Experts have urged the development of new antibiotics after a landmark global observational study found that more than 200 000 neonates (within 60 days of birth) contract life-threatening bloodstream infections and die of sepsis because the drugs treating them are not effective.
This is the first global overview to assess the extent of the problem, writes Adele Baleta for Spotlight.
The study (called NeoOBS) was published in the journal Plos Medicine, and its results were the springboard for another trial, NeoSep 1, currently under way in Kenya and South Africa.
Led by the Global Antibiotic Research and Development Partnership (GARDP), NeoOBS had recruited more than 3 200 babies in 19 hospitals in 11 countries – South Africa, Kenya, Uganda, Thailand, Vietnam, India, Greece, Italy, Bangladesh, Brazil and China.
The researchers reported great variability in mortality rates of babies with sepsis across the 19 hospitals, ranging from 1% to 27.3%.
Sepsis affects up to 3m babies a year globally. The study’s 80 authors 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). Many survivors suffer from neurodevelopmental problems.
Treatment options have become increasingly limited as about 40% of infections are reported to be resistant to standard antibiotic treatments.
Infections picked up in hospital
Almost 60% of infection-related deaths were due to infections acquired at the 19 hospitals under review: Klebsiella pneumoniae was the most common pathogen isolated.
Of the 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling. Currently, 43 adult antibiotic clinical trials are recruiting patients, compared with only six trials recruiting neonates.
New antibiotic treatments are urgently needed, especially in LMICs where almost one in five babies with sepsis died. Premature babies are particularly vulnerable to infections because of their immature immune systems.
More than 200 different antibiotic combinations were used by hospitals included in the NeoOBS study, with repeated switching of antibiotics due to high resistance to treatments. This showed a pattern of limited use of the World Health Organisation’s recommended first-line treatment.
Often, doctors have had to opt for last-line antibiotics such as carbapenems because of the high degree of antibiotic resistance in their units or because they were the only treatment available.
“Witnessing the loss of a newborn baby with sepsis is terribly traumatic, more so when the antibiotics are ineffective,” said neonatologist Professor Sithembiso Velaphi, head of paediatrics at Chris Hani Baragwanath Academic Hospital.
“For a mother to watch her seriously ill baby being pricked with drips and pumped with drugs in efforts to save its life – only to leave the hospital empty-handed, without her child – it’s painful.”
Velaphi said it was imperative to prioritise the development of antibiotics to treat these babies. “For us, success is seeing a baby get better and go home.”
He added that the risk of infections was particularly high in hospitals with a shortage of nurses, beds, and space between patients, making it difficult to stop the spread of infection.
Chris Hani Baragwanath has an 18-bed ICU that is almost always full and when the situation is desperate, there is a spillover of patients into the high-care area. The pressure on the facility is huge and the influx of people from other countries has made it even more challenging, he said.
“There is a major problem of infection control, specifically related to high-risk babies – sick babies with complications who need interventions like drips and even surgery. This increases the chances of infection. More than 70% of all deaths ascribed to prematurity at Bara were due to hospital-acquired multi-drug resistant infections.”
NeoSep 1 trial
The authors said the NeoOBS study has yielded “a wealth of high-quality data” needed to design trials for much-needed and appropriate treatments for sepsis in babies.
Encouragingly, and building on from the observational study, the first global hospital-based neonatal sepsis trial – NeoSep 1 – is under way in Kenya and South Africa.
Chris Hani Baragwanath, Tygerberg Hospital in Cape Town and KEMRI, Kilifi County Hospital in Kenya, are all taking part in the trial, which will be expanded to other countries and regions in 2024 with the aim of recruiting 3 000 newborns.
A Personalised Randomised Controlled Trial (PRACTical) design will be used. GARDP and partners said the design was 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 said the development pipeline for new antibiotic treatments was limited and the lack of a universal, effective standard of care creates huge challenges in conducting research to tackle neonatal sepsis.
The PRACTical design has been specifically developed for 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.
“We hope 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,” said Christina Obiero, principal investigator for the NeoSep1 trial for KEMRI at Kilifi County Hospital.
Severity and recovery scores
Principal investigator for the NeoSep1 trial at Tygerberg Hospital Professor Adrie Bekker said: “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 and to also make sure that the outcomes are as good as can be. This trial will help give us confidence that we are delivering more effective treatment.”
Bekker, who is also professor in the Division of Neonatology, Department of Paediatrics and Child Health at Stellenbosch University, said a positive outcome of the NeoOBS study was the development of two important tools which can be used in ICUs globally.
The first is the NeoSep Severity Score – a compilation of common symptoms and signs in a baby with clinical sepsis. The second is the NeoSep Recovery Score, which will help clinicians decide 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, compounding antibiotic resistance globally.
Diagnosis in older age groups, children and adults, is generally easier.
“It’s sometimes difficult for a clinician to know whether a baby actually has neonatal sepsis, because it can present very subtly and not always with the same symptoms,” Bekker said.
The blood culture is the gold standard for diagnosing neonatal sepsis, but Bekker said only around 10% of blood cultures will grow an organism even if the baby has sepsis, making it difficult to get a diagnosis.
“And because it’s such an aggressive disease and a baby can die very quickly from it, clinicians tend to rather over-treat than under-treat. That is correct but, just as important as it is to start antibiotics quickly, it’s important to stop them if they are not necessary. The NeoSeps Severity score will help doctors identify babies at very high risk from sepsis and those who would need treatment immediately.”
Velaphi said a major challenge was the time it takes for an outcome of the blood culture, and the general protocol is to start antibiotics immediately. Waiting between 24 and 48 hours can be too late for a child who may have sepsis and could die. On the other hand, antibiotics may be given to children who do not have sepsis, adding to the frequency of antibiotic resistance.
“So, you are damned if you do and damned if you don’t.”
He said what was needed were new diagnostic tests that were reliable and had a high degree of sensitivity and specificity. “We need antibiotics that work to reduce mortality.”
Study details
Patterns of antibiotic use, pathogens, and prediction of mortality in hospitalized neonates and young infants with sepsis: A global neonatal sepsis observational cohort study (NeoOBS)
Neal Russell, Wolfgang Stöhr, Adrie Bekker, Mike Sharland et al.
Published in PLOS Medicine on 8 June 2023
Abstract
Background
There is limited data on antibiotic treatment in hospitalised neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design.
Methods and findings
Hospitalised infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation.
A total of 3 204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1—Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2—“Low” Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3—“Medium” Watch), 18.0% (n = 566) started a carbapenem (Group 4—“High” Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%).
A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates.
Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability.
Conclusion
Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis.
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SA and Kenya in global trial for neonatal sepsis treatment
Fosfomycin for babies with neonatal sepsis and AMR – Kenya trial
WHO urges action to stem rising AMR as experts call for new neonatal drugs
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