed to coronavirus disease 2019 (COVID-19). We evaluated clinical, microbiologic and postmortem histopathologic findings in childhood deaths in whom severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified antemortem or postmortem. METHODS: Surveillance of childhood deaths was ongoing during the initial COVID-19 outbreak in South Africa from April 14, 2020, to August 31, 2020. All children hospitalized during this time had a SARS-CoV-2 test done as part of standard of care. Postmortem sampling included minimally invasive tissue sampling (MITS) of lung, liver and heart tissue; blood and lung samples for bacterial culture and molecular detection of viruses (including SARS-CoV-2) and bacteria. The cause of death attribution was undertaken by a multidisciplinary team and reported using World Health Organization framework for cause of death attribution. RESULTS: SARS-CoV-2 was identified on antemortem and/or postmortem sampling in 11.7% (20/171) of deceased children, including 13.2% (12/91) in whom MITS was done. Eighteen (90%) of 20 deaths with SARS-CoV-2 infection were <12 months age. COVID-19 was attributed in the causal pathway to death in 91.7% (11/12) and 87.5% (7/8) cases with and without MITS, respectively. Lung histopathologic features in COVID-19-related deaths included diffuse alveolar damage (n = 6, 54.5%), type 2 pneumocyte proliferation (n = 6, 54.5%) and hyaline membrane formation (n = 5, 36.4%). Culture-confirmed invasive bacterial disease was evident in 54.5% (6/11) of COVID-19 attributed deaths investigated with MITS. CONCLUSIONS: COVID-19 was in the causal pathway of 10.5% (18/171) of all childhood deaths under surveillance. The postmortem histopathologic features in fatal COVID-19 cases in children were consistent with reports on COVID-19 deaths in adults; although there was a high prevalence of invasive bacterial disease in the children.

Characteristics and Outcomes of Neonates With Blood Stream Infection Due to Listeria monocytogenes.

BACKGROUND: Infection due to Listeria monocytogenes (LM) is rare in neonates; thus, its clinical presentation and outcomes are not commonly reported, especially in low- and middle-income countries. In 2017, South Africa had an outbreak due to LM. OBJECTIVE: To determine demographic characteristics, clinical and laboratory findings and outcomes of all neonates infected with LM during the outbreak period. METHODS: This is a retrospective analytic study. Clinical and laboratory records of neonates admitted at Chris Hani Baragwanath Academic Hospital from January 2017 to May 2018 with positive blood and cerebrospinal fluid culture with LM were reviewed for demographic characteristics, clinical presentation, ancillary laboratory test results and outcomes at hospital discharge. RESULTS: There were 42 neonates with positive cultures due to LM. Thirty-four (81%) were born preterm. Mode of delivery was vaginal in 78.6% and 31.0% were HIV exposed. All patients presented within the first 6 days of life as an early-onset disease. Common clinical presentation was respiratory depression (52.4%) and respiratory distress (38.1%) with 69% requiring invasive or noninvasive respiratory support. Common abnormal laboratory findings were high C-reactive protein (77.1%) followed by leukopenia (23.8%). Fourteen patients (40%) had features of meningitis based on blood and cerebrospinal fluid findings (4 culture proven). There were 11 deaths at hospital discharge, giving a mortality rate of 26.2%. CONCLUSIONS: The majority of neonates infected with LM were born preterm, raising the possibility that LM itself may have been responsible for preterm labor. All presented in the first 6 days of life and most presented with respiratory distress or depression. A high proportion had meningitis, and there was a high-mortality overall.

Epidemiology of Culture-confirmed Candidemia Among Hospitalized Children in South Africa, 2012-2017.

BACKGROUND: We aimed to describe the epidemiology of candidemia among children in South Africa. METHODS: We conducted laboratory-based surveillance among neonates (≤28 days), infants (29 days to <1 year), children (1-11 years) and adolescents (12-17 years) with Candida species cultured from blood during 2012-2017. Identification and antifungal susceptibility of viable isolates were performed at a reference laboratory. We used multivariable logistic regression to determine the association between Candida parapsilosis candidemia and 30-day mortality among neonates. RESULTS: Of 2996 cases, neonates accounted for 49% (n = 1478), infants for 27% (n = 806), children for 20% (n = 589) and adolescents for 4% (n = 123). The incidence risk at tertiary public sector hospitals was 5.3 cases per 1000 pediatric admissions (range 0.39-119.1). Among 2943 cases with single-species infections, C. parapsilosis (42%) and Candida albicans (36%) were most common. Candida auris was among the 5 common species with an overall prevalence of 3% (n = 47). Fluconazole resistance was more common among C. parapsilosis (55% [724/1324]) versus other species (19% [334/1737]) (P < 0.001). Of those with known treatment (n = 1666), 35% received amphotericin B deoxycholate alone, 32% fluconazole alone and 30% amphotericin B deoxycholate with fluconazole. The overall 30-day in-hospital mortality was 38% (n = 586) and was highest among neonates (43% [323/752]) and adolescents (43% [28/65]). Compared with infection with other species, C. parapsilosis infection was associated with a reduced mortality among neonates (adjusted odds ratio 0.41, 95% confidence interval: 0.22-0.75, P = 0.004). CONCLUSIONS: Candidemia in this setting mainly affected neonates and infants and was characterized by fluconazole-resistant C. parapsilosis with no increased risk of death.