Criteria with regards to hemodynamic compromise or respiratory failure are not useful clinically because these symptoms often do not arise in neonates until death is imminent and unpreventable.

[citation needed] A study performed at Strong Memorial Hospital in Rochester, New York, showed that infants ≤ 60 days old meeting the following criteria were at low-risk for having a serious bacterial illness:[2] Those meeting these criteria likely do not require a lumbar puncture, and are felt to be safe for discharge home without antibiotic treatment, or with a single dose of intramuscular antibiotics, but will still require close outpatient follow-up.

They may be relatively asymptomatic until hemodynamic and respiratory collapse is imminent, so, if there is even a remote suspicion of sepsis, they are frequently treated with antibiotics empirically until cultures are sufficiently proven to be negative.

The organisms which are targeted are species that predominate in the female genitourinary tract and to which neonates are especially vulnerable to, specifically Group B Streptococcus, Escherichia coli, and Listeria monocytogenes (This is the main rationale for using ampicillin versus other beta-lactams.)

Although uncommon, if anaerobic species are suspected (such as in cases where necrotizing enterocolitis or intestinal perforation is a concern, clindamycin is often added.

There are several consequences to the overtreatment of antibiotics in newborns including "microbiome alterations, which are linked to the development of asthma, food allergies, and childhood obesity".

[22] The current challenge faced by clinicians is mainly weighing the risk and benefits of the possibility of antibiotic overtreatment vs. the effects of sepsis.

Mothers who have poor healthcare, low socioeconomic status, substance abuse, or are African American have higher rates of neonatal sepsis.

[citation needed] A very large meta-analysis investigated the effect of probiotics on preventing late-onset sepsis (LOS) in neonates.

[27] It is also still unclear if probiotic administration reduces LOS risk in extremely low birth weight infants due to the limited number of studies that investigated it.

[27] It would be beneficial to clarify the relationship between probiotic supplementation and human milk for future studies in order to prevent late onset sepsis in neonates.

[31] From 1993 to 2007, doctors at Kaiser Permanente Medical Care Program hospitals, Brigham Women's Hospital, and Beth Israel-Deaconess Medical Center conducted a nested case-control study in an effort to create a better quantitative method for determining risk factors for neonatal early-onset sepsis.

[34] Another study evaluated the impact of Integrating the SRC into the electronic health record in order to "improve compliance and accuracy through automation".

[35] The study concluded that the integration of the EOS into the electronic health record system "significantly increased calculator accuracy".