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Low- and middle-income countries (LMICs) bear 99% of the burden of mortality from neonatal sepsis globally¹ with bacterial infections being a major cause of this. WHO recently released the 2024 bacterial priority pathogen list (BPPL),² an update of the first list from 2017.³ These pathogens are of public health importance and the list aims to guide research, development, strategies, and resource allocation to prevent and control antimicrobial resistance.  

The 2024 BPPL includes 15 families of antibiotic-resistant (ABR) pathogens, grouped into critical, high, and medium priority. Critical priority pathogens include carbapenem-resistant Acinetobacter baumannii, third-generation cephalosporin-resistant Enterobacterales, and carbapenem-resistant Enterobacterales (CRE). They are listed as a critical priority because of their significant burden and mortality globally as well as high rates of treatment failure due to the severity of infection. These pathogens have limited antimicrobial options, leading to increased healthcare costs and poor outcomes. Many of them can also cause increased transmission of resistance genes, which can result in outbreaks in hospital settings, including in neonatal intensive care units. 

Neonatal sepsis due to critical priority pathogens 

Klebsiella pneumoniae, Escherichia coli, and Acinetobacter spp. among Gram-negative pathogens, and Staphylococcus aureus and coagulase-negative staphylococci (CoNS) among Gram-positive pathogens are the frequently observed pathogens among hospitalized neonates with sepsis, as reported in prospective multi-country studies (NeoOBS4 and BARNARDS²) from LMICs. In most cases, infections occur early in the life course, and the profile of pathogens does not show a clear distinction in the onset of sepsis as historically defined as ‘early’ and ‘late’ onset. In the Delhi Neonatal Infection study (DeNIS),⁵ 1,005 pathogens were isolated. Acinetobacter spp., Klebsiella pneumoniae, and CoNS were the most common pathogens, with high case-fatality rates associated with Gram-negative pathogens.  

Neonatal sepsis is increasingly caused by key pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli, leading to significant mortality and healthcare costs.

In DeNIS, a high proportion of Acinetobacter spp. (181/222, 82%), Klebsiella spp. (91/169, 54%), and E. coli (52/139, 38%) was multidrug-resistant. Carbapenem resistance was found to range from 15% to 78% among Gram-negative bacteria (GNBs), with the highest in Acinetobacter spp; and case-fatality rate (CFR) among neonates with sepsis due to carbapenem-resistant pathogens was the highest (90%) in Pseudomonas spp., 61% in Acinetobacter spp. and Klebsiella spp. and 57% in E. coli. Extended-spectrum cephalosporin resistance was highest in Klebsiella spp. (62%); with CFR of 55% among resistant pathogens.  

Another retrospective study from South Africa showed that over six years, 43,438 pathogens were isolated from positive blood and CSF samples from neonates, 57% of them being Gram-negative, 36% Gram-positive, and 7% fungi. Klebsiella pneumoniae (25%), and Acinetobacter baumannii (13%) were the most common, with A. baumannii mainly contributing to carbapenem resistance.⁶ Data from multicentre studies that include clinical detail details regarding mortality due to multi-drug resistance or carbapenem resistance are scarce. 

Table: Summary of pathogen profiles found in multi-centric studies on neonatal sepsis 

Resistance to carbapenems

Antimicrobial resistance (AMR) genes, often carried on mobile genetic elements such as plasmids, play a crucial role in causing resistance in Gram-negative bacteria by providing them with various mechanisms to evade the effects of antibiotics. Understanding the role of these genes is essential for developing strategies to combat the spread of antimicrobial resistance. Carbapenem-hydrolyzing class D β-lactamases⁹ (OXA-23, OXA-24, OXA-58, and OXA-143) are the most common enzymes, in addition to NDM-1,⁸ present in carbapenem-resistant Acinetobacter baumannii (CRAb). Results from different studies show that KPC, NDM, and OXA-48 are the carbapenemases produced by Klebsiella spp., VIM, and NDM by Pseudomonas aeruginosa.⁹ Whole genome sequencing is an effective tool to explore the resistance pattern and virulence factors in pathogens, to track outbreaks, and understand their transmission routes. Increased funding to facilitate this level of granularity in understanding resistance patterns is urgently needed. 

Fungal infections in neonatal sepsis

Fungi contribute to neonatal sepsis, especially in neonates born outside the facility or in chronically hospitalized neonates. Candida albicans (listed on the WHO fungal critical priority list¹⁰) and Candida parapsilosis were the most common fungal species found in cases of neonatal sepsis in DeNIS.¹¹ Data about fungal infections and their complications are scarce. NeoOBS data in LMICs shows 4% (127/3,249) infants had candidiasis; also in this study, C. albicans (45/127) and C. parapsilosis (38/127) were the most common. Fluconazole resistance was seen in 59% of C. parapsilosis (mainly from South Africa) and 9% of C. albicans. However, the majority were susceptible to amphotericin B, and all among those tested (36%) were susceptible to micafungin (echinocandin). Amphotericin B was the most common empiric antifungal used (74%), followed by fluconazole (22%) with echinocandins used very rarely.¹² 

Challenges in diagnostics and management

In the absence of specific clinical symptoms and the lack of consensus in the universally acceptable definition of neonatal sepsis, correct and timely diagnosis are the major problems faced in managing neonatal sepsis. Conventional microbiology culture testing remains the gold standard of sepsis diagnosis. However, it seems to be inconsistent in ruling out sepsis reliably, as evidenced by widely varying high rates of ‘culture-negative sepsis’ being reported. The role of multiplex PCR and sequencing techniques in early diagnosis of sepsis, alongside pathogen identification, and antimicrobial resistance genes looks promising. However, the cost is high, while the availability of these tests and technical expertise to interpret their results remain limited, especially in resource-limited countries where the burden of mortality due to neonatal sepsis is greatest.  

Conventional microbiology culture testing remains the gold standard of sepsis diagnosis. However, it seems to be inconsistent in ruling out sepsis reliably, as evidenced by widely varying high rates of ‘culture-negative sepsis’ being reported.

Future research

The AWaRe classification, introduced in 2017 by WHO and updated every two years, places carbapenem antibiotics under the ‘watch-group’ antibiotics. These antibiotics are to be used for treating infections associated with multidrug-resistant bacteria, which have the broadest antimicrobial activity and strongest antibacterial activity. With the emergence of carbapenem-resistant Enterobacteriaceae (CRE), a major threat, the available treatment options are limited, and only a few are in the pipeline. β-lactams in combination with β-lactamase inhibitors (BLBLI) have been shown to be beneficial as a therapy. Novel drugs like fosfomycin and BLBLI combinations such as ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam – combinations which the FDA has approved for adults – are being tested for safety and effectiveness in neonatal sepsis.¹³ The NeoOBS group has shown strong in-vitro activity of three new antibiotic combinations (flomoxef–amikacin – 100%, flomoxef–fosfomycin – 100% and fosfomycin-amikacin – 92%) against ESBL-producing K. pneumoniae and E. coli isolates, except for those strains producing an AmpC cephalosporinase and carbapenemase in addition to ESBL.¹⁴ More new drugs and combinations need to be tested, with a focus on ensuring they can be accessible to resource-constrained healthcare settings. 

Fungi contribute to neonatal sepsis, especially in neonates born outside the facility or in chronically hospitalized neonates. Candida albicans (listed on the WHO fungal critical priority list¹⁰) and Candida parapsilosis were the most common fungal species found in cases of neonatal sepsis in DeNIS.¹¹ Data about fungal infections and their complications are scarce. 

Neonatal sepsis is increasingly caused by key pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli, leading to significant mortality and healthcare costs. The WHO 2024 Bacterial Priority Pathogen List aims to guide and prioritize research and strategies to combat antimicrobial resistance in these pathogens and test novel treatment strategies. Advances in multiplex PCR and sequencing show promise but are expensive. Early detection of carbapenemase genes and treatment with alternative limited options is key to ensuring control of resistance and saving lives. 

References

1. Milton R, Gillespie D, Dyer C et al. (2022) Neonatal sepsis and mortality in low-income and middle-income countries from a facility-based birth cohort: an international multisite prospective observational study. Lancet Glob Health 2022; 10: e661–72.
2. WHO (2024) WHO Bacterial Priority Pathogens List, 2024: bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance. [Accessed 30/09/24]
3. World Health Organization (2017) Prioritization of pathogens to guide discovery, research and development of new antibiotics for drug-resistant bacterial infections, including tuberculosis. [Accessed 30/09/24]  
4. Russell NJ, Stohr W, Plakkal N, et al. (2023) Patterns of antibiotic use, pathogens and prediction of mortality in hospitalised neonates and young infants with sepsis: A global neonatal sepsis observational cohort study (NeoOBS)  PLoSMed; 20(6):e1004179. 
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6. Mashau RC, Meiring ST, Dramowski A, et al. (2022) Culture-confirmed neonatal bloodstream infections and meningitis in South Africa, 2014–19: a cross-sectional study. Lancet Glob Health; 10: e1170–78. 
7. Quoc CH, Phuong TNT, Duc HN, et al. (2019) Carbapenemase Genes and Multidrug Resistance of Acinetobacter Baumannii: A Cross Sectional Study of Patients with Pneumonia in Southern Vietnam. Antibiotics: 8(148):1-12. 
8. Elbrolosy AM, Labeeb AZ, Hassan DM. (2019) New Delhi metallo-β-lactamase-producing Acinetobacter isolates among late-onset VAP patients: multidrug-resistant pathogen and poor outcome. Infection and Drug Resistance:12 373–384.
9. Joji RM, Al-Rashed N, Saeed NK, Bindayna KM. (2019) Detection of VIM and NDM-1 metallo-beta-lactamase genes in carbapenem-resistant Pseudomonas aeruginosa clinical strains in Bahrain. J Lab Physicians;11:138-43.
10. WHO (2022) WHO fungal priority pathogens list to guide research, development and public health action. 
11. Jajoo M, Manchanda V, Chaurasia S, Sankar MJ, Gautam H, Agarwal R, et al. (2019) Alarming rates of antimicrobial resistance and fungal sepsis in outborn neonates in North India. PLoS ONE. 13(6): e0180705. 
12. Cook A, Ferreras-Antolin L, Adhisivam B, et al. (2023) Neonatal invasive candidiasis in low- and middle-income countries: Data from the NeoOBS study. Medical Mycology; 61, myad010. 
13. Poggi C, Dani C. (2023) New Antimicrobials for the Treatment of Neonatal Sepsis Caused by Multi-Drug-Resistant Bacteria: A Systematic Review. Antibiotics; 12, 956. 
14. Boceska BK, Vilken T, Xavier BB, et al. (2024) Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries. Nature Communications; 15:3947.