Table 1.

Current and future opportunities for precision medicine in neonatal bacterial infection management, with potential improvements, challenges, and specific research agenda items.

Area of opportunity	Potential improvement	Main challenges	Research agenda
Prevention
Intrapartum antibiotics	Reduced incidence of neonatal sepsis	Appropriate and timely indication	RT-PCR implementation
Vaccination	Reduced incidence of neonatal sepsis	Achieving effective antibody levels	Phase II/III trials
Treatment initiation
EOS calculator	Reduced overtreatment	Local implementation and evaluation	Cluster-randomized trials; integration in electronic healthcare systems
Serial physical examination	Reduced overtreatment; early sepsis identification	Few large studies; labor-intensive; lack of uniform practice	Development and testing of unified approach in large studies
Heart rate variability	Early sepsis identification; reduced mortality/morbidity	Very few validation studies; not validated for late preterm/term neonates	Validation studies, particularly for late preterm/term neonates
“Omics”	Improved diagnostics	Lack of validation; integration of systems biology into clinic	Validation studies of promising omics data; development of point-of-care biomarkers derived from omics data; studies focused on clinical decision-making
Computational power (machine learning)	Better identification of neonatal sepsis	Data collection and processing; validating models	Improving digital infrastructure; validation and implementation studies
Treatment optimization
Oral administration	Less invasive treatment	Few data regarding safety/efficacy	Randomized trials for oral vs. intravenous treatment
IM administration	Availability in low-resource settings or in absence of intravenous access	Reducing pain; pharmacokinetic/pharmacodynamic uncertainties	Randomized trials for IM vs. intravenous treatment
Immunomodulation	Improved treatment efficacy: less mortality/morbidity	Limited knowledge on mechanism and efficacy	Randomized clinical trials
Therapeutic drug monitoring/model-informed precision dosing	Optimal pharmacological effect for individual	Lack of reliable/validated models	Model development and prospective validation
MIC guidance	Effective treatment	Lack of PK/PD data for neonates	PK/PD studies for (preterm) neonates
Treatment duration
Automatic stop orders	Reducing overtreatment	Changing clinical paradigm	Quality improvement initiatives
Biomarker algorithms	Reducing overtreatment; better identification of sepsis	Limited or variable reference limits for biomarkers; limited sensitivity	Studies combining clinical parameters and multiple biomarkers; machine learning approaches
Blood cultures	Reducing overtreatment	Obtaining adequate volume; real-time blood culture reporting	Studies reporting time-to-positivity, Studies researching blood volume sensitivity; studies evaluating additional detection techniques
General
Neonatal sepsis definition	Reliable and clinically relevant diagnosis	Defining criteria for organ dysfunction; defining long-term outcomes	Systematic reviews on organ dysfunction
Researching understudied populations	Improvements for relatively large population	Low sepsis incidence	Large cohort studies in late preterm and term populations