LISBON, Portugal — A shift toward broader-spectrum antibiotics and increasing antibiotic resistance has led to high levels of mortality and neurodevelopmental impacts in surviving babies, according to a large international study conducted on four continents.
Results of the 3-year study were presented at this week’s European Congress of Clinical Microbiology & Infectious Diseases (ECCMID).
The observational study, NeoOBS, conducted by the Global Antibiotic Research and Development Partnership (GARDP) and key partners from 2018 to 2020, explored the outcomes of more than 3200 newborns, finding an overall mortality of 11% in those with suspected neonatal sepsis. The mortality rate increased to 18% in newborns in whom a pathogen was detected in blood culture.
More than half of infection-related deaths (59%) were due to hospital-acquired infections. Klebsiella pneumoniae was the most common pathogen isolated and is usually associated with hospital-acquired infections, which are increasingly resistant to existing antibiotic treatments, said a report produced by GARDP to accompany the results.
The study also identified a worrying trend: Hospitals are frequently using last-line agents such as carbapenems because of the high degree of antibiotic resistance in their facilities. Of note, 15% of babies with neonatal sepsis were given last-line antibiotics.
Pediatrician Julia Bielicki, MD, PhD, senior lecturer, Paediatric Infectious Diseases Research Group, St. George’s University of London, United Kingdom, and clinician at the University of Basel Children’s Hospital, Switzerland, was a coinvestigator on the NeoOBS study.
In an interview with Medscape Medical Newsshe explained that, as well as reducing mortality, the research is about managing infections better to prevent long-term events and improve the quality of life for survivors of neonatal sepsis. “It can have life-changing impacts for so many babies,” Bielicki said. “Improving care is much more than just making sure the baby survives the episode of sepsis, it’s about ensuring these babies can become children and adults and go on to lead productive lives.”
Also, only a minority of patients (13%) received the World Health Organization (WHO) guidelines for standard of care use of ampicillin and gentamicin, and there was increasing use of last-line agents such as carbapenems and even polymyxins in some settings in low- and middle-income countries. “This is alarming and foretells the impending crisis of a lack of antibiotics to treat sepsis caused by multidrug-resistant organisms,” according to the GARDP report.
There was wide variability in antibiotic combinations used across sites in Bangladesh, Brazil, China, Greece, India, Italy, Kenya, South Africa, Thailand, Uganda, and Vietnam, and often such use was not supported by underlying data.
Bielicki remarked that there was a shift toward broad-spectrum antibiotic use. “In a high-income country, you have more restrictive patterns of antibiotic use, but it isn’t necessarily less antibiotic exposure of neonates to antibiotics, but on the whole, usually narrow-spectrum agents are used.”
In Africa and Asia, on the other hand, clinicians often have to use a broader-spectrum antibiotic empirically and may need to switch to another antibiotic very quickly. “Sometimes alternatives are not available,” she pointed out.
“Local physicians are very perceptive of this problem of antibiotic resistance in their daily practice, especially in centers with high mortality,” said Bielicki, emphasizing that it is not their fault, but “due to the limitations in terms of the weapons available to treat these babies, which strongly demonstrates the growing problem of antimicrobial resistance affecting these babies on a global scale.”
Tim Jinks, PhD, Head of Drug Resistant Infections Priority Program, at Wellcome Trust, commented on the study in a series of text messages to Medscape Medical News. “This research provides further demonstration of the urgent need for improved treatment of newborns suffering with sepsis, and particularly the requirement for new antibiotics that overcome the burden of drug-resistant infections caused by [antimicrobial resistance].”
“The study is a hugely important contribution to our understanding of the burden of neonatal sepsis in low- and middle-income countries,” he added, “and points toward ways that patient treatment can be improved to save more lives.”
High-, Middle-, and Low-Income Countries
The NeoOBS study gathered data from 19 hospitals in 11 high-, middle-, and low-income countries and assessed which antibiotics are currently being used to treat neonatal sepsis, as well as the degree of drug resistance associated with them. Sites included some in Italy and Greece, where most of the neonatal sepsis data currently originate, and this helped to anchor the data, Bielicki said.
The study identified babies with clinical sepsis over a 4-week period and observed how these patients were managed, particularly with respect to antibiotics, as well as outcomes including whether they recovered, remained in hospital, or died. Investigators obtained bacterial cultures from the patients and grew them to identify which organisms were causing the sepsis.
Of note, mortality varied widely between hospitals, ranging from 1% to 27%. Bielicki explained that the investigators were currently exploring the reasons behind this wide range of mortality. “There are lots of possible reasons for this, including structural factors such as how care is delivered, which is complex to measure,” she said. “It isn’t trivial to measure why, in a certain setting, mortality is low and why in another setting of comparable income range, mortality is much higher.”
Aside from the mortality results, Bielicki also emphasized that the survivors of neonatal sepsis, frequently experience neurodevelopmental impacts. “A hospital may have low mortality, but many of these babies may have neurodevelopment problems and this has a long-term impact.”
“Even though mortality might be low in a certain hospital, it might not be low in terms of morbidity,” she added.
The researchers also collected isolates from the cohort of neonates to determine which antibiotic combinations work against the pathogens. “This will help us define what sort of antibiotic regimen warrants further investigation,” Bielicki said.
Principal Investigator, Mike Sharland, MD, also from St. George’s, University of London, who is also the Antimicrobial Resistance Programme Lead at Penta Child Health Research, said, in a press release, that the study had shown that antibiotic resistance is now one of the major threats to neonatal health globally. “There are virtually no studies underway on developing novel antibiotic treatments for babies with sepsis caused by multidrug-resistant infections.”
“This is a major problem for babies in all countries, both rich and poor,” he stressed.
NeoSep-1 Trial to Compare Multiple Different Treatments
The results have paved the way for a major new global trial of multiple established and new antibiotics with the goal of reducing mortality from neonatal sepsis — the NeoSep1 trial.
“This is a randomized trial with a specific design that allows us to rank different treatments against each other in terms of effectiveness, safety, and costs,” Bielicki explained.
Among the antibiotics in the study are amikacin, flomoxef and amikacin, or fosfomycin and flomoxef in babies with sepsis 28 days old or younger. Similar to the NeoOBS study, patients will be recruited from all over the world, and in particular from low- and middle-income countries such as Kenya, South Africa, and other countries in Africa and Southeast Asia.
Ultimately, the researchers want to identify modifiable risk factors, and enact change in practice. But Bielicki was quick to point out that it was difficult to disentangle those factors that can easily be changed. “Some can be changed in theory, but in practice it is actually difficult to change them. One modifiable risk factor that can be changed is probably infection control, so when resistant bacteria appear in a unit, we need to ensure that there is no or minimal transmission between babies.”
Luregn Schlapbach, MD, PhD, Head, Department of Intensive Care and Neonatology, University Children’s Hospital Zurich, Switzerland, welcomed the study, saying recent recognition of pediatric and neonatal sepsis was an urgent problem worldwide.
She referred to the 2017 WHO resolution recognizing that sepsis represents a leading cause of mortality and morbidity worldwide, affecting patients of all ages, across all continents and healthcare systems, but that many were pediatric. “At that time, our understanding of the true burden of sepsis was limited, as was our knowledge of current epidemiology,” she said in an email interview. “The Global Burden of Disease study in 2020 revealed that about half of the approximatively 50 million global sepsis cases affect pediatric age groups, many of those during neonatal age.”
The formal acknowledgment of this extensive need emphasizes the “urgency to design preventive and therapeutic interventions to reduce this devastating burden,” Schlapbach said. “In this context, the work led by GARDP is of great importance — it is designed to improve our understanding of current practice, risk factors and burden of neonatal sepsis across low- to middle-income settings and is essential to design adequately powered trials testing interventions such as antimicrobials to improve patient outcomes and reduce the further emergence of antimicrobial resistance.”
Bielicki and Schlapbach have disclosed no relevant financial relationships.
32nd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) 2022: Abstracts 4940, 2127, 1827.
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