Clinical pharmacokinetics of aminoglycosides in the neonate: a review

Abstract

Background Sepsis is common in neonates and is a major cause of morbidity and mortality. Sixty percent of preterm neonates receive at least one antibiotic, and 43% of the antibiotics administered to these neonates are aminoglycosides. The clearance (Cl), serum half-life (t 1/2 ), and volume of distribution (Vd) of aminoglycosides change during the neonatal life, and the pharmacokinetics of aminoglycosides need to be studied in neonates in order to optimise therapy with these drugs. Objective The aim of this work is to review the published data on the pharmacokinetics of aminoglycosides in order to provide a critical analysis of the literature that can be a useful tool in the hands of physicians. Methods The bibliographic search was performed electronically using PubMed, as the search engine, through July 11th, 2008. Firstly, a Medline search was performed with the keywords "pharmacokinetics of aminoglycosides in neonates" with the limit of "human". Other Medline searches were performed with the keywords "pharmacokinetics of … in neonates" followed by the name of the aminoglycosides: amikacin, gentamicin, netilmicin and tobramycin. In addition, the book Neofax: A Manual of Drugs Used in Neonatal Care by Young and Mangum (Thomson Healthcare, 2007) was consulted. Results The aminoglycosides are mainly eliminated by the kidney, and their elimination rates are reduced at birth. As a consequence Cl is reduced and t 1/2 is prolonged in the neonate as compared to more mature infants. The high body-water content of the neonate results in a large Vd of aminoglycosides as these drugs are fairly water soluble. Postnatal development is an important factor in the maturation of the neonate, and as postnatal age proceeds, Cl of aminoglycosides increases. Conclusion The maturation of the kidney governs the pharmacokinetics of aminoglycosides in the infant. Cl and t 1/2 are influenced by development, and this must be taken into consideration when planning a dosage regimen with aminoglycosides in the neonate. Aminoglycosides are fairly water soluble, and the larger water content of neonates yields a larger Vd in these patients.

Impact of Gestational Age and Birth Weight on Amikacin Clearance on Day 1 of Life

“…We found a positive correlation between amikacin clearance and GA, as has been described for aminoglycosides (18,20,(35)(36)(37)(38)(39). The absolute value of amikacin clearance (0.61 ml/kg per min) is comparable to previously reported values (0.52 to 0.6 ml/kg per min (17)(18)(19)40). Also, the distribution volume of amikacin was similar to previously reported values of 0.58 L/kg (18) and 0.59 L/kg (17).…”

Clinical pharmacokinetics in optimal gentamicin dosing regimen in neonates

“…The calculated values of the pharmacokinetic parameters (CL, Vd, t 1/2 ) for each of the patients were assessed, and they are comparable with the results of previous studies [7,[17][18][19]. Statistical difference in pharmacokinetic parameters was not detected between groups, confirming linear pharmacokinetics of gentamicin.…”

“…Compared with the adults, reduced content of fat and muscle tissues, increased percentage of body fluid (70-75% of total body weight) and an increased percentage of extracellular fluid (40% of total body weight) was observed [7,8]. Due to hydrophilic characteristics, gentamicin's volume of distribution (Vd) per kilogram of body weight is higher (some studies confirmed a two-fold increase) in the neonates compared with adults.…”

“…Being that gentamicin is mainly eliminated by kidney filtration, the glomerular filtration rate (physiological parameter of renal function) has an essential impact on the values of the gentamicin elimination parameters. In neonates, between 28 and 40 weeks of gestation, glomerular filtration rate is 30-50% of the value in adults, expressed as a function of body weight [7]. Renal function matures slowly, and depends on gestational and postnatal age.…”

“…Therefore, clearance (CL) of gentamicin is almost entirely dependent on glomerular filtration rate, and its values are from 0.53 to 1.72 ml/ min/kg. Elimination half-life (t 1/2 ) is longer than in adults with values of 3-11 h [7]. Thus, large inter-individual variability in the gentamicin pharmacokinetics exists as a consequence of gestational age, postnatal age, weight, disease characteristics, and co-therapy.…”