Commentary on: Kuzniewicz MW, Puopolo KM, Fischer A, Walsh EM, Li S, Newman TB, et al. A Quantitative, Risk-Based Approach to the Management of Neonatal Early-Onset Sepsis. JAMA Pediatr. 2017; 171(4):365-371. https://doi.org/10.1001/jamapediatrics.2016.4678. Antibiotics are life-saving for babies who have early-onset sepsis (EOS), and a false negative assessment for this disease can be lethal. However, the risk evaluation process is challenging: early signs are subtle, and frequently occur with other pathologies. For this reason, a careful and conservative approach is employed in clinical guidelines 1 and by clinicians charged with the decision of whether to prescribe antimicrobials to a newborn who has a small, but quantifiable, risk of infection. As is the case for any intervention, antibiotics are not without associated risk. They are generally prescribed to neonates intravenously and involve risks inherent to invasive vascular devices and parenteral medications 2. The impact of antibiotic exposure to the developing microbiome is becoming better understood, including its association with allergic pathologies 3 and metabolic diseases including obesity 4. Further, the contribution of excess antibiotic use to the global escalation of antibiotic resistance cannot be ignored 5. Thus, whilst true cases of EOS must be identified and treated, there is a strong case for reducing potentially avoidable antibiotic prescriptions to newborns. Kuzniewicz et al.'s demonstration that an EOS calculator can effect safe reduction in investigations for infection and antimicrobial use is a positive step forward. The study's large cohort and careful analysis conducted for missed cases or delayed therapy lends confidence to the EOS calculator approach. Their data confirm that contemporary rates of EOS are lower than those observed prior to the Group B Streptococcus screening era 6, underscoring the rationale of reappraising currently high antimicrobial use for suspected EOS. There are several aspects to this study, which should be interpreted in context. First, population prevalence of antibiotic use varies between neonatal health services. In this study, pre-intervention antimicrobial use was 5% and post intervention 2.6%. Recently published experience in an Australian neonatal unit showed much higher baseline antimicrobial use: 12%, reduced to 7.6% with implementation of the EOS calculator 7. By comparison, Fjalstad et al. estimated antimicrobial exposure amongst term Norwegian term infants antibiotics at 2.3%, lower than what has been published with EOS calculator use, despite a higher baseline incidence of EOS in the Norwegian study in comparison with the Australian study and Kuzniewiez et al.'s cohort (0.54/1000 versus 0.44/1000 and 0.3/1000 live births respectively) 7, 8. Assessment of the EOS calculator's efficacy in demographically similar regions where antimicrobial use is already <2.5% has not been performed, and it remains to be seen whether it might play a role where lower rates are already achieved. Further, whilst the EOS calculator can account for differing baseline disease incidence, its use will need careful appraisal for safety in regions with different pathogen distributions to the study's population. This could be particularly pertinent for health services in low and middle income regions where Gram negative infections are a more frequent cause of EOS 9. In summary, this study presents a practical, feasible and highly relevant intervention for neonatal health services to safely reduce currently high rates of neonatal antimicrobial exposure. https://ebneo.org/2018/06/a-quantitative-risk-based-approach-to-the-management-of-neonatal-early-onset-sepsis/ Naomi Spotswood is supported by an Australian Government Research Training Program Scholarship (Australian Commonwealth Government) and the Rowden White Scholarship (University of Melbourne). None.