In Depth: Risk to Newborns Rises as Antibiotics Stop Working

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The number of newborn babies dying from it is rising because the antibiotics used to treat them are not working effectively, according to a landmark international study. Neonatal sepsis is a life-threatening bacteremia that affects up to three million babies worldwide each year.

READ | Antibiotic resistance is causing more babies to die from neonatal sepsis, global study finds

The Global Antibiotic Research and Development Partnership (GARDP) and its partners recently published their findings showing that antibiotic resistance against bacterial infections and the increased use of broader-spectrum antibiotics have led to high levels mortality and neurodevelopmental problems in surviving babies.

Babies are particularly vulnerable to infections because of their underdeveloped immune systems, says Sally Ellis, project manager for GARDP’s Antibiotics for Children project. “The problem is compounded by the fact that babies are dying due to the lack of good treatment options.”

The observational study, called NeoOBS, involving more than 3,200 newborns with neonatal sepsis was conducted at 19 hospitals in 11 high-, middle- and low-income countries, including South Africa. She assessed the antibiotics currently used to treat newborns with sepsis and the extent to which resistance renders these treatments ineffective.

Often fatal

The three-year study across four continents found an overall mortality of 11% at 28 days in babies suspected of having neonatal sepsis. The rate jumped to 18% in cases where a diagnosis was confirmed by culturing the pathogen from blood samples.

More than half of infection-related deaths (59%) were due to nosocomial infections. Klebsiella pneumoniae was the pathogen most frequently isolated and most often associated with nosocomial infections, increasingly resistant to existing antibiotic treatments, according to a GARDP report accompanying the results.

A worrying trend identified was the frequent prescription of last-line antibiotics such as carbapenems due to the high degree of antibiotic resistance in healthcare settings. It should be noted that 15% of babies with neonatal sepsis received last-line antibiotics. Other key findings are that in-hospital mortality was high but variable, ranging from 1% to 27% across sites.

Antibiotic prescribing practices varied widely with limited use of World Health Organization recommended regimens in many hospitals due to high antibiotic resistance. GARDP has identified potential candidates to replace the WHO-recommended first-line treatment.

“System failure”

According to the GARDP report, policymakers, governments, institutions and businesses have for decades failed to collectively address “a systemic failure that leads to preventable infant deaths from neonatal sepsis, particularly in countries with low income”.

Lead researcher Mike Sharland of St George’s, University of London, said: “There are hardly any ongoing studies of developing new antibiotic treatments for babies with sepsis caused by multidrug-resistant infections. This is a major problem for babies in all countries, rich and poor.”

He says the study allowed GARDP to design a new global trial of new treatments to reduce mortality from neonatal sepsis. The NeoSep1 trial will begin in South Africa and Kenya later this year, with up to eight other countries participating in 2023. It will, among other objectives, test the safety and efficacy of three potential new antibiotic combination treatments, by ranking them against existing treatments commonly used antibiotic regimens.

A total of 600 of the 3,200 babies in the NeoOBS study came from three South African hospitals, namely Charlotte Maxeke in Johannesburg, Chris Hani Baragwanath in Soweto and Tygerberg Hospital in Cape Town. The three tertiary hospitals represent a mix of newborns with medical issues, including prematurity, and babies requiring surgery, including for birth defects.

Talk to Projector, Professor Angela Dramowski, senior researcher and head of the general pediatric clinical unit at Tygerberg Hospital, says neonatal survival globally is “crucial”. The latest data indicates that half of all deaths of children under five occur within the first 28 days of life. “If we want to improve child survival, we need to focus on neonatal survival,” she says. “A baby born today in an African country has a ten times higher mortality risk than a similarly sized baby born in a high-income country.”

Although there has been a huge improvement in child survival, neonatal survival has stagnated in most African countries, to the point that 95% of all newborn deaths worldwide occur in countries low or middle income, at least half to two thirds in the sub-region. -Saharan Africa, she said.

The Three Big Killers

The reasons for the deaths, she says, include the vulnerable neonatal period in particular, with the ‘big three killers’ being prematurity, lack of oxygen, birth injuries and infections.

She says the infection is often considered the least common, but a study at Chris Hani Baragwanath Hospital in 2019 showed that up to 74% of all deaths currently attributed to prematurity could be linked to serious hospital-acquired multidrug-resistant bacterial infections.

Dramowski says South African data from the Saving Babies Reports and the Perinatal Problem Identification System attributes about 10% of neonatal deaths to sepsis but, in reality, she says it’s likely to be much higher and will increase. in the future.

Factors that will add to the burden of neonatal sepsis in Africa include enormous population growth and rapid urbanization. “This means more hospital deliveries and a huge growth in the public sector maternal and neonatal care burden. This translates into overcrowding and even lower staff-to-patient ratios for a very vulnerable population group. “

Another problem is the lack of infection control. “It’s very difficult to pay attention to the fundamentals that make health care safe. In a busy neonatology unit with a huge turnover of babies, simple hand hygiene, cleaning the environment, cleaning shared equipment are unfortunately not optimally applied in most South African contexts,” she says.

In neonatal units in the Western Cape, she says, in the nine major metro hospitals and beyond, occupancy rates are over 90%. In the Eastern Cape, many hospitals have a capacity of 140-150% per day. “So you can’t even ensure adequate spacing between babies and mothers – a recipe for very easy transmission of bacteria.”

“We get very resistant bacteria which are difficult to treat, so we are increasingly using antibiotics of last resort, i.e. antibiotics which are not fully effective, which leads to the risk that more babies die or survive with a disability,” she said.

Also, she says, “We have to go back to using drugs that were abandoned in the past because they were too toxic, not approved for babies, for example, Colistin, which is a very old antibiotic that ‘needed resuscitation to treat neonatal sepsis caused by Acinetobacter. It’s a huge problem now, especially at the two sites in Johannesburg where they had Acinetobacter, the most common pathogen they cultured in affected babies of sepsis.

When those antibiotics are ruled out, Dramowski says neonatologists and pediatricians opt for the “big gun” — a broad-spectrum antibiotic called meropenem that belongs to the class of carbapenem antibiotics. “But in recent years we have had large outbreaks in several hospitals in South Africa of carbapenem-resistant Enterobacteriaceae, a group of intestinal organisms.

“One of them is Klebsiella, which is the most common and causes between 5 and 10% of all infections. of sepsis because we can’t afford to be wrong. So we often use our strongest antibiotics upfront to try to save the baby and then try to reduce our antibiotics to target the specific bug we’re growing. »

Diagnosis and Detection

Dramowski says the tests overall are very limited, not very sensitive or specific, making it difficult to distinguish whether a baby has deteriorated due to causes related to prematurity or due to infection.

“Throughout Africa where there are few microbiology and diagnostic testing labs, units will choose to give very broad-spectrum, very potent antibiotics outright, because they want to save lives and they don’t know whether it is an infection or not.

“And the result is that more babies are treated with antibiotics more often, which removes the good bacteria from the baby’s gut and replaces them with bacteria that are resistant to antibiotics, so the next time the baby gets a infection, you need to give it even stronger, broader-spectrum antibiotics to treat the next infection.

“So you’re really treating blindfolded or in the dark. And that’s why the new NeoSep1 study is going to be extremely helpful because we’ll get an idea of ​​the resistance profile of the bacteria and the antibiotic regimens that gave the best results from treatment across a wide range of settings,” she says.

Dramowski says it can take up to three to four days to identify the bacteria and the sensitivity of the bacteria to the antibiotic, at which point many babies will have died while waiting for their results. Moreover, in many settings, the antibiotics needed to treat infections are not even available in most hospitals.

The NeoOBS study represents settings where “you probably have the worst infections but also the best access to a wide range of antibiotics and critical care facilities.”

“So the mortality estimates seem pretty conservative to me where they had about 18% mortality. But, if you work in a smaller district hospital without access to intensive care, the chances of a baby with a very serious bacterial infection dying can be 50% or more. »

Dramowski says better diagnostics and better drugs are needed, and the “holy grail” is to prevent these infections from happening in the first place.

“South Africa needs to do better. We know we have recurring outbreaks in neonatal units, understaffing and overcrowding. We need to allocate resources to physical infrastructure to make neonatal and maternity care safer, [and] a skilled workforce that includes infection control and national surveillance of infections in hospitalized newborns. This will help identify hot spots and reduce the [number] antibiotics needed to treat often preventable infections,” she says.

*This article was published by Projector– public interest health journalism.

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