Burden of Antibiotic Resistance in Neonates from Developing Societies (BARNARDS)

This study investigates sources of pathogens leading to sepsis in neonates in developing countries and potential sources of antimicrobial resistance.

Introduction

“Working to ensure the unthinkable doesn’t become the inevitable”

Antimicrobial resistance (AMR) is now recognised as one of the most serious global threats to human health in the 21st century. Evidence of political traction through endorsements of statements by the UK and US governments, WHO and CDC describe a global crisis and an impending catastrophe of moving into a post-antibiotic era.

Developing countries bear the burden of 99% of neonatal mortality worldwide (WHO) with infections such as tetanus, pneumonia and sepsis acting as a leading causes of neonatal mortality. Increased antibiotic resistance in bacteria, including MDR pathogens, render infections increasingly difficult to treat, with resistance arising against last resort treatments.

The first phase of BARNARDS (2015-2018; funded by the Bill & Melinda Gates Foundation) founded at Cardiff University strove to investigate the importance of Multi-Drug Resistant (MDR) Gram-negative bacteria (GNB), particularly Enterobacteriaceae, in neonatal sepsis within 4 African and 3 Southeast Asian countries.

The main findings for these studies can be found published in Nature Microbiology, Lancet Global Health, and Lancet Infectious Diseases. However, during these studies it became apparent that an equal number of blood cultures were positive for Gram-positive bacteria, which form the focus of BARNARD phase II (2021-2026; funded by the Ineos Oxford Institute) in Cardiff University, while continuing work on Gram-negative bacterial sepsis has moved to University of Oxford.

Aims

BARNARDS (Burden of Antibiotic Resistance in Neonates from Developing Societies) phase II aims to expand investigations on the effects of antibiotic resistance on neonatal morbidity and mortality in low-middle income countries, including a greater number of hospitals in more numerous LMICs, and identify possible solutions to minimise the impact in neonatal sepsis.

The Cardiff University team will lead all investigations for isolates of Gram-positive bacteria found in the bloodstream of newborn babies from the recruiting hospitals from participating hospitals in Africa and Southeast Asia. We will examine look for important virulence-mediating factors and the examine the newborn’s mother and their environment as potential sources of the infection as well.

A network of neonatal centres within low-middle income countries has been developed through collaboration with leading neonatal scientists/ clinicians from study sites. With BARNARDS phase II, more hospitals will be partipating for each country and multiple hospitals in Nigeria, Pakistan and Bangladesh are already participating.

Current work is underway to expand this network to hospitals in Egypt, Rwanda, Burundi, Mozambique and Sierra Leonne. Clinical centres at these sites will collect relevant patient data and samples from mothers who have agreed to take part in the study as well as samples from neonates presenting with signs of infection and process microbiological specimens locally.

Samples will initially be sent to the Ineos Oxford Institute where they will be separated into Gram-negative bacteria (being investigated at the University of Oxford) and Gram-positive bacteria (which will all be sent to Cardiff University for full characterisation. Here we will determine the antimicrobial susceptibility against a broad range of antibiotics, perform both long-read (Nanopore) and short-read (Illumina) whole genome sequencing on all received isolates.

Representative strains will then be tested for virulence, ability to “donate” there resistance genes to other co-cultured bacteria, and swabs from the neonates’ mother and the hospital surroundings at the time of infection will be examined to see if the source of virulent or multi-drug resistant bacteria can be identified.

Analysis extending across the entire collaborative network will be performed to identify potential solutions to improving detection and recommending alterations to first line therapies at national and regional scales in an effort to improve survival and treatment of invasive neonatal infections in the LMIC.

Summary of aims:

Detect antimicrobial resistance patterns in Gram-positive bacteria from neonatal sepsis in developing countries
Identify sources of antimicrobial resistance in neonates
Results from this study could lead to interventional studies related to treatment to ensure that sepsis is treated with appropriate antibiotics and Infection Prevention and Control practices.

Projects

The BARNARDS phase II group is led by Ineos Oxford Institute, with all Gram-positive investigations being led by Cardiff University, and in affiliation with international research partners in Nigeria, Pakistan, and Bangladesh (and hopefully soon also with Egypt, Rwanda, Burundi, Mozambique and Sierra Leonne.