Tamara van Donge

Key components for antibiotic dose optimization 43 3 Introduction In the first two years of life, maturation processes are responsible for unique challenges in terms of dosing, compared to older children where dosing is mainly adjusted by weight. Since these changes are most evident in neonates and young infants, this article is focusing on these two special pediatric populations. We review and discuss key components and their underlying relationships important for optimal and individualized antibiotic treatment in neonates and infants with suspected or confirmed sepsis (Figure 1). Dose Exposure Response • Identify the correct diagnosis • Accessibility of antibiotic treatment (high income country vs. low-middle income country) • Administration route (iv, sc, po) • Correlated demographics (postnatal age, gestational age, weight) • Maturational changes (enzyme ontogeny, organ function) • MIC and corresponding PK/PD indices (concentration- / time dependency) • Pathogen and microbiome • Clinical outcome vs. biomarker result Treatment phase • Determination of treatment phase • Empirical phase (< 3 days) focused on efficacy • Targeted phase (> 3 days) focused on safety Figure 1: Flowchart illustrating key components and factors influencing these concepts concerning antibiotic treatment in neonates and infants. MIC: minimal inhibitory concentration, PK: pharmacokinetics, PD: pharmacodynamics, iv: intravenous, sc: subcutaneous, po: oral. Burden of sepsis in neonates and infants Despite a decline in child mortality during the last decades, close to 6 million children died before the age of five years in 2015 with almost half of these patients dying in the neonatal period. 1 Neonates are immunologically immature, have reduced skin barrier, reduced humoral response and together with a diminished microbial diversity in gut microbiota ensure that they are prone to sepsis. 2-5 In 2015, infectious diseases were responsible for 9.5% of neonatal deaths worldwide. It is obvious that geographical location associated with divergence in levels of healthcare and the accessibility to antibiotics contributes largely to this mortality rate. 1 Sepsis continues to impact not only neonates, but also infants and older children. A recent study showed that global prevalence of severe sepsis