Key Components for Antibiotic Dose Optimization of Sepsis in Neonates and Infants

Abstract

Sepsis in neonates and infants remains a major cause of death despite a decline in child mortality and morbidity over the last decades. A key factor in further reducing poor clinical outcomes is the optimal use of antibiotics in sepsis management. Developmental changes such as maturation of organ function and capacity of drug metabolizing enzymes can affect the pharmacokinetic profile and therefore the antibiotic exposure and response in neonates and infants. Optimal antibiotic treatment of sepsis in neonates and young infants is dependent on several key components such as the determination of treatment phase, the administered dose and the resulted drug exposure and microbiological response. During the initial phase of suspected sepsis, the primary focus of empirical treatment is to assure efficacy. Once bacterial infection as the cause of sepsis is confirmed the focus shifts toward a targeted treatment, ensuring an optimal balance between efficacy and safety. Interpretation of antibiotic exposure and microbiological response in neonates and infants is multifaceted. The response or treatment effect can be determined by the microbiological parameters (MIC) together with the characteristics of the pathogen (time- or concentration dependent). The antibiotic response is influenced by the properties of the causative pathogen and the unique characteristics of the vulnerable patient population such as reduced humoral response or reduced skin barrier function. Therapeutic drug monitoring (TDM) of antibiotics may be used to increase effectiveness while maximizing safety and minimizing the toxicity, but requires expertise in different fields and requires collaborations between physicians, lab technicians, and quantitative clinical pharmacologists. Understanding these clinical, pharmacological, and microbiological components and their underlying relationship can provide a scientific basic for proper antibiotic use and reduction of antibiotic resistance in neonates and infants. This highlights the necessity of a close multidisciplinary collaboration between physicians, pharmacists, clinical pharmacologists and microbiologist to assure the optimal utilization of antibiotics in neonates and young infants.

Therapeutic Drug Monitoring Is a Feasible Tool to Personalize Drug Administration in Neonates Using New Techniques: An Overview on the Pharmacokinetics and Pharmacodynamics in Neonatal Age

“…In humans, organs and metabolic pathways undergo deep and progressive maturation processes after birth. When studying neonatal pharmacology, we must take this into account [1]. Almost 65% of the drugs used to treat newborns in the Neonatal Intensive Care Units (NICUs) are off-label and need optimization in dosage administration still now.…”

Rational Use of Antibiotics in Neonates: Still in Search of Tailored Tools

“…There is a significant improvement in the knowledge on pharmacokinetics in neonates, and the impact of the maturational and non-maturational covariates on dosing regimens (how to achieve the target exposure. This has resulted in an increased volume of scientific knowledge, but we still fail to implement this knowledge in our daily practice [14,18,22]. In contrast, the knowledge on the short- and mainly long-term side effects of perinatal exposure to antibiotics (pharmacodynamics) is still much more limited and is an area in need of further research.…”

“…For LOS, practices were much more heterogeneous, with third-generation cephalosporins (52%), or carbapenems (meropenem 18%), while 48% of the units use vancomycin empirically before any methicillin-resistant Gram-positive pathogen is detected [18]. These practices are, to a large extent, in line with reported practices in other countries or regions [7,13,22]. However, drug choices are relevant when we consider potential side effects.…”

“…The choices to be made when prescribing empiric antibiotic regimens should depend on the anticipated pathogens and their resistance pattern, and on the available information on the safety and side effects of the antibiotics, specifically in neonates. Obviously, once the pathogen is isolated, the best targeted and tailored treatment regimen should be selected [22]. Pathogens to target for in EOS are either Gram-negative organisms ( Escherichia coli , Haemophilus influenzae , Citrobacter spp., or Enterobacter spp.)…”

Can we optimize antibiotic use in Norwegian neonates? A prospective comparison between a university hospital and a district hospital

“…From our data, we can not conclude whether there was a difference in severity between the hospitals. More studies focusing on therapeutic drug monitoring of antibiotics in neonates should be conducted in order to optimize dose regimes in the future (24).…”