Striking at the heart of antimicrobial resistance, the international NeoSep 1 trial to evaluate life-saving antibiotic combinations for newborns with sepsis has expanded to India, with the first baby being recruited at the Jawaharlal Postgraduate Education Institute of Medical and Research (JIPMER) in Puducherry.

This was followed by recruiting an infant for the study in Pt. B.D. Sharma PGIMS in Rohtak. The next on the list is Lokmanya Tilak Municipal College and General Hospital, Mumbai. Globally, the study, sponsored by the GARDP Foundation in collaboration with the UCL Innovative Clinical Trials Unit; City St George’s, University of London (SGUL), and Penta Foundation, is also underway in Vietnam and Pakistan, and will soon start in Malaysia, Bangladesh and Uganda.

According to a GARDP statement, NeoSep1 aims to enrol 3,000 newborns across Asia and Africa by the end of 2028. Earlier, newborns were enrolled in Ghana, Kenya and South Africa.

Life-threatening infection

Neonatal sepsis is a life-threatening bloodstream infection that occurs in babies under 90 days old, often affecting premature or low-birth-weight infants. It is categorised into early-onset (occurring within the first 72 hours of life) and late-onset (occurring up to 28–90 days), according to a book on neonatal sepsis, authored by Meenakshi Singh.

“With underdeveloped immune systems, newborns are especially prone to life-threatening sepsis,” Sally Ellis, Children’s Antibiotics Project Leader for GARDP, told The Hindu, explaining the significance the NeoSep1 has in the context of growing antimicrobial resistance.

“Today, we stand at a tipping point. The antibiotics for newborns that we have relied on for decades are failing against resistant infections, in many hospital settings. This trial, led by GARDP and partners, is about giving neonatologists new tools, and giving babies with sepsis a fighting chance at life,” she adds.

Sepsis is the second most common cause of neonatal mortality, globally responsible for over one million deaths annually. In India, neonatal sepsis remains a leading cause of neonatal mortality, contributing to approximately 30%–40% of all neonatal deaths despite advances in neonatal care, argues a recent paper ‘Neonatal Sepsis in India: Epidemiology, Risk Factors and Preventive Strategies from a Public Health Perspective’ in the Journal of Clinical Neonatology.

The author Ahmed Abdulaziz Almohammadi, writes “In India, neonatal sepsis accounts for an estimated 30%–40% of all neonatal deaths, translating to approximately 2,00,000–2,50,000 preventable deaths annually. Despite substantial reductions in under-five mortality over the past two decades, progress in reducing neonatal mortality has lagged, with sepsis representing a persistent and largely preventable cause of death.”

Divergence from global trends

It turns out that causative agents in India show a divergence from global trends. Dr. Almohammadi notes that the microbiological profile of neonatal sepsis in India differs substantially from that of high-income countries, with gram-negative organisms predominating in most Indian studies. Klebsiella pneumoniae, Escherichia coli,Acinetobacter species and Pseudomonas aeruginosa constitute the majority of bacterial isolates, often demonstrating multidrug resistance. Group B Streptococcus (GBS), which is the leading cause of neonatal sepsis in developed countries, accounts for only 2%–5% of cases in India.

This makes the NeoSep 1 critical — to evaluate and produce a profile that is India specific, addressing the circumstances that can contribute to, or ameliorate the condition in India. It is pioneering the use of a Personalised Randomised Controlled Trial (PRACTical) design, which will evaluate and rank multiple antibiotic regimens for newborns with sepsis. This approach will help clinicians choose effective treatments best suited to their local context, GARDP spokespersons say.

The goal of the trial is to identify one or more safe, effective, and affordable treatments that can reduce the high number of newborn deaths caused by drug-resistant sepsis, especially in low- and middle-income countries. Part 1 of the NeoSep1 trial, conducted in South Africa and Kenya in 2023, assessed and validated the appropriate dose for fosfomycin and flomoxef for use in newborns, in combination with other antibiotics.

Nishad Plakkal, Principal Investigator of the NeoSep1 trial in India and Head of the Department of Neonatology at JIPMER, explains:“the study is a pragmatic trial and allows clinicians to make the diagnosis of sepsis as they normally would. However, to ensure the inclusion of infants with a high probability of infection, we use a sepsis severity score that we derived from an earlier global observational study (NeoOBS). Our microbiology team cultures the baby’s blood (and sometimes spinal fluid) to help identify the organism causing sepsis, typically within a day or two. They also identify antibiotic-resistant infections.”

Dr. Plakkal explains that the primary outcome, or the main question the study is designed to answer, is death within 28 days; while secondary outcomes will include death within 90 days, need for additional antibiotics, length of hospital stay, and re-admission.