Late-Onset Neonatal Sepsis: Contemporary Epidemiology, Diagnosis, Prevention, and Precision Therapeutics

OBJECTIVES: Late-onset neonatal sepsis (LOS) remains a major challenge in modern neonatal intensive care units (NICUs), disproportionately affecting very low birth weight (VLBW) and extremely preterm infants. Despite advances in perinatal care, LOS continues to contribute to high mortality, prolonged hospitalization, and long-term neurodevelopmental impairment. Emerging trends-including evolving pathogen profiles, increased antimicrobial resistance (AMR), and widespread microbiome disruption-highlight persistent clinical and public health concerns. This review synthesizes current evidence on the epidemiology, pathophysiology, diagnosis, and management of LOS, with emphasis on evolving diagnostics, antimicrobial stewardship, prevention strategies, and emerging precision approaches. Key gaps and research priorities are highlighted to inform future clinical practice and neonatal health policy. STUDY DESIGN: This narrative review synthesizes contemporary literature, including multicenter cohort studies, national registries, and emerging diagnostic and predictive technologies. RESULTS: LOS arises from the complex interplay between neonatal immune immaturity, invasive NICU interventions, and microbial exposure. Gram-positive organisms predominate in high-income settings, while multidrug-resistant Gram-negative pathogens are increasingly reported in low- and middle-income countries, contributing to higher morbidity and mortality. Early-life antibiotic exposure and dysbiosis compromise the gut microbiome, further increasing susceptibility. Clinical recognition remains challenging due to nonspecific signs, often leading to delayed or excessive empiric antibiotic therapy. Rapid molecular diagnostics, emerging predictive tools, including early-warning models, and serial biomarker monitoring offer opportunities for pathogen-directed therapy, individualized pharmacokinetic optimization, and safe antimicrobial stewardship. Prevention through central-line bundles, human milk feeding, probiotics, strict hand hygiene, and context-specific infection-control strategies remains central to reducing LOS incidence. CONCLUSIONS: LOS represents a multifactorial syndrome with profound implications for survival and neurodevelopment in preterm and VLBW infants. Effective management requires integration of precision diagnostics, individualized therapy, microbiome-preserving strategies, neuroprotective interventions, and equitable implementation of prevention and stewardship programs. Bridging mechanistic understanding with scalable, context-sensitive approaches is critical to improving survival, reducing morbidity, and optimizing long-term outcomes.