Editorial: Advancing Understanding of Neonatal Bacterial Infections

Shelley M. Lawrence^1,2*Susana Chavez-Bueno^3,4

• ¹Department of Pediatrics, Neonatology, The University of Utah, Salt Lake City, United States
• ²Primary Children's Hospital, Intermountain Health, Salt Lake City, United States
• ³Children’s Mercy Hospital, Kansas City, Missouri, Kansas City, United States
• ⁴Department of Pediatrics, Pediatric Infectious Diseases, University of Missouri-Kansas City, Kansas City, United States

The use of inconsistent methodologies in the investigation of neonatal sepsis, coupled with insufficient research funding, hampers our capacity to accurately define its incidence and to ensure that potential treatments and clinical interventions are rigorously investigated. Consequently, the medical management of neonatal sepsis, septic shock, and multisystem organ dysfunction is predominantly guided by protocols established for critically ill pediatric and adult patients. Despite these limitations, antimicrobial stewardship initiatives have led to hospital-specific modifications to the recommended duration of antibiotic therapy for neonatal sepsis and pneumonia, as established by the American Academy of Pediatrics and the Committee on Infectious Diseases, as highlighted by Lawrence et al. Alarmingly, these modified treatment regimens are often implemented without parental consent, consideration of the infant's gestational age, regard for the causative bacteria, or evidence of long-term safety.Improved testing methods are necessary for more precise identification of neonatal sepsis.Increasing diagnostic accuracy is key to better determine which newborns will benefit the most from receiving empiric antibiotic therapy, particularly those born preterm. Numerous biomarkers have been proposed as ancillary tools for the diagnosis of sepsis, but no individual test has been deemed sufficiently accurate to be recommended for routine clinical application. Chen et al.present data on the role of heparin-binding protein (HBP) as a promising biomarker for early diagnosis and severity assessment of neonatal sepsis. HBP is significantly elevated in neonates with severe sepsis. The authors highlight the existing evidence demonstrating that HBP outperformed traditional markers like procalcitonin and high-sensitive C-reactive protein in the Commented [SC1]: Agree! I suggest to move this up. diagnostic accuracy of neonatal sepsis. Moreover, their manuscript presents evidence that in older populations, HBP aids in differentiation between patients with bacterial vs. non-bacterial infections, potentially helping to guide more rational antibiotic use. Studies show HBP's sensitivity and specificity are high at various cut-off values for the diagnosis of sepsis in adults, making it a promising biomarker that necessitates further evaluation in neonatal populations for this application.Another article in this collection presents data on the characterization of the host response to infections in neonates, which can aid in the diagnosis of sepsis. Gharaibeh et al. analyzed the differential expression of 100 genes in neonates with sepsis to establish a transcriptomic mortality signature. Gene profiling distinguished the infants into three well-defined groups, with endotype "A" exhibiting the highest mortality rate. A dysregulated hyperinflammatory response accompanied by emergency granulopoiesis was characteristic of these infants, potentially informing the necessity for targeted sepsis therapies.In addition to the relevant role of innate immune responses in the pathogenesis of neonatal bacterial infections, the interaction of commensal and pathogenic bacteria within the host also determines important clinical outcomes. In this compilation, human trials were conducted to assess potential associations between the placental microbiome and neonatal pneumonia. Zhang et al. Alternatively, the investigation of adjunctive therapeutics concurrent with antibiotics was tested in a neonatal murine model of E. coli sepsis. In this investigation, Speer et al. detailed renal tissue damage and inflammation, showing that acute kidney injury could be reduced by coadministration of pentoxifylline with targeted antibiotics. This combination therapy also decreased plasma levels of interleukin-6, tumor necrosis factor-alpha, and neutrophil gelatinaseassociated lipocalin (NGAL), among others. Additional studies are needed to determine the optimal therapeutic approach, which will involve modulating host responses to infection in conjunction with the use of targeted, effective antimicrobial agents.In summary, the field of neonatal sepsis is continually evolving, with the goal of developing improved, personalized diagnostic approaches and more effective treatment strategies. To ensure equitable outcomes, these interventions must be tailored to diverse populations and settings around the world.