SOUTH AFRICA— The Neonatal Sepsis Observational Cohort Study (NEoOBS) has published its finding in the first global overview to assess the extent of Anti-Microbial resistance in neonatal sepsis.

NEoOBS was led by the Global Antibiotic Research and Development Partnership (GARDP) which recruited more than 3200 babies in 19 hospitals in 11 countries.

The study’s authors shockingly estimate that 214,000 newborns die every year from sepsis that has become antibiotic resistant, and this is mostly in low- to middle-income countries (LMIC).

The study published in the journal Plos Medicine found that many neonates (within 60 days of birth) get life-threatening bloodstream infections, or sepsis, and are dying because the antibiotics used to treat them are not effective.

The researchers reported great variability in mortality rates of babies with sepsis across the 19 hospitals, ranging from 1% to 27.3%.

Unfortunately, the study shows that treatment options have become increasingly limited as about 40% of infections are reported to be resistant to standard antibiotic treatments.

NEoOBS, a much-needed investigation into a silent killer

The authors say the NeoOBS study has at least yielded a wealth of high-quality data needed to design trials for much-wanted and appropriate treatments for sepsis in babies.

Encouragingly, and building on from the observational study the first global hospital-based neonatal sepsis trial called NeoSep 1 is underway in Kenya and South Africa.

Chris Hani Baragwanath Hospital is taking part in the trial together with Tygerberg Hospital in Cape Town and KEMRI, Kilifi County Hospital in Kenya.

It’s planned that the trial will be expanded to other countries and regions in 2024 with the aim of recruiting 3000 newborns.

A Personalised Randomised Controlled Trial (PRACTical) design will be used and according to GARDP and partners the design is a new way of comparing antibiotic treatments for neonatal sepsis.

In addition, doctors can choose treatment regimens that are likely to work well for newborns in their specific hospital settings.

Researchers say 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.

The intersection of PRACTical and NEoOBS

The PRACTical design has been specifically developed to address these challenges in important public health emergencies such as neonatal sepsis.

The trial will compare the safety and efficacy of three new combinations of older antibiotics (fosfomycin-amikacin, flomoxef-amikacin, and flomoxef-fosfomycin) against the current standard of care.

It will also assess and validate the doses of two antibiotics (fosfomycin and flomoxef) for use in newborns.

The trial will also evaluate new combinations of generic antibiotics.

Christina Obiero, Principal Investigator for the NeoSep1 trial for KEMRI at Kilifi County Hospital said, “We are hoping the trial will provide robust evidence that the antibiotic combinations are safe and effective and that this will lead to a change in both WHO and local treatment guidelines.”

In South Africa at Chris Hani Baragwanath Academic Hospital, one of the study partner hospitals, Prof Sithembiso Velaphi, Head of Paediatrics said, “The death of a child affects us all. Witnessing the loss of a newborn baby who has sepsis is terribly traumatic, especially so when antibiotics used to treat the child are ineffective.”

Dr. Velaphi noted that there was a major problem with infection control, specifically related to high-risk babies – sick babies with complications who need interventions such as drips and even surgery.

He added that this increased the chances of infection as more than 70% of all deaths ascribed to prematurity at the hospital were due to hospital-acquired multi-drug resistant infections.

Principal Investigator for the NeoSep1 trial at Tygerberg Hospital, Professor Adrie Bekker added, “We have so few antibiotics that work effectively against these very sick babies. And even for those that we have, we are still not 100% sure how to dose these drugs to get accurate concentrations in the blood.”

Better diagnostic tools for neonatal sepsis

Bekker who is also a Professor in the Division of Neonatology, Department of Paediatrics and Child Health at Stellenbosch University says a positive outcome of the NeoOBS study is the development of two important diagnostic tools which can be used in ICUs globally.

The first is the NeoSep Severity Score which is a compilation of common symptoms and signs that can occur in a baby with clinical sepsis.

The second is the NeoSep Recovery Score, which will assist clinicians in deciding if they can stop antibiotics earlier.

The tools are expected to help prevent the often excessive and inappropriate use of antibiotics for over too long a period, which compounds the problem of antibiotic resistance globally.

“It’s sometimes difficult for a clinician to know whether a baby actually neonatal sepsis has because it can present very subtly and not always with the same symptoms,” Bekker explains.

The blood culture is the gold standard for diagnosing neonatal sepsis, but Bekker says only around 10% of blood cultures will grow an organism even if the baby has sepsis, making it very difficult to get a diagnosis.

The NeoSeps Severity score will help doctors identify babies that are at very high risk from sepsis and those that would need treatment immediately.

Velaphi says a major challenge is the time it takes for an outcome of the blood culture and the general protocol is to start antibiotics immediately.

Waiting between 24 to 48 hours can be too late for a child who may have sepsis and could die, and antibiotics may be given to children who don’t have sepsis, and this adds to the frequency of antibiotic resistance.

Velaphi added, “So, you are damned if you do, and you are damned if you don’t.”

Velaphi said new diagnostic tests are needed, that are reliable and that have a high degree of sensitivity and specificity.

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