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

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

Neonatal pain management: still in search for the Holy Grail.

Inadequate pain management but also inappropriate use of analgesics in early infancy has negative effects on neurodevelopmental outcome. As a consequence, neonatal pain management is still in search for the Holy Grail. At best, effective pain management is based on prevention, assessment, and treatment followed by a re-assessment of the pain to determine if additional treatment is still necessary. Unfortunately, epidemiological observations suggest that neonates are undergoing painful procedures very frequently, unveiling the need for effective preventive, non-pharmacological strategies. In addition, assessment is still based on validated, multimodal, but subjective pain assessment tools. Finally, in neonatal intensive care units, there is a shift in clinical practices (e.g., shorter intubation and ventilation), and this necessitates the development and validation of new pharmacological treatment modalities. To illustrate this, a shift in the use of opioids to paracetamol has occurred and short-acting agents (remifentanil, propofol) are more commonly administered to neonates. In addition to these new modalities and as part of a more advanced approach of the developmental pharmacology of analgesics, pharmacogenetics also emerged as a tool for precision medicine in neonates. To assure further improvement of neonatal pain management the integration of pharmacogenetics with the usual covariates like weight, age and/or disease characteristics is needed

Pharmacologic management of the opioid neonatal abstinence syndrome.

Opioid use in pregnant women has increased over the last decade. Following birth, infants with in utero exposure demonstrate signs and symptoms of withdrawal known as the neonatal abstinence syndrome (NAS). Infants express a spectrum of disease, with most requiring the administration of pharmacologic therapy to ensure proper growth and development. Treatment often involves prolonged hospitalization. There is a general lack of high-quality clinical trial data to guide optimal therapy, and significant heterogeneity in treatment approaches. Emerging trends in the treatment of infants with NAS include the use of sublingual buprenorphine, transition to outpatient therapy, and pharmacogenetic risk stratification

Clinical pharmacology in neonates: Small size, huge variability

Drug therapy is a powerful tool for improving neonatal outcome. Despite this, neonatologists still routinely prescribe off-label compounds developed for adults and extrapolate doses from those used for children or adults. Knowledge integration through pharmacokinetic modeling is a method that could improve the current situation. Such predictive models may convert neonatal pharmacotherapy from explorative to confirmatory. This can be illustrated by research projects related to the prediction of neonatal renal clearance and neonatal glucuronidation. This type of model will also improve the current knowledge of neonatal (patho)physiology. In the meanwhile, the fields of clinical pharmacology (e.g. pharmacokinetic/pharmacodynamic modeling and pharmacogenetics) and neonatology (e.g. whole-body cooling and the lower limit of viability) have both matured, resulting in new research topics. However, in order for the modeling and the newly emerging topics to become effective tools, they need to be tailored to the specific characteristics of neonates. Consequently, the field of neonatal pharmacotherapy needs dedicated neonatologists who continue to raise the awareness that off-label practices, eminence-based dosing regimens and the absence of neonatal drug formulations all reflect suboptimal care

Endotracheal instillation of prostacyclin in preterm infants with persistent pulmonary hypertension

Does endotracheal instilled prostacyclin (epoprostenol) improve oxygenation in preterm infants with persistent pulmonary hypertension? Four preterm infants were studied. Prostacyclin (50 ng x kg(-1)) was injected as an endotracheal bolus. In two patients the prostacyclin bolus was repeated and in one patient prostacyclin was administered continuously. Oxygenation was evaluated through the oxygenation index and the ratio of arterial oxygen tension to the fraction of inspired oxygen. The mean arterial blood pressure was used to evaluate systemic circulation. The oxygenation index (+/-SD) decreased significantly from 39 (+/-13.3) to 7 (+/-2.5) and the ratio of arterial oxygen tension to the fraction of inspired oxygen (+/-SD) increased significantly from 47 (+/-13) to 218 (+/-67), most likely related to a reduction of the pulmonary vascular resistance with a reversal of the extrapulmonary shunting at the ductus arteriosus and atrial level. The blood pressure did not change. All effects were reversed on drug withdrawal. Repeated or continuous endotracheal administration of prostacyclin in three children demonstrated a sustained response without tachyphylaxis, and without overt side-effects. Endotracheal instillation of prostacyclin resulted in an improved oxygenation without systemic vascular repercussions in four preterm infants with persistent pulmonary hypertension. Repeated or continuous administration showed a sustained response and no overt side-effects were noticed