Gentamicin and Tobramycin in Neonates: Comparison of a New Extended Dosing Interval Regimen with a Traditional Multiple Daily Dosing Regimen
Because of a lack of data supporting traditional dosing regimens for aminoglycosides, especially in extremely low-birth-weight infants, the authors developed revised dosing guidelines. The new guidelines increased doses to 5 mg/kg (over traditional doses of 2.5 mg/kg) and lengthened the dosing interval. When results of the two regimens were compared in 120 infants, 26.8% of infants in the traditional dosing group had subtherapeutic levels at <5 microg/mL, whereas only 1.3% of infants in the new practice dosing group were subtherapeutic. With the new dosing practice, serum levels in 1.3% of infants also exceeded the upper therapeutic range of 12 microg/mL. In conclusion, by increasing the dose of aminoglycosides and extending the dosing intervals, therapeutic levels-as defined by a C min <2 microg/mL and a C max of 5 to 12 microg/mL--were obtained significantly more often. In essence the regimen involves once daily dosing for infants <1200 g who are >30 days of age and for infants <1200 g who are >7 days of age. Serum concentrations still need to be monitored where clinically indicated.
Available from: mdpi.com
- "Later, it appeared that once-daily gentamicin dosing of 4–5 mg/kg yields higher peak and lower trough gentamicin concentration than twice-daily dosing [for review see Rao et al.  and Miron . Recently, administering 5 mg/kg gentamicin and extending the dose interval to 36-48 h has been recommended [73,74,75,76,77,78]. Extending the dose interval to 48 h and increasing the gentamicin dose to 5 mg/kg causes an increase in peak concentration as compared with the dose of 2.5 mg/kg every 12 h [74,75,76,77,78]. "
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ABSTRACT: Bacterial infections are common in the neonates and are a major cause of morbidity and mortality. Sixty percent of preterm infants admitted to neonatal intensive care units received at least one antibiotic during the first week of life. Penicillins, aminoglycosides and cephalosporins comprised 53, 43 and 16%, respectively. Kinetic parameters such as the half-life (t1/2), clearance (Cl), and volume of distribution (Vd) change with development, so the kinetics of penicillins, cephalosporins and aminoglycosides need to be studied in order to optimise therapy with these drugs. The aim of this study is to review the pharmacokinetics of penicillins, cephalosporins and aminoglycosides in the neonate in a single article in order to provide a critical analysis of the literature and thus provide a useful tool in the hands of physicians. The bibliographic search was performed electronically using PubMed, as the search engine, until February 2nd, 2010. Medline search terms were as follows: pharmacokinetics AND (penicillins OR cephalosporins OR aminoglycosides) AND infant, newborn, limiting to humans. Penicillins, cephalosporins and aminoglycosides are fairly water soluble and are mainly eliminated by the kidneys. The maturation of the kidneys governs the pharmacokinetics of penicillins, cephalosporins and aminoglycosides in the neonate. The renal excretory function is reduced in preterms compared to term infants and Cl of these drugs is reduced in premature infants. Gestational and postnatal ages are important factors in the maturation of the neonate and, as these ages proceed, Cl of penicillins, cephalosporins and aminoglycosides increases. Cl and t1/2 are influenced by development and this must be taken into consideration when planning a dosage regimen with these drugs. More pharmacokinetic studies are required to ensure that the dose recommended for the treatment of sepsis in the neonate is evidence based.
Available from: benthamscience.com
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ABSTRACT: Background: Sepsis is common in neonates and is a major cause of morbidity and mortality. 60% of preterm neonates receive at least one antibiotic and 43% of the antibiotics administered to these neonates are aminoglycosides. Gentamicin is an aminoglycoside which is largely used. Dosing of gentamicin gives rise to two concentrations, the peak concentration which is measured soon after dosing, and the trough concentration which is measured before the next administration. There has been a long debate about the appropriate dose of gentamicin to administer to neonates and the interval between doses. The ideal dosing of gentamicin should yield a peak concentration of 10g/ml and a trough concentration of 1g/ml. Objectives: The aim of this work is to compare the peak and trough concentrations of gentamicin in the neonate after twice-daily dosing, once-daily dosing and extended interval dosing to establish the safest one for neonates. Another aim of this note is 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, until January 14 th 2008. Medline searches were performed with the following keywords "twice-daily dosing of gentamicin in neonates" with the limit of "human"; "once-daily dosing of gentamicin in neonates"; "extended interval dosing of gentamicin in neonates"; "pharmacokinetics of gentamicin in neonates". In addition, the book Neofax: a Manual of Drugs Used in the Neonatal Care by Young and Mangum  was consulted. Results: The peak and trough concentrations were compared after the following dosing schedules of gentamicin 2.5 mg/kg twice-daily dosing, 4 mg/kg once-daily dosing and 5 mg/kg every 48 h defined "extended interval dosing". Twice-daily dosing was associated with the lowest peak gentamicin concentration and with the highest trough concentration. The lowest trough concentration was associated with the extended interval dosing of gentamicin. Gentamicin is mainly eliminated through glomerular filtration whose rate increases with the growth of the infant. The trough concentration was negatively correlated with the body weight indicating that in better developed neonates gentamicin was more rapidly eliminated. Conclusions: The dosing schedule contributes to determining the peak and trough concentrations of gentamicin in the neonate. There are numerous articles comparing the peak and trough concentrations after twice-daily dosing and once-daily dosing of gentamicin. In contrast, little is known about the peak and trough concentration of extended interval dosing of gentamicin. More studies are required to better highlight the peak and trough concentrations of extended interval dosing of gentamicin at different gestational age.
Available from: Roland Broadbent
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ABSTRACT: To investigate the effect of sepsis upon the volume of distribution (Vd) of gentamicin in neonates.
A retrospective chart review was conducted of neonates admitted to Dunedin Hospital who had gentamicin concentrations performed between 1st January 2000 and 30th October 2003. Data from 277 neonates, including a total of 576 gentamicin concentrations, were included in the pharmacokinetic analysis. Fifteen (5.4%) of the neonates had confirmed sepsis. Pharmacokinetic analyses were performed with NONMEM using a one compartment first order elimination model. Duration of infusion (D) was included as a parameter in the model. Covariates included sepsis (SEP), chronological age, gestational age (GA), birth weight, current weight, gender, Apgar score at 1 (AP1) and 5 (AP2) minutes, plasma C-reactive protein and serum creatinine.
The initial model provided a mean estimates of clearance (CL) of 0.0460 l kg(-1) h(-1), volume of distribution (Vd) of 0.483 l kg(-1) and D of 0.748 h. The magnitudes of interpatient variability, expressed as CV%, were 29.2% for CL, 20.8% for Vd and 71.5% for D. The magnitude of residual variability in gentamicin concentrations was 88.0%. The final pharmacokinetic model was: CL = (0.0177 + 0.00147.(GA-20) + 0.000635.AP2) l kg(-1) h(-1), Vd = (0.483 +0.0656. sepsis) l kg(-1), D = 0.672 h. The interpatient variability (CV%) was 22.8% for CL, 22.8% for Vd and 97.7% for D. The magnitude of residual variability in gentamicin concentrations was 83.3%.
The 14% increase in Vd in septic neonates implies that larger doses may be required to achieve peak therapeutic concentrations in the presence of sepsis. D is an important parameter in neonatal pharmacokinetic models.
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