Clinical Summary | Paediatrics & Neonatology
Beyond early-and late-onset neonatal sepsis definitions:
What are the current causes of neonatal sepsis globally? A systematic review and meta-analysis of the evidence
Time to read: 04: 29
Time to listen: 07:13
Published on MedED: 8 October 2024
Originally Published: 12 September 2024
Source: Pediatric Infectious Diseases Journal
Type of article: Clinical Research Summary
MedED Catalogue Reference: MICS005
Category: Paediatrics & Neonatology
Cross-reference: Infectious Diseases & Antimicrobials
Keywords: early-onset sepsis, late-onset sepsis, gram-positive bacteria, gram-negative bacteria, antimicrobials
Originally Published: 12 September 2024
Source: Pediatric Infectious Diseases Journal
Type of article: Clinical Research Summary
MedED Catalogue Reference: MICS005
Category: Paediatrics & Neonatology
Cross-reference: Infectious Diseases & Antimicrobials
Keywords: early-onset sepsis, late-onset sepsis, gram-positive bacteria, gram-negative bacteria, antimicrobials
Key Take Aways
1. Neonatal sepsis continues to be a leading cause of mortality, especially in low- and lower-middle-income countries
2. The predominant pathogens have shifted from traditional Gram-positive bacteria to Gram-negative organisms across both early- and late-onset sepsis.
3. Antimicrobial resistance is changing the landscape of neonatal sepsis, potentially rendering current empirical treatment guidelines ineffective against the pathogens causing these infections
4. The research underscores the need to evaluate neonatal sepsis aetiology across different economic contexts, emphasising the differences in pathogen prevalence between high, low- and lower-middle-income countries
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Overview | Study Design | Findings | Discussion| Limitations | Conclusion | Original Research | Funding | References
Overview
Nearly 47% of deaths among children under the age of five occur within the first 28 days of life. Neonatal sepsis is a significant contributor to this statistic, with approximately 3 million cases reported worldwide each year, leading to as many as 570,000 fatalities annually.1,2,3
Early-onset neonatal sepsis (EOS)—defined as sepsis occurring within the first 72 hours of life—has typically been linked to the maternal transfer of bacteria, either in utero or during delivery. In contrast, late-onset sepsis (LOS) has been associated with nosocomial infections or those acquired from the community.
Recently, however, as the researchers of this study, Harrison & Dickson et al. indicate, multidrug-resistant Gram-negative bacteria are increasingly implicated in EOS, indicating a shift in epidemiology. The rise in antimicrobial resistance (AMR) further complicates this situation.4
The World Health Organization currently recommends ampicillin/benzylpenicillin and gentamicin as the first-line treatments for neonatal sepsis. However, these guidelines primarily draw on data from high-income countries (HIC). Given that 98% of neonatal sepsis-related deaths occur in low- and middle-income countries (LMICs), where differing pathogen profiles are emerging, the effectiveness of these regimens is diminishing, contributing to rising mortality rates.
Reports indicate that AMR rates in LMICs can reach as high as 97% for ampicillin and 70% for gentamicin, making standard empirical treatment increasingly ineffective.4 Consequently, many clinicians in LMICs are beginning to deviate from WHO recommendations due to their lack of efficacy. Unfortunately, there is insufficient evidence to inform the development of new empirical treatment regimens, highlighting the urgent need for global attention to this issue.
Study Purpose
The researchers of this study, Harrison & Dickson et al., conducted a comprehensive review of 48 articles published between 2017 and 2022 to evaluate the current bacterial pathogens causing early and late-onset sepsis in neonates across high-income and low- and lower-middle-income countries. Based on their findings, to further determine whether traditional empirical treatment regimens are effective in the face of evolving pathogen profiles.
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Study Design
This study, a systematic review and meta-analysis of 48 studies, was conducted over five years (2017-2022). The final data sample included 311,359 neonates from 25 countries.
The studies included data from various income settings: 14 studies were from HICs, seven from upper-middle-income countries (UMICs), and 27 from low- and lower-middle-income countries (LLMICs). A significant portion of the data came from the United States, accounting for about 45.9%, while African data represented only 9.2% (See Limitations).
The studies included data from various income settings: 14 studies were from HICs, seven from upper-middle-income countries (UMICs), and 27 from low- and lower-middle-income countries (LLMICs). A significant portion of the data came from the United States, accounting for about 45.9%, while African data represented only 9.2% (See Limitations).
Findings
In total, the analysis identified 10,150 significant bacterial pathogens, including 4,358 isolated from neonates with early-onset sepsis and 3,894 from infants with late-onset sepsis
In neonates with early-onset sepsis, 52.9% of the 4,347 significant pathogens isolated were Gram-negative, while 46.8% were Gram-positive. For late-onset sepsis, 71% of the 3,894 pathogens were Gram-negative, with meta-analyses estimating the combined prevalence of Gram-negative pathogens at 62.6% for EOS and 71.0% for late-onset sepsis.
Streptococcus agalactiae and Listeria spp. were more frequently associated with early-onset sepsis, while Klebsiella spp. and S. aureus were predominant in late-onset sepsis.
Although the overall burden of Gram-negative pathogens in early-onset sepsis was high, the predominant pathogen causing early-onset sepsis was Streptococcus agalactiae, at 23.3%, followed by E. coli (18.0%), Klebsiella spp.(14.8%) and Staphylococcus aureus (9.7%).
When country income levels were analysed, the predominant pathogens causing early-onset sepsis differed significantly. In lower-middle-income countries, Klebsiella spp. was most prevalent at 31.7%, followed by Staphylococcus aureus at 17.5%, while Streptococcus agalactiae accounted for only 13.8%. This highlights the variation in pathogen distribution between different regions and income classifications.
The predominant bacterial species responsible for late-onset sepsis were Klebsiella spp. (30.7%), E. coli (16.5%), and S. aureus (15.5%). When analysing the data for high-income countries and low- and middle-income countries, Klebsiella spp. remained the leading cause of late-onset sepsis in low- and middle-income countries at 30.6%, followed by S. aureus at 25.6% and E. coli at 9.7%
In neonates with early-onset sepsis, 52.9% of the 4,347 significant pathogens isolated were Gram-negative, while 46.8% were Gram-positive. For late-onset sepsis, 71% of the 3,894 pathogens were Gram-negative, with meta-analyses estimating the combined prevalence of Gram-negative pathogens at 62.6% for EOS and 71.0% for late-onset sepsis.
Streptococcus agalactiae and Listeria spp. were more frequently associated with early-onset sepsis, while Klebsiella spp. and S. aureus were predominant in late-onset sepsis.
Although the overall burden of Gram-negative pathogens in early-onset sepsis was high, the predominant pathogen causing early-onset sepsis was Streptococcus agalactiae, at 23.3%, followed by E. coli (18.0%), Klebsiella spp.(14.8%) and Staphylococcus aureus (9.7%).
When country income levels were analysed, the predominant pathogens causing early-onset sepsis differed significantly. In lower-middle-income countries, Klebsiella spp. was most prevalent at 31.7%, followed by Staphylococcus aureus at 17.5%, while Streptococcus agalactiae accounted for only 13.8%. This highlights the variation in pathogen distribution between different regions and income classifications.
The predominant bacterial species responsible for late-onset sepsis were Klebsiella spp. (30.7%), E. coli (16.5%), and S. aureus (15.5%). When analysing the data for high-income countries and low- and middle-income countries, Klebsiella spp. remained the leading cause of late-onset sepsis in low- and middle-income countries at 30.6%, followed by S. aureus at 25.6% and E. coli at 9.7%
Discussion
This review's findings reveal significant shifts in the global landscape of neonatal sepsis. Gram-negative bacteria are now the leading cause of both early-onset sepsis and late-onset sepsis worldwide, raising concerns about antimicrobial resistance.
The traditional distinctions between EOS and LOS are becoming less clear, especially in LLMICs, due to factors such as increased facility-based births and longer hospital stays for premature infants.
Notably, Klebsiella spp. has emerged as a significant player, particularly in LLMICs, where it is now the most common cause of EOS. In contrast, Streptococcus agalactiae remains the top pathogen for EOS in high-income countries (HICs), though its dominance is less pronounced in LLMICs.
The traditional distinctions between EOS and LOS are becoming less clear, especially in LLMICs, due to factors such as increased facility-based births and longer hospital stays for premature infants.
Notably, Klebsiella spp. has emerged as a significant player, particularly in LLMICs, where it is now the most common cause of EOS. In contrast, Streptococcus agalactiae remains the top pathogen for EOS in high-income countries (HICs), though its dominance is less pronounced in LLMICs.
A major shift observed was in late-onset sepsis, where less than a third of the bacteria identified were Gram-positive. The rise in facility-based births and longer hospital stays for premature infants could be contributing to early colonization with Gram-negative pathogens, including those resistant to multiple drugs.
Interestingly, the long-held view that EOS is acquired vertically and LOS horizontally may need reevaluation, as the data shows a more complex interplay in bacterial transmission, especially with multidrug-resistant Gram-negative bacteria being common in hospital-admitted neonates.
Learn more | Gram-negative neonatal sepsis in low- and lower-middle-income countries and WHO empirical antibiotic recommendations
Wen SCH, Ezure Y, Rolley L, et al. Gram-negative neonatal sepsis in low- and lower-middle-income countries and WHO empirical antibiotic recommendations: a systematic review and meta-analysis. PLoS Med. 2021;18:e1003787
Wen SCH, Ezure Y, Rolley L, et al. Gram-negative neonatal sepsis in low- and lower-middle-income countries and WHO empirical antibiotic recommendations: a systematic review and meta-analysis. PLoS Med. 2021;18:e1003787
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Limitations
The researchers indicated a number of limitations, including heterogeneity of the study sample group and the poor quality of observational data included in some of the studies. Furthermore, the studies were mostly in-hospital studies, leading to a possible bias when compared to community-based studies. Geographic bias and the predominance of data from the United States may also have introduced a bias towards the prevalence of Gram-positive organisms.
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Conclusion
The results of this review revealed an increasing prevalence of Gram-negative pathogens in both early- and- late-onset sepsis, challenging existing definitions and assumptions about neonatal sepsis. This shift, particularly prominent in LLMICs, necessitates a reevaluation of current antibiotic recommendations.
The researchers propose that new classifications, focusing on the source of infection rather than the timing of symptom onset, may lead to more effective empirical antibiotic regimens. This approach could better align neonatal sepsis management with pediatric and adult populations, potentially reducing morbidity and mortality in infants.
In conclusion, Harrison & Dickson et al. advocates for empirical antibiotic treatment recommendations that are region-specific, addressing local pathogens and resistance patterns associated with neonatal sepsis, especially in resource-constrained settings.
Access the original research
Harrison, M. L., Dickson, B. F. R., Sharland, M., & Williams, P. C. M. (2024). Beyond Early- and Late-onset Neonatal Sepsis Definitions: What are the Current Causes of Neonatal Sepsis Globally? A Systematic Review and Meta-analysis of the Evidence. The Pediatric infectious disease journal, 10.1097/INF.0000000000004485. Advance online publication. https://doi.org/10.1097/INF.0000000000004485
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Harrison, M. L., Dickson, B. F. R., Sharland, M., & Williams, P. C. M. (2024). Beyond Early- and Late-onset Neonatal Sepsis Definitions: What are the Current Causes of Neonatal Sepsis Globally? A Systematic Review and Meta-analysis of the Evidence. The Pediatric infectious disease journal, 10.1097/INF.0000000000004485. Advance online publication. https://doi.org/10.1097/INF.0000000000004485
Conflict of Interest, Funding and Support
Conflict of Interest Disclosures
The researchers declared that there were no conflicts of interests
Funding/Support
1197335/National Health and Medical Research Institute, Australia Back to top
References
1. World Health Organization. Levels and trends in child mortality report. Online: World Health Organization; 2021. Available from: https://data.unicef.org/resources/levels-and-trends-in-child-mortality/ Accessed 8 October 2024
2. UNICEF. Neonatal Mortality Online2021. Available from: https://data.unicef.org/topic/child-survival/neonatal-mortality/. Accessed 8 October 2024
3. Fleischmann, C., Reichert, F., Cassini, A., Horner, R., Harder, T., Markwart, R., Tröndle, M., Savova, Y., Kissoon, N., Schlattmann, P., Reinhart, K., Allegranzi, B., & Eckmanns, T. (2021). Global incidence and mortality of neonatal sepsis: a systematic review and meta-analysis. Archives of disease in childhood, 106(8), 745–752. https://doi.org/10.1136/archdischild-2020-320217
4. Wen SCH, Ezure Y, Rolley L, et al. Gram-negative neonatal sepsis in low- and lower-middle-income countries and WHO empirical antibiotic recommendations: a systematic review and meta-analysis. PLoS Med. 2021;18:e1003787.
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