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[Pharmacokinetics of combined antibiotic therapy in the newborn infant]
Insights
Individual drug monitoring is crucial for newborn infants with septicemia. Gentamicin dosing requires significant adjustments to maintain therapeutic levels, unlike ampicillin and cefotaxim, which achieve sufficient concentrations.
Area of Science:
- Neonatal pharmacology
- Pediatric infectious diseases
- Pharmacokinetics and drug metabolism
Context:
- Neonatal septicemia presents a significant challenge due to immature organ systems affecting drug processing.
- Antibiotic therapy in neonates requires careful consideration of drug levels to balance efficacy and toxicity.
- Established fixed-dose regimens may not ensure optimal therapeutic drug concentrations in this vulnerable population.
Purpose:
- To determine the concentration-time courses of gentamicin, ampicillin, and cefotaxime in newborn infants with septicemia.
- To evaluate the pharmacokinetic variability of these antibiotics under a fixed-dose regimen.
- To assess the impact of combining gentamicin with ampicillin or cefotaxime on pharmacokinetic parameters.
Summary:
- Pharmacokinetic analysis of gentamicin, ampicillin, and cefotaxime was performed in 66 neonates with septicemia.
- Gentamicin exhibited highly variable pharmacokinetic parameters, necessitating dose adjustments ranging from -17% to +110% to achieve target serum concentrations.
- Ampicillin and cefotaxime (100 mg/kg/day) generally achieved sufficient serum concentrations, though gentamicin doses of 5-7 mg/kg/day were sometimes insufficient or near toxic levels.
- Combining gentamicin with ampicillin did not alter pharmacokinetics, but combining it with cefotaxime significantly reduced gentamicin's elimination half-life.
Impact:
- Highlights the critical need for individualized drug monitoring, especially for gentamicin, in neonatal septicemia to optimize therapeutic outcomes.
- Provides data supporting the use of ampicillin and cefotaxime at 100 mg/kg/day for achieving adequate serum concentrations in neonates.
- Demonstrates potential drug-drug interactions affecting gentamicin's elimination when co-administered with cefotaxime, underscoring the importance of monitoring combined therapies.
Abstract:
In 66 newborn infants (AGA) suffering from septicemia concentration time courses of gentamicin, ampicillin and cefotaxim were determined to perform and an individual drug monitoring. Gentamicin was analysed from capillar blood samples using EMIT, Ampicillin and Cefotaxim by HPLC-technique. Volumes of distribution, apparent elimination half lives, maximum -, minimum and steady state concentrations were calculated using digital iteration programs. Based on a fixed dose regimen the kinetic parameters of gentamicin were extremely variable. To achieve a median steady state concentration of 3 micrograms/ml gentamicin in serum corrections from -17% to +110% of the foregoing dose were necessary. With 100 mg/kg ampicillin or cefotaxim per day sufficient concentrations in serum were reached. But in some patients a dosage of 5-7 mg/kg/d of gentamicin is too low, while others show concentrations near to the toxic levels. By a combination of gentamicin plus ampicillin pharmacokinetic parameters are not influenced; while if gentamicin is combined with cefotaxim the apparent elimination halflife of gentamicin (beta-slope) is significantly reduced. Therefore an individual drug monitoring of drugs with a small therapeutic range, for example gentamicin, is necessary to optimize therapeutic results.