DESCRIBING THE BURDEN OF NEONATAL SEPSIS AT SECONDARY-LEVEL HOSPITALS IN SOUTH AFRICA

Worldwide, neonatal mortality remains high accounting for 46% of childhood deaths in 2015, with infectious diseases responsible for approximately 600 000 neonatal deaths. In sub-Saharan Africa, which carries a high burden of global childhood deaths, the aetiology of these infections and their resulting burden are not well understood.  Studies in Africa have been limited to tertiary-level institutions, with few, if any, population-based surveillance studies reporting on incidence risks or rates. Some of the contributing factors to this lack of data include under-utilisation/ unavailability of health care services for neonates, suboptimal specimen-taking to confirm an infectious disease diagnosis, limited capacity of diagnostic pathology laboratories to detect, identify and characterise pathogens, absence of appropriate denominator data for calculating incidence risks or rates and limited resources for setting up and maintaining population-based surveillance studies.

We aim to improve neonatal and child health by gaining a deeper understanding of the burden and aetiological factors of neonatal sepsis in urban and rural sub-Saharan Africa through the development of a two-tiered surveillance programme, with a focus on neonatal sepsis occurring at secondary-level institutions. The primary outcome is to determine the national burden of neonatal sepsis in the public sector in South Africa and provide a detailed characterization of risk factors, outcomes and antimicrobial-resistant pathogens associated with neonatal sepsis at secondary-level facilities by setting up a sustainable and in-country-led surveillance system, in order to monitor the impact of future public health interventions aimed at reducing sepsis in these young children.

Ultimately, these surveillance data can be used to address Sustainable Development Goal 3 by aiming to improve neonatal and child health by using a two-tiered laboratory-based surveillance programme to gain a deeper understanding of the aetiology and burden of neonatal and infant sepsis – with a future aim of addressing these factors and thus reducing neonatal morbidity and mortality in low- and middle-income settings.

The impact of this project will be seen on a number of levels:

• Globally, this data will allow us to gain a better understanding of neonatal sepsis and the antimicrobial susceptibility and molecular relatedness of neonatal bacterial and fungal pathogens in a low- and middle-income country – particularly in secondary-level institutions serving less urbanised and rural communities.
• Locally, the National Department of Health in South Africa could use these data to understand the burden of neonatal sepsis, to design appropriate interventions (such as antimicrobial stewardship and infection prevention and control programmes), to prioritise facilities requiring urgent intervention and to tailor these interventions for those at highest risk of neonatal sepsis.
• The hospitals at which we will conduct enhanced surveillance will benefit from the additional information that will come from further characterisation of the isolates causing neonatal sepsis and gain a better understanding on how they can tailor their empiric antimicrobial regimens to better fit the spectrum of organisms that are being cultured.
• Individual neonates at these hospitals will benefit from the doctors adjusting their empirical therapy accordingly.
• We will strongly encourage enhanced surveillance sites to implement local antimicrobial stewardship and infection prevention and control programmes for neonatal units and will design facility-level dashboards based on their local surveillance data to allow them to monitor key indicators for neonatal sepsis.
• Policymakers can use the data on the burden of disease, mortality and risk factors associated with neonatal sepsis and the aetiological patterns of pathogens causing neonatal sepsis to align their strategies on the Continuum of Maternal and Newborn Care to help meet South Africa’s goal to reduce neonatal sepsis by 84% by the year 2025.

By setting up this surveillance programme, we will facilitate future sustainable funding of the project and we will be able to objectively record the change in the incidence of neonatal sepsis over time as new interventions are implemented. Ultimately, we hope that policies put in place through the data generated by this project will save the lives of many newborn babies and improve the quality of life of others in the years ahead.

Globally, an estimated 690,000 lives were lost to AIDS-related illnesses in 2019. Cryptococcal meningitis (CM), a rare but severe fungal infection of the brain and spinal column, is the second leading cause of AIDS deaths behind tuberculosis (TB).

If left untreated, CM almost certainly causes death, and even with treatment in low- and middle-income countries, mortality ranges from 30-80% depending on types of treatment available.

Cryptococcal antigen, or CrAg, is a highly specific biomarker for cryptococcal disease and is present in the bloodstream weeks to months prior to the onset of meningitis symptoms. Screening for and pre-emptively treating cryptococcal disease offers opportunity to reduce the burden of CM and CM-related deaths, particularly in low- and middle-income countries where incidence remains high and optimal treatment is often unavailable.

This CrAg screen-and-treat approach has been recommended by the WHO since 2011 and is a key part of care for people living with advanced HIV disease. South Africa became the first country to implement a national CrAg screening programme in 2016, automatically screening all individuals with a CD4 cell count below 100 cells/µL of blood.

NHLS/NICD surveillance data shows that the programme has achieved very high coverage, screening over 98% of all patients eligible for a CrAg test. However, clinical treatment and outcomes are not routinely reported, creating a challenge in measuring the impact of the programme and identifying areas for improvement.

The Cryptococcal Antigen Screen-and-Treat National Evaluation (CAST-NET) study is a National Institutes of Health (NIH)-funded project designed with two main objectives:

• To assess the performance of South Africa’s national reflex CrAg screening programme, and
• To subsequently design programmatic interventions to optimize implementation and patient outcomes.

CAST-NET will retrospectively evaluate the national programme primarily through patient chart review and abstraction for all patients screened CrAg-positive over a 25-month period (February 2017 – February 2019) at 468 facilities across a nationally representative sample of 27 sub-districts covering all 9 provinces.

In the first phase of CAST-NET, an enhanced retrospective surveillance is being implemented at all study sites. Nearly 4,500 patients have been screened positive at study sites over the 25-month enrolment period. Data capturers travel to study facilities and image charts for as many CrAg-positive patients as possible at each health facility. Chart images are then checked for quality and de-identification and subsequently abstracted by clinical study staff to determine primary and secondary endpoints. 

The primary endpoint of the CAST-NET study is to estimate the 6-month cryptococcal meningitis-free survival of all patients with a CrAg-positive screening test result. Additional endpoints to be determined from chart abstraction include indicators such as 6-month retention in care, time from testing to treatment initiation, and proportion of patients’ CrAg test results appearing in their clinical chart.

Analysis of these endpoints aims to reveal weaknesses in the current national CrAg screening programme. The second phase of CAST-NET seeks to design programmatic interventions that address identified gaps, such as enhanced training or test result delivery and follow-up. These programmatic interventions will then be evaluated for impact using a pre/post study design in a subset of CAST-NET study sub-districts.n

South Africa pledged its commitment to the World Health Assembly resolution “Combating antimicrobial resistance including antibiotic resistance”, adopted in May 2014, to develop a National Action Plan on AMR. By October 2014, the Antimicrobial Resistance National Strategic Framework, 2014-2024 (AMR Strategic Framework) was developed and launched with the commitment of most of the key stakeholders within the human and animal health, agriculture, as well as science and technology sectors.

The AMR Strategic Framework defines South Africa’s approach to manage AMR and limit further increases in resistant microbial infections and improve patient outcomes and livestock production and health. The vision is “to ensure the appropriate use of antimicrobials by healthcare and animal health professionals in all health establishments in South Africa to conserve the efficacy of antimicrobials for the optimal management of infections in human and animal health”.

This report was developed in fulfilment of one of the main pillars of the AMR Strategic Framework – “Enhance surveillance” with a corresponding objective “to optimise and report on surveillance of AMR and antimicrobial use in humans and livestock in order to provide reliable data to optimise policy decisions and treatment choice”. The report also seeks to create a consolidated, representative view of AMR and antimicrobial use in South Africa and to monitor trends going forward to evaluate the impact of the AMR Strategy Framework.

 National AntSurveillance for Antimicrobial Resistance and Consumption of Antibiotics in South Africa (2018-2022)

Carbapenem-resistant Enterobacterales (CRE) are a group of gram-negative bacteria that are resistant to carbapenem antibiotics, last line class of antibiotics generally reserved for severe infections. These includes organisms such as Klebsiella spp, Escherichia coli, Enterobacter spp, Serratia spp, Citrobacter spp, etc. They pose a significant public health threat as they cause healthcare-associated infections are linked with major outbreaks in healthcare facilities and are difficult to treat because of limited remaining antimicrobial treatment options. Infections caused by CRE’s includes pneumonia, bloodstream infections, urinary tract infections (UTIs), wound infections and meningitis. Given the growing threat of CRE infections, World Health Organism has categorized CRE’s as a critical-priority group of pathogens urgently needing new drugs. Infections caused by Carbapenem-resistant Enterobacterales are associated with high rates of morbidity, mortality, and high healthcare costs. Wastewater surveillance has emerged as a valuable tool in monitoring antimicrobial resistance and it supports the One-Health approach that recognizes the interdependence of human, animal and environmental health and tackles antimicrobial resistance (AMR) in a multifaceted manner.

Therefore, the wastewater surveillance for CRE is conducted concurrently with CRE clinical surveillance. This project aims to identify and determine the prevalence of carbapenem-resistant enterobacterales and antibiotic resistance genes conferring resistance to carbapenems. The project is nested within wastewater surveillance project currently on-going at the centre for Vaccine and Immunology (CVI). Wastewater samples are thus collected from CVI. The samples are collected from all 9 provinces in South Africa in various collection sites. This is a short-term project conducted over a period of six months (from November 2024 – April 2025). The surveillance involves collection and analysis of samples originating from treatment facilities, hospitals, agricultural runoff and community settings. The surveillance will shed light on organisms that may be missed in clinical surveillance alone. Wastewater surveillance is efficient and has great potential for early warnings of transmission and outbreaks of infectious disease. It provides real-time information on what is happening at a population level.

Invasive candidiasis (IC) remains a serious global health challenge, with high mortality rates despite treatment, particularly in regions like South Africa where healthcare systems are burdened by factors such as HIV and limited access to antifungals. Antifungal resistance, especially in non-albicans Candida species, has become a growing issue, further complicating management. Existing research on IC is largely conducted in high-income settings, leaving gaps in understanding the specific dynamics of antifungal resistance, Candida colonisation, and transmission patterns in low- and middle-income countries (LMICs).

This study is nested within a multi-centre, prospective cohort study which aims to explore the relationship between antifungal use and the development of resistance in Candida species among ICU patients in four major hospitals in Johannesburg, South Africa and Mozambique. The primary hypothesis posits that systemic antifungal use in the ICU setting influences local fungal ecology and drives resistance development, leading to colonisation and infection with less susceptible strains. Additionally, the study will investigate whether invasive candidiasis arises from the colonizing flora, particularly focusing on how skin and gut mycobiota serve as reservoirs for invasive infection.

The study comprises three key components:

1. Surveillance of Candida colonisation and candidaemia over a period of 6-12 months
2. A unit-wide antifungal consumption tracking,
3. An evaluation of antifungal stewardship (AFS) and infection prevention and control (IPC) practices.

Over 6-12 months, 800-1000 ICU patients will be enrolled, with serial swabs and blood cultures conducted to assess colonisation, species distribution, and resistance development. Environmental sampling and whole-genome sequencing will aid in understanding transmission dynamics, while detailed antifungal prescription data will be analyzed to evaluate stewardship practices. Antifungal consumption will be tracked longitudinally, providing insights into usage patterns and trends across hospital units.

The primary outcome of the study will be the incidence rate of resistance emergence in colonising or invasive Candida isolates in patients exposed to antifungal agents. Secondary outcomes include rates of colonisation and candidaemia with resistant species, the emergence of resistance-associated genetic mutations, and changes in Candida species distribution. This study will also assess gaps in IPC and antifungal stewardship, providing a foundation for targeted interventions to reduce antifungal resistance and improve patient care.

By generating setting-specific data on Candida colonisation, resistance patterns, and antifungal use, this study will contribute valuable insights to guide antifungal stewardship and infection control programs in South African ICUs. These findings will support the development of tailored national and regional guidelines to optimize antifungal use, improve patient outcomes, and reduce the burden of antifungal resistance.

The current running project at the NICD is the Carbapenemase-Resistant Enterobacterales (CRE) and Enterobacter cloacae complex (ECC) surveillance project. This project aims at monitoring, understanding, and mitigating the spread of CRE infections in healthcare settings. These bacteria have developed resistance, over time, to carbapenems, an effective class of antibiotics that represent the last line of treatment against serious infections. These infections confer a very serious public health risk, as limited options for their treatment are related to high morbidity and mortality rates, especially among vulnerable populations. Surveillance activities are nested under GERMS SA, and it is given enhanced collection of demographics, clinical and epidemiological data collection. Enterobacter cloacae complex has not previously been studied as part of national surveillance in South Africa. As such, prevalence, antimicrobial susceptibility and genomic profiles are important to determine.

Key activities involve laboratory testing and analysis. Each sample received undergoes additional laboratory testing with bacterial identification and antibiotic susceptibility testing, the molecular testing. The CRE Surveillance Project enables infection surveillance with data generated to allow for the early detection of outbreaks. It builds capacity for managing the problem of CRE through training and technical assistance, thereby enhancing the capacity for ongoing infection control to meet the goals of preparedness and resilient health systems.

We expect that tracking and managing CRE infections reduces the infection rate burden and results in reduced morbidity and mortality, which in turn leads to improvements in patient health outcomes. Data-driven infection control practices enhance quality of care, promote a safer healthcare environment, and facilitate equity in access to quality care-all elements of patient-centered goals.

This insightful surveillance data will inform long-term public health policy and ensure proper, sustainable infection control practices. It equips healthcare providers with knowledge and tools to take appropriate case management actions for the durability of CRE and aligns with RISE’s mission of sustainable health system strengthening. This project is supported by Reaching Impact, Saturation, and Epidemic Control (RISE) program under GHSA under USAID and NICD.