Neonatology Zero To Finals
Sandra Grady
The Department of Pediatrics at the University of California, Davis School of Medicine is launching a national search for one full-time academic neonatology faculty clinician-scientist or clinician-educator. This position will be open to Assistant/Associate/Full Professor level candidates (commensurate with credentials) in the Clinical X or Health Sciences Clinical Professor series. Ideal candidates will have a strong interest in clinical research, preferably with a well-developed program.
Candidates will be expected to participate in clinical care, teaching of medical students, residents and fellows, scholarly and/or research activities of the Department of Pediatrics, and serve on departmental committees.
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Neonates undergo rapid and significant maturation and development, leading to changes in body composition, expression of drug-metabolizing enzymes, fluid distribution, and variable hepato-renal function. This can be further complicated by pathological conditions (such as growth restriction, sepsis, associated cardiomyopathy, and organ failure) or administered treatment (e.g., co-medication, surgical intervention, extracorporeal membrane oxygenation) (9,10). Adult drug doses, even after adjustment for body weight can be risky in neonates as it may expose this vulnerable population to potentially toxic doses and adverse drug reactions. Even now, approximately 65% of the drugs used in the neonatal intensive care units (NICUs) are still off-label and need dose optimization before administration (11). Therapeutic drug monitoring (TDM) may be helpful for clinical efficacy and to prevent therapeutic misadventures. Consequently, there is an obvious need to focus on the covariates contributing to this variability within this vulnerable population and adopt TDM for safe and efficacious drug administration whenever feasible (11).
The absorption of a drug refers to its translocation from the administered site into the systemic circulation. The absorption of a drug is influenced by multiple factors, including the dose, route of administration, carrier-mediated transport, molecular weight, lipid solubility, degree of ionization, and metabolism of the drug. Gestational age at birth, postnatal age, and developmental changes in neonates, add to the complexity of the process (12).
Intravascular drugs have rapid and better systemic availability compared to the ones administered from extravascular sites. The portion of a dose that enters the systemic circulation intact is defined as drug bioavailability. Delayed absorption may affect drug bioavailability and predicted peak concentrations, leading to a less than desired response (15).
The bioavailability of medications from enteral routes is determined by gastric acidity and emptying, gastrointestinal (GI) secretions, transport, first-pass metabolism, and bacterial flora (16). These also affect the time to achieve maximal plasma level of drugs (13). Many neonates tend to regurgitate orally administered drugs intermittently some times during therapy, which necessitates readministration. Moreover, many infants especially extreme premature infants are not on significant feeds in the initial few days of life, precluding the use of oral drugs in this population.
At birth there is an immature pancreatic exocrine and biliary system (26), leading to insufficient synthesis of bile salts and lipase (27,28). Inefficient solubilization and intraluminal hydrolysis lead to reduced absorption and bioavailability of lipophilic compounds such as fat-soluble vitamins. However, these functions develop rapidly in the postnatal period (29).
Emptying times and intestinal motility are functions of postconceptional and postnatal age and affect drug absorption (30). Neonates exhibit relatively delayed gastric emptying compared to adults (31). Thus, gastric emptying times are prolonged in more premature infants.
Although feeding stimulates the development of gastric motility, feed composition also affects gastric emptying (32). For example, consumption of human milk and low-calorie formulas increases the rate of gastric emptying in contrast to the formulas containing higher caloric density and long-chain fatty acids (33,34).
Carrier-mediated uptake systems in the gastrointestinal mucosa are crucial for efficient absorption. An immature transport function may reduce the bioavailability of medications (35). On the other hand, some transport proteins [e.g., multidrug resistance 1 (MDR1)] promote the extrusion of drugs from enterocytes into the gastrointestinal lumen, thereby decreasing their bioavailability (36). The intestinal influx oligopeptide transporter peptide transporter 1 (PEPT1) mRNA expression in neonates is marginally lower (0.8-fold) than older children (37). Expression of these transporter proteins improves with increasing postnatal age. Neonatal intestinal expressions of MDR1 and multidrug resistance protein 2 (MRP2) are similar to that in adults (38). Inconsistent drug absorption can also occur with congenital pathological processes (e.g., duodenal atresia) or surgical interventions (e.g., short bowel syndromes), which lead to deficient intestinal transporters like PEPT1 (39).
Bacterial flora influences intestinal motility and metabolism of a drug, playing an important role in its absorption (42,43). The ileum and colon are the primary concentration sites of bacterial flora. Immature gastrointestinal metabolic reactions and ineffective gastrointestinal first-pass metabolism results in improved oral bioavailability in neonates. It takes approximately four years for an infant to develop a mature, adult-like bacterial flora (42,44). This contributes to substantial inter-and intra-individual variability in oral bioavailability.
Genetic factors and underlying pathophysiology (endocrinopathies, gastrointestinal disorders, central nervous system disorders, and metabolic derangements), concomitant administration of drugs also contribute to variable enteral absorption. In summary, enteral bioavailability is influenced by a multitude of factors like postnatal developmental in a newborn, gestation specific factors, and underlying pathophysiology. Knowledge of differences in enteral bioavailability is essential to understand and guide dose adjustment for orally administered medications. This also explains the reliance on intravascular route for administration of critical medications such as antibiotics in neonates.
Drugs administered through non-enteral routes such as sublingual, intramuscular, subcutaneous, inhalation, and intravascular have an associated variability in absorption, depending on the route and developmental differences.
The sublingual route is highly variable in neonates and is not preferred because of uncertain and uncontrolled absorption. The intramuscular absorption is also reduced in neonates because of poor regional blood supply and decreased muscle mass. Lipophilic drugs, which rapidly diffuse into the capillaries, are an exception to this. There is also a concern of some drugs leading to adverse local tissue reactions and injury like calcium gluconate. Thus, these routes are rarely utilized except for a few drugs such as Vitamin K, aminoglycosides, and cephalosporin administration (45,46).
Drugs administered through the subcutaneous route can also have unpredictable systemic bioavailability because of multiple factors including a thin epidermis, reduced stratum corneum, a high degree of hydration, and the higher body surface area ratio of a preterm infant. These may aid in increased percutaneous absorption, while poor skin perfusion may reduce absorption (2,3). Both theophylline and caffeine have been successfully administered via topical gel, with the achievement of therapeutic serum drug concentrations. However, the inadvertent toxicity after percutaneous drug absorption is often overlooked. Historically, boric acid, hexachlorophene, alcohol, and corticosteroids toxicities have been reported after percutaneous administration (47,48).
Rectal absorption is less predictable in newborns than in older children and adults due to variable GI motility and drug insertion depth. The first-pass effect is more apparent with deeper administration of drugs, as the superior rectal vein drains into the portal vein via the inferior mesenteric vein. Drugs administered into the lower rectum have more bioavailability as the lower and middle rectal veins drain directly into the systemic circulation via the inferior vena cava bypassing the liver. Acetaminophen and diazepam have been traditionally administered by this route (48,49).
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