London School of Hygiene & Tropical Medicine

Achieving health equity requires innovative approaches tailored to the unique challenges of settings with high disease burdens, as highlighted in a recent World Economic Forum article by Melanie Saville (Chief Scientific Officer at PATH).1 This is particularly relevant when addressing the impact of neonatal sepsis through the implementation of new diagnostics. Each year, approximately 30 million newborns require hospital care globally, where they face significant risks from healthcare-associated infections (HCAIs) caused by drug-resistant pathogens.2 Infection contributes to roughly 24% of the 2.3 million neonatal deaths annually, half of which are linked to HCAIs due to issues like overcrowding, excessive antibiotic use, and diagnostic challenges.

Diagnostic Dilemma: Blood Cultures vs ‘Leapfrog’ Technologies 

 Neonatal sepsis demands timely and precise diagnosis to guide treatment and enhance survival outcomes. Blood culture has been the gold standard for nearly a century, facilitating pathogen identification and antibiotic sensitivity testing across many healthcare systems. Despite this, data from the Mapping Antimicrobial Resistance and Antimicrobial Use Partnership (MAAP) project, supported by the African Union, African CDC, and others, highlights critical gaps in laboratory capacity within 14 African countries. Shockingly, only 1.3% of these laboratories perform bacteriological testing, and over 80% conduct fewer than 1,000 antimicrobial susceptibility tests annually.4 Furthermore, a study of 144,146 newborns from 61 hospitals across 5 African countries revealed that 70% received antibiotics, yet only 6% underwent blood cultures, with 40% of hospitals not performing any blood cultures at all.

 ‘Leapfrog’ molecular diagnostic technologies hold immense promise in the battle against neonatal sepsis and AMR. These state-of-the-art, often large pieces of equipment, regularly showcased at conferences and in catalogues, use automated processes to deliver fast, accurate, and reliable results while boasting sleek designs. However, the reality is that high costs, specialised consumables, and maintenance requirements pose significant challenges for district-level hospital laboratories in many settings where diagnostic tests are most urgently needed. 

Essential Infrastructure for Clinical Laboratories 

 Robust infrastructure is imperative for traditional blood culture and modern ‘leapfrog’ diagnostic methods. In my experience, hospital-based laboratories in high neonatal sepsis burden settings often struggle with unreliable electricity, inadequate water quality, and/or insufficient technical training, which hampers the effectiveness of diagnostic techniques (i.e. blood culture) – resulting in the degradation of trust in the available tests at the clinician’s disposal. These challenges extend to logistics, where poor transport infrastructure delays critical reagent deliveries. Furthermore, without a sustainable co-designed transition strategy with facility management, much of the advanced equipment from short research-funded projects can often become non-operational post-project, forming clinical laboratory equipment graveyards. 

Increasing Diagnostic Coverage and Surveillance 

 Since its inception in 2015, the UK's Fleming Fund has emerged as a pivotal force in the global battle against AMR. As an international programme dedicated exclusively to AMR surveillance, the fund has spurred significant advancements across Asia and Africa. It facilitates the generation, sharing, and application of vital data essential in combating AMR through a robust strategy that enhances surveillance systems with a combination of country-specific and regional grants, global initiatives, and fellowship programmes. 

 Simultaneously, organisations such as the African Society of Laboratory Medicine (ASLM) collaborate with various nations and stakeholders to intensify the fight against AMR.7 ASLM oversees numerous regional grants, like MAAP, which play a crucial role in fortifying laboratory systems and networks, thus boosting surveillance capabilities and clinical testing. 

 Despite these collective improvements, the extent to which these enhancements filter down to local hospital laboratories remains to be determined. There is an urgent need to sustain current gains and deepen their impact at the level of individual patient care. Ongoing support, collaboration, and infrastructure reinforcement are not just important, they are essential to address this challenge effectively. 

Opportunities for Innovation 

 New, simplified, cost-effective blood culture systems are poised to transform diagnostic practices in high-burden settings.9 Recent advances, primarily by Chinese manufacturers, in simplified continuously monitoring blood culture systems, have introduced a new dynamic in the market. However, their uptake outside of China still needs to be improved. These innovative systems maintain optimal conditions for microbial growth and feature advanced sensors that continuously monitor this growth, all at a lower cost than many existing alternatives. Moreover, these systems represent a substantial improvement over traditional manual methods, which are labour-intensive and prone to human error. 

 Point-of-care tests (POCTs), particularly microfluidics-based devices, already demonstrate great potential in clinical care settings.10 These tests, now often enhanced with smartphones or artificial intelligence, provide rapid and on-site diagnostic capabilities crucial for effective patient management. However, the broader deployment of POCTs faces significant challenges, including affordability, accessibility, and environmental adaptability. Implementing strategies such as local manufacturing, subsidies, and robust design is essential for extending vital healthcare services to populations worldwide. Equally, a target product profile (TPP) for neonatal sepsis point-of-care tests (POCTs) is needed to establish essential sensitivity, specificity, and usability standards. 

Conclusion 

 To effectively combat neonatal sepsis and its associated AMR globally, it is essential to strengthen the foundational aspects of local clinical laboratories. By enhancing infrastructure, training, and supply chain management, we set the stage for future advanced diagnostics to thrive. Initiatives like the Fleming Fund and the integration of cutting-edge technologies are crucial for making significant strides in saving newborn lives. Now is the time to act, balancing gradual improvements in blood culture coverage and quality, with innovative technological ‘leaps’, to achieve transformative outcomes for vulnerable newborns. 

References:  

1. World Economic Forum. 5 steps towards health equity in low- and middle-income countries through tailored innovation. 29 May 2024. https://www.weforum.org/agenda/2024/05/health-equity-low-middle-income-countries/
2. World Health Organization, United Nations Children's Fund (UNICEF), PMNCH, UNFPA. Born too soon: decade of action on preterm birth. Geneva: WHO; 2023.
3. Allegranzi B, Nejad SB, Combescure C, Graafmans W, Attar H, Donaldson L, et al. Burden of endemic health-care-associated infection in developing countries: systematic review and meta-analysis. Lancet. 2011;377:228–41.
4. Mapping Antimicrobial Resistance and Antimicrobial Use Partnership (MAAP) https://aslm.org/what-we-do/maap/
5. Murless-Collins, S., Kawaza, K., Salim, N. et al. Blood culture versus antibiotic use for neonatal inpatients in 61 hospitals implementing with the NEST360 Alliance in Kenya, Malawi, Nigeria, and Tanzania: a cross-sectional study. BMC Pediatr 23 (Suppl 2), 568 (2023). https://doi.org/10.1186/s12887-023-04343-0
6. The Fleming Fund. https://www.flemingfund.org
7. African Society of Laboratory Medicine. https://aslm.org
8. Seale AC, Hutchison C, Fernandes S, Stoesser N, Kelly H, Lowe B, Turner P, Hanson K, Chandler CIR, Goodman C, Stabler RA, Scott JAG. Supporting surveillance capacity for antimicrobial resistance: Laboratory capacity strengthening for drug resistant infections in low and middle income countries. Wellcome Open Res. 2017 Sep 26;2:91
9. Hardy L, Vermoesen T, Genbrugge E, Natale A, Franquesa C, Gleeson B, Ferreyra C, Dailey P, Jacobs J. Affordable blood culture systems from China: in vitro evaluation for use in resource-limited settings. EBioMedicine. 2024 Mar;101:105004. doi: 10.1016/j.ebiom.2024.105004. Epub 2024 Feb 12. PMID: 38350332; PMCID: PMC10874707.
10. Yang SM, Lv S, Zhang W, Cui Y. Microfluidic Point-of-Care (POC) Devices in Early Diagnosis: A Review of Opportunities and Challenges. Sensors (Basel). 2022 Feb 18;22(4):1620. doi: 10.3390/s22041620. PMID: 35214519; PMCID: PMC8875995.