Antimicrobial-resistant neonatal sepsis: A problem in need of multi-sectoral solutions

For a long time, the decline in infant mortality has been equated to progress in a country’s medical services and overall socioeconomic status. From widespread infant mortality, in the 21st century, due to polio, diarrhea or tuberculosis, today global likelihood of survival is tenfold higher[1].

In spite of this progress, annually, 2.3 million infant deaths are reported globally, primarily in low and middle-income countries (LMICs).

Neonatal sepsis is one of the leading causes of infant deaths in the global south [2]. It can rapidly lead to tissue damage, organ failure, and ultimately death.

To make matters worse, the treatment of sepsis is becoming challenging because there is an increase in infections caused by bacteria that are no longer susceptible to the present treatment regimen [3]. Coupled with the high AMR burden in India, neonatal sepsis is a major cause of concern.

“In India alone, bacteria resistant to first-line antibiotics are responsible for sixty thousand neonatal deaths annually [4].”

Neonatal sepsis

Neonatal sepsis is a bloodstream infection in infants, primarily by bacteria. It is classified into two types based on the time after birth when the neonate is infected. It is called early onset is if the bacteria is passed from the mother to the infant. The infant is infected in-utero or during delivery by Group B streptococcus, Escherichia coli, or other pathogens. Since the 1990s, the incidence of early-onset neonatal sepsis has decreased due to the introduction of universal screening of Group B streptococcus among pregnant women.

When the infection occurs after birth, it is called late-onset neonatal sepsis. These infections are thought to be acquired in the hospital or from healthcare workers in the first week of birth [5].

Infections can be easily prevented by screening pregnant women for Group B Streptococcus and promoting hand hygiene and infection control practices in the hospital. Yet, globally 3 million cases of neonatal sepsis are recorded each year out of which 5, 70, 000 cases are fatal due to resistance to available antibiotics [6].

To complicate matters, timely diagnosis of the illness is challenging. The symptoms are generic, and the tests, although practical, are time-consuming. This delays critical treatment decisions. Additionally, diagnostic facilities are scarce and ill-equipped especially in LMICs. So, many cases go undiagnosed and unreported.

Upon pathogen identification, antibiotics are the primary form of treatment. The usual treatment is administering antibiotics with supportive care, such as oxygen therapy, intravenous fluids, and respiratory support. But the situation is exacerbated by Antimicrobial resistance. Around 50% of the bacteria responsible for neonatal infections are resistant to first and second lines of antibiotics [7].

AMR

AMR is now recognized by the global health community as well as political leadership as a major issue and various steps and initiatives are being taken towards tackling it.

WHO in its Global Action Plan identified “AMR as a growing global health threat that seriously affects public health, animal health, and the environment. It can lead to a prolonged illness, disability, and death. It can also increase healthcare costs, extend hospital stays, and cause a loss of productivity. Furthermore, it can render routine medical procedures, such as surgeries, organ transplantation, and chemotherapy, unsafe. Antimicrobial resistance threatens the very core of modern medicine” [8].

The shift now is to look at AMR through the holistic lens of One Health.

A study conducted by the Global Antibiotic Research and Development Partnership (GARDP) in collaboration with the All India Institute of Medical Sciences (AIIMS) found that a growing number of newborns die of infections as the current antibiotics have become ineffective. There is an opportunity to avoid preventable deaths by intervening quickly, equitably, and safely. Infection prevention, time of diagnosis, informed clinical decisions, and judicious use of antibiotics thus become crucial [9].

Current State of innovation

The strategy employed by the global innovation ecosystem to tackle neonatal sepsis is two pronged. The first prong is development of diagnostic solutions utilizing novel biomolecules to reduce the time of diagnosis compared to culture-based methods. The second prong in this strategy is development of vaccines specifically against common pathogens implicated in neonatal sepsis.

The biomolecules being focused upon are protein components released after infection or inflammation. Biomolecules related to infection like Interleukin 6 (IL-6), Interleukin 8 (IL-8), TNF-α [10], or cell adhesion markers related to Leucocyte activity like Cluster differentiation molecule-64 (CD64), CD14 fragment (presepsin), Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) are being studied for their suitability [11].

Researchers are also conducting proteomics studies on cord blood and amniotic fluid to biomarkers to identify intra-amniotic infections to reduce the time of diagnosis [12].

Point-of-care solution is also an active area of research. One such innovation is Spotsense’s Spittle, a fast diagnostic tool for neonatal sepsis that is supported by the Centre for Cellular and Molecular Platforms (C-CAMP) [13]. It screens for diseases in newborn babies using saliva. Also, Seeker is a platform from Baebies that detects bacterial pathogens in newborns [14]. It is supported by the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X).

Funding Support

CARB-X has been instrumental in aiding the development of vaccines to combat sepsis. Now, CARB-X seeks to support new vaccines for neonatal sepsis in its 2022–2023 funding rounds, and to fill other major gaps in the global pipeline, including oral therapeutics and gonorrhea products.

The final deadline to submit an expression of interest for CARB-X funding is May 1.

For more information, visit the Apply section at CARB-X.org, watch the 40-minute video with comprehensive information on the application process, and read the regularly updated FAQ page.

Disclaimer: The blog is a compilation of information on a given topic that is drawn from credible sources; however, this does not claim to be an exhaustive document on the subject. The mention of entities, networks, consortiums, or partnerships is merely to highlight the stakeholders working in the field and does not reflect attestations, validations or promotion of their work. It is not intended to be prescriptive, nor does it represent the opinion of C-CAMP or its partners. The blog is intended to encourage discussion on an important topic that may be of interest to the larger community and stakeholders in associated domains.

Sources:-

1. Learning From History About Reducing Infant Mortality: Contrasting the Centrality of Structural Interventions to Early 20th‐Century Successes in the United States to Their Neglect in Current Global Initiatives — PMC
2. Levels and trends in child mortality — UNICEF DATA
3. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis — The Lancet
4. Antibiotics needed to treat multidrug-resistant infections in neonates — PMC
5. Neonatal Sepsis — StatPearls — NCBI Bookshelf
6. Antibiotics needed to treat multidrug-resistant infections in neonates — PMC
7. Tackling antimicrobial resistance in neonatal sepsis — The Lancet Global Health
8. Global action plan on antimicrobial resistance
9. Experts call for urgent action to develop antibiotics for newborns | GARDP
10. https://www.nature.com/articles/s41390-021-01696-z
11. https://www.nature.com/articles/s41390-021-01696-z
12. Mangioni, D. et al. Toward rapid sepsis diagnosis and patient stratification: What’s new from microbiology and omics science. J. Infect. Dis. 221, 1039–1047 (2020).
13. https://www.biospectrumindia.com/news/91/21435/c-camp-selco-foundation-to-support-neonatal-health-in-tribal-areas-of-karnataka.html
14. https://baebies.com/products/seeker/