Thousands of newborns die within the first few weeks of life in South Africa due to sepsis, with statistics showing that bacterial infections remain the leading cause of mortality.
Public health experts warn that given the substantial number of antimicrobial resistance and outbreaks of infections in the country’s neonatal units, including the high number of deaths in Africa — about 250,000 and 1-million infections each year — many African countries were not expected to meet the UN sustainable development goal of reducing newborn mortality to less than 12 per 1,000 live births by 2020.
But a groundbreaking international clinical trial that has just started in South Africa to evaluate new antibiotic combinations for newborn babies with sepsis offers hope that this trajectory will change and evolve into life-saving treatments for this life-threatening condition.
Two tertiary public hospitals, Tygerberg Hospital in Cape Town and Chris Hani Academic Hospital in Soweto, plus Kilifi Country Hospital in Kenya, are the first sites that will test the safety and efficacy of the NeoSep1 trial.
The trial, sponsored by the Global Antibiotic Research and Development Partnership (GARDP) in collaboration with the Medical Research Council Clinical Trials Unit at University College London and other international research centres, will be expanded to other countries in 2024, with the aim of recruiting up to 3,000 newborns.
The NeoSep1 trial will evaluate new combinations of existing antibiotics and compare them to treatment regimens used in newborn babies with suspected neonatal sepsis.
It will test three new combinations of older antibiotics, fosfomycin-amikacin, flomoxef-amikacin and flomoxef-fosfomycin, against the existing standard of care, and will validate the doses of two antibiotics (fosfomycin and flomoxef) for use in newborns. The trial will also consider how these combination treatments can best be used in hospital settings with varying levels of antibiotic resistance.
“Many babies are dying because of limited treatment options. The NeoSep1 trial is an opportunity to shift this trajectory by identifying new antibiotic combinations that we can tailor to treat neonatal sepsis in settings where there is widespread resistance to current recommended options. This is vital if we are going to address the impact of antimicrobial resistance on the burden of disease related to neonatal sepsis,” said Seamus O’Brien, director of research and development at GARDP.
It will not only allow researchers to compare various antibiotic treatments for neonatal sepsis, but the trial will also enable doctors to “choose treatment regimens that are likely to work well for newborns in their particular hospital settings”.
Adrie Bekker, lead researcher for the NeoSep1 trial at Tygerberg Hospital and a professor within the department of paediatrics and child health at Stellenbosch University, said doctors often have to treat babies “with a combination of the antibiotics of last resort”.
“On top of this we are not 100% sure about how to dose these drugs. We’re dealing with fragile newborns, so we need to be aware of the potential toxicity of the antibiotics and dosages we use. This trial will help in giving us confidence that we are delivering more effective treatment. This is critical as we want the best possible outcome for newborns in our care.”
The NeoSep1 trial builds on findings from a global observational study of sepsis in newborn babies, conducted by GARDP and partners in 19 hospitals across 11 countries from 2018 to 2020. The study found a worryingly wide variation in treatment and frequent switching of antibiotics because of high resistance to treatments.
According to the perinatal problem identification programme data, sepsis in South Africa is estimated to cause about 13% of neonatal deaths among babies above 1kg from 2012 to 2016, but the latest post-mortem minimally invasive tissue sampling done at Chris Hani Baragwanath Academic Hospital shows that hospital-acquired antimicrobial-resistant infections are now the leading cause of late neonatal mortality after the first week of life.
Globally, sepsis affects up to 3-million babies a year, with an increasing number of newborns becoming resistant to the World Health Organisation (WHO)-recommended antibiotic treatments, particularly the ampicillin-gentamicin regimen.
One of the researchers involved in the study, Sarah Walker, professor of medical statistics and epidemiology at the Medical Research Council Clinical Trials Unit at University College, said the development pipeline for new antibiotic treatments is limited, and “the lack of a universal, effective standard of care creates huge challenges in conducting research to tackle neonatal sepsis”.
“Novel trial designs such as the practical design have been specifically developed to address these challenges in important public health emergencies such as neonatal sepsis,” she said.
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