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Background. Diagnosing meningitis in sick neonates is challenging because they are often unstable for lumbar puncture (LP). In this scenario, antibiotic selections are based on positive blood culture (BC), assuming concordance between blood and cerebrospinal fluid (CSF) cultures. The value of CSF cultures is diminished when LP is performed after initiating antibiotics. Therefore, CSF white cell count (CSF-WCC) and chemistry serve as proxies for diagnosing meningitis. Objective. To assess concordance between blood and CSF cultures and identify differences in CSF-WCC and protein levels between positive and negative CSF cultures. Methods. We enrolled neonates who had both CSF and BCs taken for sepsis workup. Comparisons between blood and CSF cultures were performed to assess concordance. CSF-WCC and protein level discrepancies were compared between positive and negative CSF cultures. Results. Ultimately, 448 neonates over 12 months met the criteria. Among those with positive BC results, 16.7% had positive CSF cultures, whereas for those with culture-positive CSF, 59.2% had positive BC. The concordance of organisms was 82.8% among those with positive blood and CSF cultures. Among neonates with culture-positive CSF, 24.5% and 59.3% had abnormal CSF-WCC and protein levels, respectively. Neonates with a positive CSF culture, compared with a negative culture, had higher CSF-WCC (24.5% v. 10.4%; p<0.001) and protein levels (59.3% v. 37.5%; p<0.001). Conclusion. High proportion of neonates with positive CSF cultures had negative BCs. Therefore, meningitis cannot be excluded based on negative BC without LP, for normal CSF-WCC and protein levels without CSF culture results do not exclude meningitis. [ABSTRACT FROM AUTHOR]

Background. Staphylococcus aureus infection is associated with considerable morbidity and mortality. There are relatively few studies describing invasive S. aureus infections in children, particularly in low- and middle-income countries. Objectives. To describe the clinical spectrum and outcomes associated with S. aureus infection in children <14 years of age hospitalised at Chris Hani Baragwanath Academic Hospital (CHBAH), South Africa, and to identify risk factors of invasive disease. Methods. A retrospective, descriptive study was conducted at CHBAH to define the spectrum of clinical presentation, risk factors, duration of treatment and outcomes of paediatric S. aureus infections for the period January through December 2013. Data were sought for all children <14 years of age. Results. Four hundred and twenty-two episodes of S. aureus infection were identified. Three hundred and forty-two (81%) infections were caused by methicillin-susceptible S. aureus (MSSA) and 80 (19%) by methicillin-resistant S. aureus (MRSA). Clinical data were obtained for 286 (67.8%) cases, on which all further analyses were based. Clinical presentations for MSSA bacteraemia included skin and soft tissue infection (45%), pneumonia (10%), meningitis (6%), bone/joint infections (5%) and urinary tract infections (3%). Five (8.3%) cases of MRSA were community-acquired. Admission to intensive care unit (ICU) was the only risk factor associated with MRSA infection (adjusted odds ratio (aOR) 125.55; 95% confidence interval (CI) 11.67 - 1 350.68). Hospital-acquired S. aureus infection was the only factor associated with mortality on multivariate analysis (aOR 8.70; 95% CI 1.55 - 48.77). Conclusion. S. aureus is frequently isolated in paediatric bacterial infections. Closer attention to infection control would impact on MRSA and S. aureus mortality rates in our setting. [ABSTRACT FROM AUTHOR]

Background: Currently, prompt phenotypic detection of carbapenemase-producing Enterobacterales by clinical laboratories is a challenge. Available techniques are expensive and strenuous. Results are delayed and the techniques are unsuitable for highthroughput laboratories. Objective: This study evaluates the performance of the sCIM against the Modified Hodge and Imi-EDTA tests as an alternative method to detect carbapenemase enzymes in Gram-negative bacilli. Methods: This is a prospective laboratory-based study, comprising 137 well-characterised stored isolates. These isolates include: 96 Enterobacterales, 23 Acinetobacter baumannii and 18 Pseudomonas aeruginosa tested with the sCIM. The performance of the sCIM was compared to the Modified Hodge and Imi-EDTA tests with the multiplex PCR used as a reference gold standard. Results: Overall, we report 95.8% accuracy of the sCIM when testing Enterobacterales, 95.6% for Acinetobacter baumannii, and 77.8% for Pseudomonas aeruginosa using PCR as the gold standard. There was a significant correlation of 95.4% sensitivity and 100% specificity in testing both Enterobacterales and Acinetobacter baumannii isolates with the sCIM. Contrary to expectation, both Enterobacterales and Acinetobacter baumannii showed a low negative predictive value (NPV) of 69.8% and 50%, respectively, while the positive predictive value (PPV) was 100% for both. Pseudomonas aeruginosa isolates showed 40% sensitivity, 92.3% specificity, 66.6% PPV and 80% NPV. Conclusion: Notwithstanding the lack of agreement with our low NPV, the sCIM demonstrated an acceptable performance, as described in previous studies. It is inexpensive, less tedious and suitable for use in high-throughput laboratories with reliable and consistent results. [ABSTRACT FROM AUTHOR]

Enhanced surveillance for CREs was established at national sentinel sites in South Africa. We aimed to apply an epidemiological and microbiological approach to characterise CREs and to assess trends in antimicrobial resistance from patients admitted to tertiary academic hospitals. A retrospective analysis was conducted on patients of all ages with CRE bacteraemia admitted at any one of 12 tertiary academic hospitals in four provinces (Gauteng, KwaZulu-Natal, Western Cape and Free State) in South Africa. The study period was from July 2015 to December 2018. A case of CRE bacteraemia was defined as a patient admitted to one of the selected tertiary hospitals where any of the Enterobacteriaceae was isolated from a blood culture, and was resistant to the carbapenems (ertapenem, meropenem, imipenem and/or doripenem) or had a positive result for the Modified Hodge Test (MHT) according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. A positive blood culture result obtained after 21 days of the last blood culture result was regarded as a new case. To distinguish hospital-acquired (HA) from the community-acquired (CA) bacteraemia, the following definitions were applied: the HA CRE bacteraemia was defined as a patient with CRE isolated from blood culture ≥ 72 h of hospital admission or with any prior healthcare contact, within 1 year prior to the current episode or referral from a healthcare facility where the patient was admitted before the current hospital. A case of the CA CRE bacteraemia was defined as a patient with CRE isolated from blood culture < 72 h of hospital admission and with no prior healthcare contact. The majority of carbapenem-resistant Enterobacteriaceae (CRE) (70%) were hospital-acquired (HA) with Klebsiella pneumoniae being the predominant species (78%). In-hospital mortality rate was 38%. The commonest carbapenemase genes were bla-OXA-48 (52%) and bla-NDM (34%). The high mortality rate related to bacteraemia with CRE and the fact that most were hospital-acquired infections highlights the need to control the spread of these drug-resistant bacteria. Replacement with OXA-48 is the striking finding from this surveillance analysis. Infection control and antibiotic stewardship play important roles in decreasing the spread of resistance. [ABSTRACT FROM AUTHOR]

Background: Invasive bacterial disease causes significant morbidity and mortality in children in developing countries. The burden of invasive disease caused by Staphylococcus aureus and S. aureus antimicrobial resistance patterns in African children in settings with a high prevalence of HIV infection remain ill-defined. Aims and Objectives: To describe the burden of community-onset bacteraemic S. aureus infections in children in an area with a high prevalence of paediatric HIV infection, and to describe the antimicrobial resistance patterns. Methods: A retrospective record review of children hospitalised at Chris Hani Baragwanath Hospital, Soweto, with S. aureus bacteraemia between January 2005 and December 2006 was conducted. Community-onset S. aureus bloodstream infections were defined as S. aureus cultured from blood obtained within 48 hours of admission. Results: Community-onset S. aureus bacteraemia was identified in 161 children, representing an incidence of 26/100,000, with 63 (39%) isolates identified as methicillin-resistant (10/100,000). The incidence of community-onset S. aureus bacteraemia, both methicillin-susceptible and methicillin-resistant, was inversely related to age and greater in HIV-infected than uninfected children. High rates of antibiotic resistance were observed in MRSA isolates and only resistance to amikacin, fusidic acid and ciprofloxacin was <40%. MRSA isolates were frequently multidrug-resistant. Among HIV-infected children, resistance to trimethoprim-sulfamethoxazole was 100% and to rifampicin was 78%. Conclusions: This study highlights the burden of S. aureus bacteraemia in a setting with a high prevalence of paediatric HIV infection. The high incidence of S. aureus bacteraemia coupled with a high prevalence of methicillin resistance, particularly in HIV-infected children, needs to be considered in the empirical management of paediatric sepsis in settings such as ours. [ABSTRACT FROM AUTHOR]

Background and Objectives: Neonatal mortality due to severe bacterial infections is a pressing global issue, especially in low-middle-income countries (LMICs) with constrained healthcare resources. This study aims to validate the Neonatal Healthcare-associated infectiOn Prediction (NeoHoP) score, designed for LMICs, across diverse neonatal populations., Methods: Prospective data from three South African neonatal units in the Neonatal Sepsis Observational (NeoOBS) study were analysed. The NeoHoP score, initially developed and validated internally in a South African hospital, was assessed using an external cohort of 573 sepsis episodes in 346 infants, focusing on different birth weight categories. Diagnostic metrics were evaluated, including sensitivity, specificity, positive predictive value and area under the receiver operating characteristic curve., Results: The external validation cohort displayed higher median birth weight and gestational age compared with the internal validation cohort. A significant proportion were born before reaching healthcare facilities, resulting in increased sepsis evaluation, and diagnosed healthcare-associated infections (HAIs). Gram-negative infections predominated, with fungal infections more common in the external validation cohort.The NeoHoP score demonstrated robust diagnostic performance, with 92% specificity, 65% sensitivity and a positive likelihood ratio of 7.73. Subgroup analysis for very low birth weight infants produced similar results. The score's generalisability across diverse neonatal populations was evident, showing comparable performance across different birth weight categories., Conclusion: This multicentre validation confirms the NeoHoP score as a reliable 'rule-in' test for HAI in neonates, regardless of birth weight. Its potential as a valuable diagnostic tool in LMIC neonatal units addresses a critical gap in neonatal care in low-resource settings., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria., (© 2024. The Author(s).)

Background: Viridans Group Streptococci (VGS) are often considered organisms of low virulence; however, infection can result in clinically significant sepsis and life-threatening complications in paediatric patients., Objectives: This study aimed to describe the spectrum of clinical presentation of VGS bacteraemia in paediatric patients, to analyse risk factors, and to describe the antibiotics resistance patterns of VGS., Method: Cultures of VGS in paediatric patients admitted to Chris Hani Baragwanath Academic Hospital in 2019 were identified through National Health Laboratory Service. Data were extracted from archived clinical records and analysed. Sepsis scores were calculated at the time of bacteraemia., Results: A total of 133 cultures were identified; 64 (48.1%) polymicrobial cultures and no records 4 (0.03%) were excluded; 65 (48.9%) were analysed. The median age was 1.5 months (range 0.03 to 168, interquartile range [IQR]: 0.3-13.25), 27/65 (42%) were neonates. The median duration of hospitalisation was 7 days (IQR: 3-21). The commonest diagnoses were neonatal sepsis 30.8% ( n = 20) and pneumonia 28% ( n = 18). The systemic inflammatory response syndrome (SIRS) score was ≥ 2 in 57% (16/28) patients; paediatric sequential organ failure assessment (pSOFA) score was > 2 in 10/24 (42%). Fifty-seven (88%) patients were discharged; three (5%) required ICU admission and 8/65 (12.3%) died. Malnutrition was present in 50% of patients who died. Cephalosporins and penicillin had sensitivity of 89% and 55%, respectively., Conclusion: Viridans Group Streptococci bacteraemia was common in neonates, and pneumonia was a common presentation in this cohort. The VGS bacteraemia was associated with morbidity and deaths in this cohort., Contribution: The VGS should be considered a significant organism when cultured from sterile sites and routine antibiotic susceptibility testing should be performed. Prospective studies are recommended., Competing Interests: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article., (© 2024. The Authors.)

Background: Malaria is a leading cause of childhood mortality worldwide. However, accurate estimates of malaria prevalence and causality among patients who die at the country level are lacking due to the limited specificity of diagnostic tools used to attribute etiologies. Accurate estimates are crucial for prioritizing interventions and resources aimed at reducing malaria-related mortality., Methods: Seven Child Health and Mortality Prevention Surveillance (CHAMPS) Network sites collected comprehensive data on stillbirths and children <5 years, using minimally invasive tissue sampling (MITS). A DeCoDe (Determination of Cause of Death) panel employed standardized protocols for assigning underlying, intermediate, and immediate causes of death, integrating sociodemographic, clinical, laboratory (including extensive microbiology, histopathology, and malaria testing), and verbal autopsy data. Analyses were conducted to ascertain the strength of evidence for cause of death (CoD), describe factors associated with malaria-related deaths, estimate malaria-specific mortality, and assess the proportion of preventable deaths., Findings: Between December 3, 2016, and December 31, 2022, 2673 deaths underwent MITS and had a CoD attributed from four CHAMPS sites with at least 1 malaria-attributed death. No malaria-attributable deaths were documented among 891 stillbirths or 924 neonatal deaths, therefore this analysis concentrates on the remaining 858 deaths among children aged 1-59 months. Malaria was in the causal chain for 42.9% (126/294) of deaths from Sierra Leone, 31.4% (96/306) in Kenya, 18.2% (36/198) in Mozambique, 6.7% (4/60) in Mali, and 0.3% (1/292) in South Africa. Compared to non-malaria related deaths, malaria-related deaths skewed towards older infants and children (p < 0.001), with 71.0% among ages 12-59 months. Malaria was the sole infecting pathogen in 184 (70.2%) of malaria-attributed deaths, whereas bacterial and viral co-infections were identified in the causal pathway in 24·0% and 12.2% of cases, respectively. Malnutrition was found at a similar level in the causal pathway of both malaria (26.7%) and non-malaria (30.7%, p = 0.256) deaths. Less than two-thirds (164/262; 62.6%) of malaria deaths had received antimalarials prior to death. Nearly all (98·9%) malaria-related deaths were deemed preventable., Interpretation: Malaria remains a significant cause of childhood mortality in the CHAMPS malaria-endemic sites. The high bacterial co-infection prevalence among malaria deaths underscores the potential benefits of antibiotics for severe malaria patients. Compared to non-malaria deaths, many of malaria-attributed deaths are preventable through accessible malaria control measures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Determining the death burden for prioritising public health interventions necessitates detailed data on the causal pathways to death. Postmortem minimally invasive tissue sampling (MITS), incorporating histology, molecular and microbial culture diagnostics, enhances cause-of-death attribution, particularly for infectious deaths. MITS proves a valid alternative to full diagnostic autopsies, especially in low- and middle-income countries. In Soweto, South Africa (SA), the Child Health and Mortality Prevention Surveillance (CHAMPS) programme has delineated over 1 000 child and stillbirth deaths since 2017. This SA CHAMPS site supports advocating for the use of postmortem MITS as routine practice, for more granular insights into under-5 mortality causes. This knowledge is crucial for SA's pursuit of Sustainable Development Goal 3.2, targeting reduced neonatal and under-5 mortality rates. This commentary explores the public health advantages and ethicolegal considerations surrounding implementing MITS as standard of care for stillbirths, neonatal and paediatric deaths in SA. Furthermore, based on the data from CHAMPS, we present three pragmatic algorithmic approaches to the wide array of testing options for cost-effectiveness and scalability of postmortem MITS in South African state facilities.

Objectives: To report the in vitro susceptibility of Enterobacterales (n = 3905) and Pseudomonas aeruginosa (n = 1,109) isolates, collected from patients in sub-Saharan Africa (four countries) in 2017-2021, to a panel of 10 antimicrobial agents with a focus on ceftazidime-avibactam activity against resistant phenotypes and β-lactamase carriers., Methods: MICs were determined by CLSI broth microdilution and interpreted using both 2022 CLSI and EUCAST breakpoints. β-lactamase genes were identified in select β-lactam-nonsusceptible isolate subsets using multiplex PCR assays., Results: Among Enterobacterales, 96.2% of all isolates were ceftazidime-avibactam-susceptible (MIC 90 , 0.5 µg/mL), including all serine carbapenemase-positive (n = 127), 99.6% of ESBL-positive, carbapenemase-negative (n = 730), 91.9% of multidrug resistant (MDR; n = 1817), and 42.7% of DTR (difficult-to-treat resistance; n = 171) isolates. Metallo-β-lactamase (MBL) genes were identified in most (n = 136; 91.2%) ceftazidime-avibactam-resistant isolates (3.5% of all Enterobacterales isolates). Ceftazidime-avibactam percent susceptible values ranged from 99.5% (Klebsiella species other than Klebsiella pneumoniae) to 92.5% (K. pneumoniae) for the various Enterobacterial taxa examined. Greater than 90% of Enterobacterales isolates from each country (Cameroon, Ivory Coast, Nigeria, South Africa) were ceftazidime-avibactam-susceptible. Among P. aeruginosa, 88.9% of all isolates were ceftazidime-avibactam-susceptible (MIC 90 , 16 µg/mL). Most (88.5%) MBL-negative, meropenem-resistant (n = 78), 68.1% of MDR (n = 385), and 19.2% of DTR isolates (n = 99) were ceftazidime-avibactam-susceptible. MBL genes were identified in 43.1% of ceftazidime-avibactam-resistant isolates (n = 53; 4.8% of all P. aeruginosa isolates). Country-specific ceftazidime-avibactam percent susceptible values for P. aeruginosa ranged from 94.1% (Cameroon) to 76.2% (Nigeria)., Conclusion: Reference in vitro antimicrobial susceptibility testing demonstrated that most recent Enterobacterales (96%) and P. aeruginosa (89%) clinical isolates from four sub-Saharan African countries were ceftazidime-avibactam susceptible., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.

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.

Neonatal invasive candidiasis (NIC) has significant morbidity and mortality. Reports have shown a different profile of those neonates affected with NIC and of fluconazole-resistant Candida spp. isolates in low- and middle-income countries (LMICs) compared to high-income countries (HICs). We describe the epidemiology, Candida spp. distribution, treatment, and outcomes of neonates with NIC from LMICs enrolled in a global, prospective, longitudinal, observational cohort study (NeoOBS) of hospitalized infants <60 days postnatal age with sepsis (August 2018-February 2021). A total of 127 neonates from 14 hospitals in 8 countries with Candida spp. isolated from blood culture were included. Median gestational age of affected neonates was 30 weeks (IQR: 28-34), and median birth weight was 1270 gr (interquartile range [IQR]: 990-1692). Only a minority had high-risk criteria, such as being born <28 weeks, 19% (24/127), or birth weight <1000 gr, 27% (34/127). The most common Candida species were C. albicans (n = 45, 35%), C. parapsilosis (n = 38, 30%), and Candida auris (n = 18, 14%). The majority of C. albicans isolates were fluconazole susceptible, whereas 59% of C. parapsilosis isolates were fluconazole-resistant. Amphotericin B was the most common antifungal used [74% (78/105)], followed by fluconazole [22% (23/105)]. Death by day 28 post-enrollment was 22% (28/127). To our knowledge, this is the largest multi-country cohort of NIC in LMICs. Most of the neonates would not have been considered at high risk for NIC in HICs. A substantial proportion of isolates was resistant to first choice fluconazole. Understanding the burden of NIC in LMIC is essential to guide future research and treatment guidelines., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Omicron lineages BA.4 and BA.5 drove a fifth wave of COVID-19 cases in South Africa. Here, we use the presence/absence of the S-gene target as a proxy for SARS-CoV-2 variant/lineage for infections diagnosed using the TaqPath PCR assay between 1 October 2021 and 26 April 2022. We link national COVID-19 individual-level data including case, laboratory test and hospitalisation data. We assess severity using multivariable logistic regression comparing the risk of hospitalisation and risk of severe disease, once hospitalised, for Delta, BA.1, BA.2 and BA.4/BA.5 infections. After controlling for factors associated with hospitalisation and severe outcome respectively, BA.4/BA.5-infected individuals had a similar odds of hospitalisation (aOR 1.24, 95% CI 0.98-1.55) and severe outcome (aOR 0.72, 95% CI 0.41-1.26) compared to BA.1-infected individuals. Newly emerged Omicron lineages BA.4/BA.5 showed similar severity to the BA.1 lineage and continued to show reduced clinical severity compared to the Delta variant., (© 2022. The Author(s).)

Objective: We aimed to provide an analysis of A. baumannii complex (ABC) isolated from blood cultures in South Africa., Materials and Methods: ABC surveillance was conducted from 1 April 2017 to 30 September 2019 at 19 hospital sites from blood cultures of any age and sex. Organism identification was performed using the MALDI-TOF MS and antimicrobial susceptibility testing (AST), MicroScan Walkaway System. We confirmed colistin resistance with Sensititre, FRCOL panel, and selected for whole-genome sequencing., Results: During the study period, we identified 4822 cases of ABC, of which 2152 cases were from 19 enhanced surveillance sites were reported during the enhanced surveillance period (1 August 2018 to 30 September 2019). Males accounted for 54% (2611/4822). Of the cases with known age, 41% (1968/4822) were infants (< 1-year-old). Seventy-eight percent (1688/2152) of cases had a known hospital outcome, of which 36% (602/1688) died. HIV status was known for 69% (1168/1688) of cases, and 14% (238/1688) were positive. Eighty-two percent (1389/1688) received antimicrobial treatment in admission. Three percent (35/1389) of cases received single colistin. Four percent (75/2033) were resistant to colistin. At least 75% of the isolates (1530/2033) can be classified as extensively drug-resistant (XDR), with resistance to most antibiotics except for colistin. The majority, 83% (20/24), of the colistin-resistant isolates were of the sequence type (ST) 1. Resistance genes, both plasmid- and chromosomal- mediated were not observed. Although all isolates had, nine efflux pump genes related to antimicrobial resistance., Conclusion: Our surveillance data contributed to a better understanding of the natural course of A. baumannii disease, the patient characteristics among infants, and the level of resistance. At least two-thirds of the isolates were extensively drug-resistant, and four percent of isolates were resistant to colistin., Competing Interests: The authors have declared that no competing interests exist.

Background: The SARS-CoV-2 omicron variant of concern was identified in South Africa in November, 2021, and was associated with an increase in COVID-19 cases. We aimed to assess the clinical severity of infections with the omicron variant using S gene target failure (SGTF) on the Thermo Fisher Scientific TaqPath COVID-19 PCR test as a proxy., Methods: We did data linkages for national, South African COVID-19 case data, SARS-CoV-2 laboratory test data, SARS-CoV-2 genome data, and COVID-19 hospital admissions data. For individuals diagnosed with COVID-19 via TaqPath PCR tests, infections were designated as either SGTF or non-SGTF. The delta variant was identified by genome sequencing. Using multivariable logistic regression models, we assessed disease severity and hospitalisations by comparing individuals with SGTF versus non-SGTF infections diagnosed between Oct 1 and Nov 30, 2021, and we further assessed disease severity by comparing SGTF-infected individuals diagnosed between Oct 1 and Nov 30, 2021, with delta variant-infected individuals diagnosed between April 1 and Nov 9, 2021., Findings: From Oct 1 (week 39), 2021, to Dec 6 (week 49), 2021, 161 328 cases of COVID-19 were reported in South Africa. 38 282 people were diagnosed via TaqPath PCR tests and 29 721 SGTF infections and 1412 non-SGTF infections were identified. The proportion of SGTF infections increased from two (3·2%) of 63 in week 39 to 21 978 (97·9%) of 22 455 in week 48. After controlling for factors associated with hospitalisation, individuals with SGTF infections had significantly lower odds of admission than did those with non-SGTF infections (256 [2·4%] of 10 547 vs 121 [12·8%] of 948; adjusted odds ratio [aOR] 0·2, 95% CI 0·1-0·3). After controlling for factors associated with disease severity, the odds of severe disease were similar between hospitalised individuals with SGTF versus non-SGTF infections (42 [21%] of 204 vs 45 [40%] of 113; aOR 0·7, 95% CI 0·3-1·4). Compared with individuals with earlier delta variant infections, SGTF-infected individuals had a significantly lower odds of severe disease (496 [62·5%] of 793 vs 57 [23·4%] of 244; aOR 0·3, 95% CI 0·2-0·5), after controlling for factors associated with disease severity., Interpretation: Our early analyses suggest a significantly reduced odds of hospitalisation among individuals with SGTF versus non-SGTF infections diagnosed during the same time period. SGTF-infected individuals had a significantly reduced odds of severe disease compared with individuals infected earlier with the delta variant. Some of this reduced severity is probably a result of previous immunity., Funding: The South African Medical Research Council, the South African National Department of Health, US Centers for Disease Control and Prevention, the African Society of Laboratory Medicine, Africa Centers for Disease Control and Prevention, the Bill & Melinda Gates Foundation, the Wellcome Trust, and the Fleming Fund., Competing Interests: Declaration of interests CC has received grant support from the South African Medical Research Council, the UK Foreign, Commonwealth and Development Office, the Wellcome Trust, the US Centers for Disease Control and Prevention, and Sanofi Pasteur. NW and MdP have received grant support from Sanofi Pasteur and the Bill & Melinda Gates Foundation. AvG has received grant support from Sanofi Pasteur, the US Centers for Disease Control and Prevention, the South African Medical Research Council, the Bill & Melinda Gates Foundation, WHO, the Fleming Fund, and the Wellcome Trust. RW declares personal shareholding in Adcock Ingram Holdings, Dischem Pharmacies, Discovery, Netcare, and Aspen Pharmacare Holdings. WS has received grant support from the South African Medical Research Council, with funds received from the Department of Science and Innovation, and the Bill & Melinda Gates Foundation. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Licensure of a group B Streptococcus (GBS) polysaccharide-protein conjugate vaccine for protecting infants against invasive GBS disease (IGbsD) will likely need to be based on demonstrating vaccine safety in pregnant women, and benchmarking immunogenicity against a serological threshold associated with risk reduction of IGbsD. We investigated the association between naturally derived GBS serotype Ia and III IgG and risk reduction of IGbsD in infants ≤90 days of age., Methods: In a matched case-control study, IGbsD cases were identified from a cohort of 38 233 mother-newborn dyads. Mothers colonized vaginally with serotype Ia or III at birth and their healthy infants were eligible as matched controls. GBS serotype-specific anticapsular immunoglobulin G (IgG) was measured on maternal and cord blood/infant sera by multiplex Luminex assay, and the IgG threshold associated with 90% risk reduction of IGbsD was derived by estimating absolute disease risk., Results: In infants born at ≥34 weeks' gestational age, cord-blood IgG geometric mean concentrations (GMCs) were lower in cases than controls for serotypes Ia (0.05 vs 0.50 µg/mL; P = .004) and III (0.20 vs 0.38 µg/mL; P = .078). Cord-blood IgG concentrations ≥1.04 and ≥1.53 µg/mL were associated with 90% risk reduction of serotype Ia and III IGbsD, respectively. The maternal sera IgG threshold associated with 90% risk reduction was ≥2.31 µg/mL and ≥3.41 µg/mL for serotypes Ia and III, respectively., Conclusions: The threshold associated with a reduced risk for serotype Ia and III IGbsD identified on infant sera supports the case for licensure of a GBS polysaccharide-protein conjugate vaccine based on an immunogenicity evaluation benchmarked against the defined thresholds., Clinical Trials Registration: NCT02215226., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pneumonia is the major contributor to under 5 childhood mortality globally. We evaluated the etiology of pneumonia amongst HIV-uninfected South African children enrolled into the Pneumonia Etiology Research for Child Health case-control study., Methods: Cases, 1-59 months of age hospitalized with World Health Organization clinically defined severe/very severe pneumonia, were frequency-matched by age and season to community controls. Nasopharyngeal-oropharyngeal swabs were analyzed using polymerase chain reaction for 33 respiratory pathogens, and whole blood was tested for pneumococcal autolysin. Cases were also tested for Mycobacterium tuberculosis. Population etiologic fractions (EF) of pneumonia with radiologic evidence of consolidation/infiltrate were derived for each pathogen through Bayesian analysis., Results: Of the 805 HIV-uninfected cases enrolled based on clinical criteria, radiologically confirmed pneumonia was evident in 165 HIV-exposed, -uninfected, and 246 HIV-unexposed children. In HIV-exposed and HIV-unexposed children, respiratory syncytial virus was the most important pathogen with EFs of 31.6% [95% credible interval (CrI), 24.8%-38.8%] and 36.4% (95% CrI, 30.5%-43.1%), respectively. M. tuberculosis contributed EFs of 11.6% (95% CrI, 6.1%-18.8%) in HIV-exposed and 8.3% (95% CrI, 4.5%-13.8%) in HIV-unexposed children, including an EF of 16.3% (95% CrI, 6.1%-33.3%) in HIV-exposed children ≥12 months of age. Bacteremia (3.0% vs. 1.6%) and case fatality risk (3.6% vs. 3.7%) were similar in HIV-exposed and HIV-unexposed children., Conclusions: Vaccination strategies targeting respiratory syncytial virus should be prioritized for prevention of pneumonia in children. Furthermore, interventions are required to address the high burden of tuberculosis in the pathogenesis of acute community-acquired pneumonia in settings such as ours., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: HIV-1 infection predisposes to an increased burden of pneumonia caused by community-acquired and opportunistic pathogens., Methods: Within the context of the Pneumonia Etiology Research for Child Health case-control study of under 5 pneumonia, we investigated the etiology of World Health Organization-defined severe/very severe pneumonia requiring hospitalization in South African HIV-infected children. Nasopharyngeal-oropharyngeal swabs and blood, collected from cases and age- and season-matched HIV-infected controls attending outpatient antiretroviral therapy (ART) clinics, were analyzed using molecular diagnostic methods. Cases were also investigated for tuberculosis. Etiologic fractions among cases with radiologically confirmed pneumonia were derived using Bayesian analytic techniques., Results: Of 115 HIV-infected cases, 89 (77.4%) had radiologically confirmed pneumonia. Severe immunosuppression (adjusted odds ratio, 32.60; 95% confidence interval, 7.25-146.64) was significantly associated with radiologically confirmed pneumonia. Cotrimoxazole prophylaxis (46.4% vs. 77.4%) and ART (28.2% vs. 83.1%) coverage were significantly lower in cases compared with ART-clinic controls. An etiologic agent was identified in 99.0% of the radiologically confirmed cases. The 'top 4' pathogens associated with radiologically confirmed pneumonia were Pneumocystis jirovecii [23.0%; 95% credible interval (CrI), 12.4%-31.5%], Staphylococcus aureus (10.6%; 95% CrI, 2.2%-20.2%), pneumococcus (9.5%; 95% CrI, 2.2%-18.0%) and respiratory syncytial virus (9.3%; 95% CrI, 2.2%-14.6%). Bacteremia (6.7%) and in-hospital death (10.1%) were frequent among those with radiologically confirmed disease., Conclusions: Pneumocystis jirovecii, S. aureus, pneumococcus and respiratory syncytial virus contribute a considerable burden of radiologically confirmed pneumonia in South African HIV-infected children under 5 years. Expediting access to ART and cotrimoxazole prophylaxis would decrease the burden of pneumonia in these children., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Candida auris is a multidrug-resistant fungal pathogen that is endemic in South African hospitals. We tested bloodstream C. auris isolates that were submitted to a reference laboratory for national laboratory-based surveillance for candidemia in 2016 and 2017. We confirmed the species identification by phenotypic/molecular methods. We tested susceptibility to amphotericin B, anidulafungin, caspofungin, micafungin, itraconazole, posaconazole, voriconazole, fluconazole, and flucytosine using broth microdilution and Etest methods. We interpreted MICs using tentative breakpoints. We sequenced the genomes of a subset of isolates and compared them to the C. auris B8441 reference strain. Of 400 C. auris isolates, 361 (90%) were resistant to at least one antifungal agent, 339 (94%) to fluconazole alone (MICs of ≥32 µg/ml), 19 (6%) to fluconazole and amphotericin B (MICs of ≥2 µg/ml), and 1 (0.3%) to amphotericin B alone. Two (0.5%) isolates from a single patient were pan-resistant (resistant to fluconazole, amphotericin B, and echinocandins). Of 92 isolates selected for whole-genome sequencing, 77 clustered in clade III, including the pan-resistant isolates, 13 in clade I, and 2 in clade IV. Eighty-four of the isolates (91%) were resistant to at least one antifungal agent; both resistant and susceptible isolates had mutations. The common substitutions identified across the different clades were VF125AL, Y132F, K177R, N335S, and E343D in ERG11 ; N647T in MRR1 ; A651P, A657V, and S195G in TAC1b ; S639P in FKS1HP1 ; and S58T in ERG3 . Most South African C. auris isolates were resistant to azoles, although resistance to polyenes and echinocandins was less common. We observed mutations in resistance genes even in phenotypically susceptible isolates.

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Clostridioides difficile infection (CDI) is a problem in both developed and developing countries and is a common hospital-acquired infection. This guideline provides evidence-based practical recommendations for South Africa and other developing countries. The scope of the guideline includes CDI diagnostic approaches; adult, paediatric and special populations treatment options; and surveillance and infection prevention and control recommendations., Competing Interests: W.L. received speakers honoraria from Astellas pharmaceutical company. G.R. is the secretary-treasurer of Federation of Infectious Diseases Societies of Southern Africa (FIDSSA). J. Wojno provided Clostridioides difficile-associated disease training for Astellas pharmaceutical company staff and received compensation for this., (© 2020. The Authors.)

Introduction: Despite widespread access to antiretroviral therapy (ART), the burden of advanced HIV disease in South Africa is high. This translates into an increased risk of AIDS-related opportunistic infections, including invasive mycoses., Methods: Using a limited number of non-culture-based diagnostic assays, we aimed to determine the prevalence of invasive mycoses and tuberculosis among hospitalised adults with very advanced HIV (CD4 counts < 100 cells/µL) at a large academic hospital. We conducted interviews and prospective medical chart reviews. We performed point-of-care finger stick and serum cryptococcal antigen lateral flow assays; serum (1 → 3) ß-D-glucan assays; urine Histoplasma galactomannan antigen enzyme immunoassays and TB lipoarabinomannan assays., Results: We enrolled 189 participants from 5280 screened inpatients. Fifty-eight per cent were female, with median age 37 years (IQR: 30-43) and median CD4 count 32 cells/µL (IQR: 13-63). At enrolment, 60% (109/181) were receiving ART. Twenty-one participants (11%) had a diagnosis of an invasive mycosis, of whom 53% (11/21) had cryptococcal disease. Thirteen participants (7%) had tuberculosis and a concurrent invasive mycosis. ART-experienced participants were 60% less likely to have an invasive mycosis than those ART-naïve (adjusted OR: 0.4; 95% CI 0.15-1.0; P = .03). Overall in-hospital mortality was 13% (invasive mycosis: 10% [95% CI 1.2-30.7] versus other diagnoses: 13% (95% CI 8.4-19.3))., Conclusions: One in ten participants had evidence of an invasive mycosis. Diagnosis of proven invasive fungal disease and differentiation from other opportunistic infections was challenging. More fungal-specific screening and diagnostic tests should be applied to inpatients with advanced HIV disease., (© 2020 Blackwell Verlag GmbH.)

Background: Fluconazole is used in combination with amphotericin B for induction treatment of cryptococcal meningitis and as monotherapy for consolidation and maintenance treatment. More than 90% of isolates from first episodes of cryptococcal disease had a fluconazole minimum inhibitory concentration (MIC) ≤4 μg/ml in a Gauteng population-based surveillance study of Cryptococcus neoformans in 2007-2008. We assessed whether fluconazole resistance had emerged in clinical cryptococcal isolates over a decade., Methodology and Principal Findings: We prospectively collected C. neoformans isolates from 1 January through 31 March 2017 from persons with a first episode of culture-confirmed cryptococcal disease at 37 South African hospitals. Isolates were phenotypically confirmed to C. neoformans species-complex level. We determined fluconazole MICs (range: 0.125 μg/ml to 64 μg/ml) of 229 C. neoformans isolates using custom-made broth microdilution panels prepared, inoculated and read according to Clinical and Laboratory Standards Institute M27-A3 and M60 recommendations. These MIC values were compared to MICs of 249 isolates from earlier surveillance (2007-2008). Clinical data were collected from patients during both surveillance periods. There were more males (61% vs 39%) and more participants on combination induction antifungal treatment (92% vs 32%) in 2017 compared to 2007-2008. The fluconazole MIC50, MIC90 and geometric mean MIC was 4 μg/ml, 8 μg/ml and 4.11 μg/ml in 2017 (n = 229) compared to 1 μg/ml, 2 μg/ml and 2.08 μg/ml in 2007-2008 (n = 249) respectively. Voriconazole, itraconazole and posaconazole Etests were performed on 16 of 229 (7%) C. neoformans isolates with a fluconazole MIC value of ≥16 μg/ml; only one had MIC values of >32 μg/ml for these three antifungal agents., Conclusions and Significance: Fluconazole MIC50 and MIC90 values were two-fold higher in 2017 compared to 2007-2008. Although there are no breakpoints, higher fluconazole doses may be required to maintain efficacy of standard treatment regimens for cryptococcal meningitis., Competing Interests: The authors have declared that no competing interests exist.

Background: Despite approximately 2.6 million stillbirths occurring annually, there is a paucity of systematic biological investigation and consequently knowledge on the causes of these deaths in low- and middle-income countries (LMICs). We investigated the utility of minimally invasive tissue sampling (MITS), placental examination, and clinical history, in attributing the causes of stillbirth in a South African LMIC setting., Methods: This prospective, observational pilot study undertook sampling of brain, lung, and liver tissue using core biopsy needles, blood and cerebrospinal fluid collection, and placental examination. Testing included microbial culture and/or molecular testing and tissue histological examination. The cause of death was determined for each case by an international panel of medical specialists and categorized using the World Health Organization's International Classification of Diseases, Tenth Revision application to perinatal deaths., Results: A cause of stillbirth was identifiable for 117 of 129 (90.7%) stillbirths, including an underlying maternal cause in 63.4% (n = 83) and an immediate fetal cause in 79.1% (n = 102) of cases. The leading underlying causes of stillbirth were maternal hypertensive disorders (16.3%), placental separation and hemorrhage (14.0%), and chorioamnionitis (10.9%). The leading immediate causes of fetal death were antepartum hypoxia (35.7%) and fetal infection (37.2%), including due to Escherichia coli (16.3%), Enterococcus species (3.9%), and group B Streptococcus (3.1%)., Conclusions: In this pilot, proof-of-concept study, focused investigation of stillbirth provided granular detail on the causes thereof in an LMIC setting, including provisionally highlighting the largely underrecognized role of fetal sepsis as a dominant cause., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Current estimates for causes of childhood deaths are mainly premised on modeling of vital registration and limited verbal autopsy data and generally only characterize the underlying cause of death (CoD). We investigated the potential of minimally invasive tissue sampling (MITS) for ascertaining the underlying and immediate CoD in children 1 month to 14 years of age., Methods: MITS included postmortem tissue biopsies of brain, liver, and lung for histopathology examination; microbial culture of blood, cerebrospinal fluid (CSF), liver, and lung samples; and molecular microbial testing on blood, CSF, lung, and rectal swabs. Each case was individually adjudicated for underlying, antecedent, and immediate CoD by an international multidisciplinary team of medical experts and coded using the International Classification of Diseases, Tenth Revision (ICD-10)., Results: An underlying CoD was determined for 99% of 127 cases, leading causes being congenital malformations (18.9%), complications of prematurity (14.2%), human immunodeficiency virus/AIDS (12.6%), diarrheal disease (8.7%), acute respiratory infections (7.9%), injuries (7.9%), and malignancies (7.1%). The main immediate CoD was pneumonia, sepsis, and diarrhea in 33.9%, 19.7%, and 10.2% of cases, respectively. Infection-related deaths were either an underlying or immediate CoD in 78.0% of cases. Community-acquired pneumonia deaths (n = 32) were attributed to respiratory syncytial virus (21.9%), Pneumocystis jirovecii (18.8%), cytomegalovirus (15.6%), Klebsiella pneumoniae (15.6%), and Streptococcus pneumoniae (12.5%). Seventy-one percent of 24 sepsis deaths were hospital-acquired, mainly due to Acinetobacter baumannii (47.1%) and K. pneumoniae (35.3%). Sixty-two percent of cases were malnourished., Conclusions: MITS, coupled with antemortem clinical information, provides detailed insight into causes of childhood deaths that could be informative for prioritization of strategies aimed at reducing under-5 mortality., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Postmortem minimally invasive tissue sampling (MITS) is a potential alternative to the gold standard complete diagnostic autopsy for identifying specific causes of childhood deaths. We investigated the utility of MITS, interpreted with available clinical data, for attributing underlying and immediate causes of neonatal deaths., Methods: This prospective, observational pilot study enrolled neonatal deaths at Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. The MITS included needle core-biopsy sampling for histopathology of brain, lung, and liver tissue. Microbiological culture and/or molecular tests were performed on lung, liver, blood, cerebrospinal fluid, and stool samples. The "underlying" and "immediate" causes of death (CoD) were determined for each case by an international panel of 12-15 medical specialists., Results: We enrolled 153 neonatal deaths, 106 aged 3-28 days. Leading underlying CoD included "complications of prematurity" (52.9%), "complications of intrapartum events" (15.0%), "congenital malformations" (13.1%), and "infection related" (9.8%). Overall, infections were the immediate or underlying CoD in 57.5% (n = 88) of all neonatal deaths, including the immediate CoD in 70.4% (58/81) of neonates with "complications of prematurity" as the underlying cause. Overall, 74.4% of 90 infection-related deaths were hospital acquired, mainly due to multidrug-resistant Acinetobacter baumannii (52.2%), Klebsiella pneumoniae (22.4%), and Staphylococcus aureus (20.9%). Streptococcus agalactiae was the most common pathogen (5/15 [33.3%]) among deaths with "infections" as the underlying cause., Conclusions: MITS has potential to address the knowledge gap on specific causes of neonatal mortality. In our setting, this included the hitherto underrecognized dominant role of hospital-acquired multidrug-resistant bacterial infections as the leading immediate cause of neonatal deaths., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)