Researchers develop a novel glycopeptide antibiotic similar to vancomycin that is bactericidal against many gram-positive bacteria. From animal studies, they determine that the effective drug dosage is 5 mg/kg/day administered intravenously in divided doses. In a clinical trial, the antibiotic is administered to adult and neonatal patients with gram-positive infections. The drug is found to be effective in adults but not in neonates. During further analysis, plasma concentrations of the drug are measured in both groups, with the results shown in the image below: Compared to adults, which of the following neonatal factors is the most likely cause of the difference in drug effectiveness?

Question

Researchers develop a novel glycopeptide antibiotic similar to vancomycin that is bactericidal against many gram-positive bacteria.  From animal studies, they determine that the effective drug dosage is 5 mg/kg/day administered intravenously in divided doses.  In a clinical trial, the antibiotic is administered to adult and neonatal patients with gram-positive infections.  The drug is found to be effective in adults but not in neonates.  During further analysis, plasma concentrations of the drug are measured in both groups, with the results shown in the image below:  Compared to adults, which of the following neonatal factors is the most likely cause of the difference in drug effectiveness?

Quizplus · Accepted Answer

11ec160b_3c26_7fe2_9249_9314ab068158_MD0001_00 In this example, a novel glycopeptide antibiotic is administered to adult and neonatal patients using the same weight-based dosing regimen (eg, 5 mg/kg). However, plasma concentrations of the drug are lower in neonates compared to the adults, resulting in decreased effectiveness. Neonates have substantial pharmacokinetic differences compared to adult patients that affect drug absorption, distribution, and elimination. Changes in gastrointestinal parameters in neonates (eg, decreased gastric pH, reduced intestinal motility) can have a variable effect on the absorption of orally administered drugs. However, in this case, the drug is being administered intravenously, so changes in absorption are unlikely to be the cause of the plasma concentration discrepancy. Neonates also have an increased proportion of total body water with a lower content of body fat compared to adults. This difference in body composition results in water-soluble drugs (eg, aminoglycosides, vancomycin) having a larger than expected volume of distribution relative to body mass, leading to lower plasma concentrations when the drug is administered at the same weight-based dosage as given to adult patients. Furthermore, neonates have an immature blood-brain barrier that increases the permeability of many substances into the CNS compartment, which (in addition to increasing the distribution volume) can increase the risk of CNS toxicity. (Choice A) The liver is not fully developed in neonates and has decreased expression of drug-metabolizing enzymes (eg, cytochrome P450 isoenzymes, glucuronidation enzymes). This can lead to decreased clearance of drugs that are hepatically metabolized (eg, acetaminophen, morphine). However, this would result in increased (not decreased) plasma drug levels. (Choice B) Renal blood flow and glomerular filtration rate are decreased in neonates compared to adults. For drugs that are renally excreted, reduced renal clearance would cause increased serum drug concentrations, potentially leading to toxicity. However, in this study the serum concentration is lower in neonates than in adults. (Choice C) Neonates have decreased (not increased) plasma protein concentrations compared to adults, which can increase free levels of highly protein-bound drugs (eg, phenytoin, penicillin). Elevated bilirubin levels in neonates can further increase the concentration of unbound drug by displacing them from albumin binding sites. Educational objective: Neonates have a higher proportion of body water compared to adults. This can result in lower plasma concentrations of water-soluble drugs if they are administered at the same weight-based dosage as given to adult patients.

Researchers Develop a Novel Glycopeptide Antibiotic Similar to Vancomycin That