Geneva – An observational study conducted globally between 2018 and 2020 showed that many newborns die because the antibiotics used to treat sepsis are losing their effectiveness. The study involved more than 3.200 newborns suffering from sepsis in 19 hospitals in 11 different countries around the world. For Europe, the Bambino Gesù Children’s Hospital participated as a quality control facility compared to the developing countries included in the research, where high mortality has been detected among newborns with positive blood cultures (on average almost 1 in 5) and a high level of antibiotic resistance. Thanks to the study, important data has been collected and new tools that will help improve the treatment of newborns with sepsis have been developed.

The results of the observational study were published in an article in PLOS Medicine, contributed by a group of more than 80 researchers from four different continents.

The study was conducted by the Global Antibiotic Research and Development Partnership (GARDP), in collaboration with St George’s University in London; Penta – Child Health Research, an independent scientific research network that deals with maternal and child health, based in Padua; the Medical Research Council Clinical Trials Unit of University College London, whose research team led the data analysis; and finally, the University of Antwerp.

“This study was instrumental in better understanding the type of infections that affect newborns in hospitals, the germs that cause them, the treatments used and why there are so many deaths. The study has provided us with valuable insights that will help us better design clinical trials and ultimately improve the care and clinical outcomes of infants with sepsis,” said Manica Balasegaram, executive director of GARDP.

Sepsis is a life-threatening blood infection, affecting 3 million children worldwide each year. 214.00 newborns die each year from antibiotic-resistant sepsis, mostly in low – and middle – income countries. Newborns are among the patients most at risk of developing serious infections, as their immune systems are still underdeveloped. 

The mortality rate in the 19 hospitals involved in the study varied widely, ranging from 1.6% to 27.3%, with much higher numbers in low – and middle – income countries. The study involved specialists from hospitals in Bangladesh, Brazil, China, Greece, India, Italy, Kenya, South Africa, Thailand, Vietnam and Uganda.

“The study has exposed the stark reality of antibiotic-resistant infections, especially in hospitals in less developed countries, where there is often a shortage of nurses, beds and space. The risk of infections is very high and most infections are resistant to antibiotics. If an antibiotic does not work, the child often dies. This situation needs to change urgently. We need antibiotics that cover all bacterial infections,” said Sithembiso Velaphi, chief pediatrician at Chris Hani Baragwanath Academic Hospital in Johannesburg, South Africa.

The study also revealed a wide and worrying difference in treatments. More than 200 different combinations of antibiotics in use were identified in the hospitals taking part in the study, with frequent changes of antibiotics during the course of therapy to cope with the high resistance to treatments. 

For this same reason, many doctors have been forced to use antibiotics such as carbapenems, classified by the World Health Organization as “Watch” antibiotics, i.e. to be preferred only for specific and limited cases, since it is important to preserve their use. However, carbapenems have often been found to be the only antibiotics capable of curing the infection. 

Finally, last-line antibiotics were prescribed in 15% of infants with sepsis who took part in the study. The most common bacterium was found to be Klebsiella pneumoniae, usually acquired within the hospital environment.

Based on the data collected, the team developed two tools to be used in clinical trials and in neonatal intensive care units around the world: the NeoSep Severity Score, based on 10 clinical signs and symptoms, which doctors can use to identify infants most at risk and ensure they receive the care they need quickly; and the NeoSep Recovery Score, which using many of the same clinical signs and symptoms, will provide clinicians with key insights into whether to step up care.

“The observational study was instrumental in providing the high-quality data we need to design studies on neonatal sepsis and appropriate treatments. It was a large collaborative effort by researchers and clinicians from Africa, Asia, Latin America, and Europe,” said Neal Russell, principal investigator in the neonatal sepsis study at St George’s University in London. 

In this study, the Bambino Gesù Children’s Hospital of Rome was involved for Europe as a quality control facility for the developing countries included in the research. “We hope that NeoObs will be the first step in planning clinical studies in the near future aimed at identifying new biomarkers of sepsis and studying the safety and efficacy over time of new agents active against multi-resistant bacteria” underlined Maia de Luca, pediatric infectious disease specialist at Bambino Gesù who collaborated in the investigation together with the clinicians of the Infectious Diseases Operating Unit and the researchers of the Microbiology Laboratory of the Hospital.

The study will serve to update WHO guidelines on the treatment of sepsis in newborns. “Organisms evolve, drug resistance changes; that is why clinical guidelines for neonatal sepsis need to be constantly updated. This process requires robust and recent scientific evidence; this observational study is a significant step towards better treatments,” declared Wolfgang Stöhr, statistician in the observational study at the Medical Research Council Clinical Trials Unit of University College London. 

Study results were used to design NeoSEP1, a strategic clinical trial to find better treatments for neonatal infections in the context of growing resistance to existing treatments. The NeoSEP1 trial is led by GARDP, St George’s University London and the Medical Research Council Clinical Trials Unit of University College London, and is conducted at Chris Hani Baragwanath Academic Hospital in Soweto, Johannesburg, Tygerberg Hospital in Cape Town and Kilifi County Hospital in Kenya. The trial will also look at drug formulations and doses that are appropriate for infants.

“Research on the formulation and dosing of medicines for children is essential. Children are not small adults. Medicines need to be formulated to meet their needs safely and effectively,” said Alessandra Nardone, Clinical Project Manager of Penta – Child Health Research.

The new trial will benefit from the important laboratory work performed during the observational study. “The Laboratory of Medical Microbiology (LMM LAB-Net) served as the central laboratory, supporting local laboratory analyses for the observational study. We also performed in-depth molecular analysis on the collected pathogens. Together, these results provide valuable insights for the NeoSEP1 study,” said Surbhi Malhotra-Kumar, head of the Laboratory of Medical Microbiology at the University of Antwerp. 

PLOS Medicine neonatal sepsis press release