Neonatal sepsis: the new threat posed by superbugs

When Mukta's baby boy was born in December 2021 in Dhaka, Bangladesh, it quickly became clear to doctors that he needed emergency care. The 32-year-old mother, who prefers to go by her first name, and her husband had struggled to conceive for 11 years before she finally became pregnant following infertility treatment. Due to complications during the pregnancy, her baby was delivered prematurely by emergency caesarian at 32 weeks.

Her son weighed just 1.4kg (3lbs) and was put on ventilator support. He was also injected with antibiotics to prevent bacterial infections that affect the bloodstream – a life-threatening condition known as neonatal sepsis.

While her son appeared to do well at first, things took a turn for the worse when he was 11 days old. He was lethargic, and the oxygen levels in his blood dipped. Doctors ran a blood test that revealed he was suffering from neonatal sepsis, but they couldn't figure out which germ was causing it. A blood culture didn't turn up any results. Their best bet seemed to treat him with another round of antibiotics, different from those used in his first injection. This helped – until he contracted another round of sepsis, caused by a bug called Serratia marcesens, a common source of neonatal infections. This time, there was no hope. The bug was resistant to all the antibiotics they tried. Before a month had passed, Mukta lost her beloved, longed-for baby.

Around the world, an estimated 15% to 24% of all neonatal deaths are due to sepsis. The devastating condition, which can initially look harmless but then quickly deteriorate, is more common in newborns than in any other age group, affecting an estimated three million babies worldwide. They can become infected with harmful bacteria before, during or after birth, for example if the mother has an infection that passes to their child, or the environment is not sterile. Since their immune systems are not yet fully developed, babies may then struggle to fight it off.

Newborns in poorer countries, where access to healthcare and sterile equipment and facilities can be difficult, are particularly at risk. The incidence of neonatal sepsis is an estimated 1.8 times higher in middle-income countries and 3.5-fold higher in low-income countries, compared with wealthier nations. South Asia has one of the highest burdens of this devastating condition: 39% of all global neonatal sepsis deaths occur in this region.

Now a new enemy is making newborn sepsis even more dangerous: so-called superbugs, bacteria that have become resistant to antibiotics. Such antimicrobial resistance, known as AMR, can leave doctors helpless in the face of raging infections. Previously effective drugs no longer work, and the tiny patient's life slips away despite every effort to help.

"We've seen that growing antimicrobial resistance in developing countries is making the problem of neonatal sepsis much worse," says Mohammed Shahidullah, a professor of neonatology at Bangabandhu Sheikh Mujib Medical University in Bangladesh. He is also chair of the National Technical Working Committee (NTWC) on Newborn Health in Bangladesh and was one of the doctors who tried to save Mukta's baby. "Neonatal sepsis is now one of the major causes of hospital admissions and deaths in Bangladesh. It's a devastating loss." 

But how did the over-use of antibiotics, which have saved so many human lives since they were introduced in the 1940s, end up unintentionally breeding a super-threat to the world's most vulnerable babies?

The superbug problem 

In 2021, Bangladesh's Prime Minister, Sheikh Hasina, warned world leaders that antimicrobial resistance could grow into a bigger public health emergency than Covid-19 if not addressed. By then, scientists had already been warning for many years that the heavy use of antibiotics was turning into a problem.

All over the world, hospitals have been dealing with drug-resistant, deadly superbugs. These evolve because antibiotics kill most, but not all, bacteria – some survive, because they have genes that make them resistant. They then reproduce and can transfer their drug resistance genes to other bacteria (including other species of bacteria) nearby, through a process known as horizontal gene transfer.

As a result, hospitals can become breeding grounds for resistant strains, and once-powerful drugs become less and less effective. That's why when infants are infected with sepsis in a hospital setting, the bacteria responsible are far more likely to be resistant to the available drugs than when they contract an infection after returning to their homes, says Shahidullah.

One key recommendation from global health authorities is to avoid this resistance by using antibiotics cautiously in the first place – only when they are really needed, instead of scattering them about, and effectively training bacteria in surviving them.

Meanwhile, however, antibiotics overuse, and the superbugs this helps create, are already wreaking havoc. Ailments such as urinary tract infections and sepsis are becoming harder to treat, putting vulnerable people at risk. And one particularly vulnerable group are newborns.

"Invisible" babies

While under-5 mortality has fallen sharply in recent decades, "neonatal survival has lagged",  according to a report by Global Antibiotic Research and Development Partnership (GARDP). Sepsis is a particularly deadly risk: "Within hours, a baby with sepsis can be in a life-threatening situation. To make matters worse, antibiotic resistance reduces the odds of a baby surviving neonatal sepsis," states the report. As in the case of Mukta's baby, it can mean doctors desperately try one drug after the other, only to find that none of them work.

"The biggest challenge in dealing with sepsis in infants is to know which organism is causing the infection — it's not always possible to isolate in some cases, or to even determine whether they have an infection," says Sally Ellis, project leader of the children's antibiotics programme at GARDP. The diagnosis is complicated by the frequent presence of other conditions that resemble sepsis, especially in preterm infants, and the absence of optimal diagnostic tests, she says.

A separate study found that globally in 2019, nearly 140,000 newborn deaths were caused by bacterial antimicrobial resistance. And yet, "babies remain neglected and invisible within the broader response to antibiotic resistance", according to the GARDP report.

GARDP and its partners analysed 3,200 cases of newborn babies with clinically diagnosed sepsis in an effort to better understand the impact of antibiotics resistance. The focus was on finding out which antibiotics are used to treat newborns with sepsis, and to what extent drug-resistance rendered these treatments ineffective. It was carried out at 19 hospitals in 11 countries across four continents, spanning different income levels.

One key finding was that hospitals treating newborns with sepsis were increasingly using drugs intended as a last resort – because the original options had lost their power. Ampicillin and gentamicin, drugs that are recommended as a first, standard option, were only used for 13% of the babies. Powerful antibiotics intended as a very last defence – known as carbapenems – were prescribed to 15% of the babies, a surprisingly large number.

"This is alarming and foretells the impending crisis of a lack of antibiotics to treat sepsis caused by multidrug-resistant organisms," the researchers said in their report.

In other words, doctors are reaching for ever more powerful weapons in the form of last-resort drugs – until those no longer work, either.

The sepsis detectives

In India, around 20% of the country's one million neonatal deaths a year are caused by sepsis, according to data from the US and India-based public health research orgnaisation, the Center for Disease Dynamics, Economics and & Policy (CDDEP). Of these, 58,000 deaths are a direct result of antimicrobial resistance. In other countries, the data is incomplete or lacking altogether, making it hard to grasp the scale of the crisis. And even in India, the problem is under-researched, says M Jeeva Sankar, a neonatologist at the All India Institute of Medical Sciences in New Delhi.

In 2019, Sankar and his colleagues trawled through two major databases of published scientific papers to find studies on neonatal sepsis. They found that very little data on sepsis exists across Asia, even though the region is home to such a huge proportion of the world's population.

"For the 25 million babies born in India every year, nearly the size of the population of Australia, we've had only 64 studies on neonatal sepsis from Jan 2000 to August 2018," says Sankar. "In the same time frame, Pakistan published 16 studies, Bangladesh six, and Sri Lanka just one.  We definitely need more data and more surveillance to study this better." 

They reported their findings on this huge data gap in a paper published in the British Medical Journal, pointing out that South Asia and sub-Saharan Africa are particularly afflicted by neonatal sepsis – making it even more urgent to gather reliable data there. They also highlight that poverty and unequal access to healthcare make babies more vulnerable to contracting sepsis in the first place, a situation worsened by "spiraling antimicrobial resistance".

Early detection of sepsis can help, but in low-income countries, where the diagnostic facilities are scarce, the undiagnosed and unreported cases remain high, says Shyam Sundar Budhathoki, a clinician specialising in public health at Imperial College London, who previously worked in Nepal. In these countries, drug resistance may also not be given the attention it needs because "priorities in public health are set based on immediate and visible problem-solving priorities", he says. In other words, other threats to newborns' health may simply seem more pressing – say, infections in general, or malnutrition. That can mean a more complex causal chain, like antimicrobial resistance leading to neonatal deaths from sepsis, "is ignored", he says.

A new picture

However, researchers have also gained some recent, potentially groundbreaking insights that might help in the fight against drug resistant neonatal sepsis. For example, there are key differences in the nature of the bacteria causing neonatal sepsis in high-income countries compared to low-and-middle income countries. This in turn affects how they should be treated.

In wealthier countries, a high number of neonatal sepsis is caused by bacteria that are classified as "Gram-positive" – organisms that give a positive result in a test known as the Gram stain test which is used to classify bacteria – says Sankar. Importantly, these cases seem to be predominantly caused by just a few different types of bacteria – certain strains of Streptococcus (typically found in the gut and mother's vaginal tract) and Staphylococcus (which are found on the surface of the skin), for example.

However, in low- and middle-income countries, there appears to be a higher proportion of infections "driven by Gram-negative bacteria, typically found in the gut", says Sankar. This can be due to poor sanitation, for example. A wide range of different microbes also appear to be responsible for these Gram-negative sepsis infections, and they tend to show high rates of antimicrobial resistance – between 50–70%.

"That's why low-and -middle income countries are seeing a greater mortality from neonatal sepsis than developed nations," he says. The many different microbes mean it's harder to standardise the protocol for treatment in "the way it is done in the West".

Instead, doctors in poorer countries have to figure out which microbe caused the sepsis, hope it shows up in the available tests, and then see if it's even treatable with their antibiotics.

Many of the last-ditch antibiotics available bring with them the risk of serious side-effects in patients and so using them in newborns carries additional risks. There are hopes, however, that combinations of several antibiotics at once could provide new ways of combating drug-resistant strains while being safe to use in babies. But the availability of such complex alternative antibiotic treatments is still limited in developing countries.

Defeating the superbugs

As terrifying as drug-resistant bugs are, doctors and patients have another, important and more basic tactic in their arsenal: good hygiene. In the past, it was assumed that, when a baby was infected within 72 hours of birth, it tended to be caused by bacteria they had contracted from the mother's vaginal tract or gut at birth. If the sepsis occurred later, it was thought to be the result of poor hygiene, either in a neonatal care unit or at home. But this view has become a great deal more nuanced in recent years.

However, recent research, including a study by Sankar and his colleagues, have suggested that the bacteria causing early and late-onset sepsis were not that different. This suggests that poor hygiene may play a role in a range of sepsis cases, even the ones right after birth.

"This makes the need for disinfection and maintaining a protocol that ensures a clean, hygienic environment exceedingly important," says Sankar. However, basic soap and water are lacking in half the healthcare facilities across the globe, according to a WHO/UNICEF report released in  in 2022, contributing to the risk of infections in mothers and newborns.

Other simple measures can help prevent infection in healthcare settings, such as wearing sterile gowns in intensive care units, swabbing and cleaning surfaces and equipment, and disinfecting the skin of the newborn before administering injections or drips. But it requires training and adequate staffing to implement them, alongside teaching good hygiene practices to parents, says Shahidullah.

Bangladesh is also aiming to encourage more women to give birth in hospitals – which despite their own superbug struggles, tend to be the safer option. Almost half of Bangladeshi women still give birth at home, which comes with a higher risk of contracting infections. In Nepal, neonatal sepsis was found to be higher among babies born to mothers who did not attend antenatal check-ups, again highlighting the importance of support for prospective parents.

Ultimately, tackling the drug resistance crisis will require a broad range of tools, experts say. 

"For more widespread change, we need to consider antimicrobial resistance as a socio-political challenge and not just a medical one," says Abdul Ghafur, a consultant in infectious diseases at the Apollo Cancer Institute in the Southern Indian city of Chennai. Together with other Indian doctors, he is also a vocal campaigner on fighting the superbug threat. "Proper sanitation at home, in healthcare institutions and in communities is key to dealing with neonatal sepsis aggravated by [antimicrobial resistance] and to prevent re-infection in children."   

Finding new antibiotics should be seen as an immediate priority: "Covid has shown us that India can be the pharmacy of the world, and develop state-of-the-art drugs," he says.

Ghafur suggests focusing on developing tests to identify the source of the infection as quickly as possible. "A rapid diagnostic test could help doctors zero in on the right antibiotic to prescribe within an hour, which could significantly lower the risk of death. New antibiotics and vaccines can be developed for bacteria that are now resistant to existing antibiotics," he says. In his view this should be a global effort, with governments working together with private companies.

For families like Mukta's, who lost her son to sepsis, these advances come too late. But tackling the antibiotics crisis, and the infection risk around birth, could help others give their babies a safe start – and help doctors protect and save those in their care.

Source: BBC