Adaptation in Neonatology of the Once-Daily Concept of Aminoglycoside Administration: Evaluation of a Dosing Chart for Amikacin in an Intensive Care Unit

Langhendries, Jean Paul; Battisti, Oreste; Bertrand, Jacques; François, Ayme; Kalenga, Masendu; Darimont, Jutta; Scalais, Emmanuel; Wallemacq, Pierre

doi:10.1159/000014053

Cited by 67 publications

(63 citation statements)

References 25 publications

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“…However, many other regimens have been proposed (23,41,45). Once-daily regimens have been suggested for children (20 mg/kg [25] or 15 mg/kg [5]) and neonates (24,27,28). We did not aim to assess every dose schedule mentioned in this nonexhaustive list.…”

Section: Methodsmentioning

confidence: 99%

Nonparametric Population Pharmacokinetic Analysis of Amikacin in Neonates, Infants, and Children

Tréluyer

Merlé

Tonnelier

et al. 2002

Antimicrob Agents Chemother

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The therapeutic and toxic effects of amikacin are known to depend on its concentration in plasma, but the pharmacokinetics of this drug in neonates, infants, and children and the influences of clinical and biological variables have been only partially assessed. Therapeutic drug monitoring data collected from 155 patients (49 neonates, 77 infants, and 29 children) receiving amikacin were analyzed by a nonparametric population-based approach, the nonparametric maximum-likelihood method. We assessed the effects of gestational and postnatal age, weight, Apgar score, and plasma creatinine and urea concentrations on pharmacokinetic parameters. There is no specific formulation of amikacin for neonates and infants. We therefore used an error model to account for errors due to dilution during preparation of the infusion. The covariates that reduced the variance of clearance from plasma and the volume of distribution by more than 10% were postnatal age (43 and 28%, respectively) and body weight (30.4 and 17.4%, respectively). The expected reduction of clearance was about 10% for the plasma creatinine concentration. The other covariates studied (Apgar scores, plasma urea concentration, gestational age, sex) were found to have little effect. Simulations showed that a smaller percentage of patients had a maximum concentration in plasma/MIC ratio greater than 8 with a regimen of 7.5 mg/kg of body weight twice daily than with a regimen of 15 mg/kg once a day for MICs of 1 to 8 mg/liter.Amikacin is widely used in neonates and infants, as well as in adults, for the treatment of severe infections caused by gramnegative bacteria. Previous studies have shown that both the therapeutic response and toxic effects depend on plasma amikacin concentrations. Achieving a therapeutic maximum concentration of amikacin in plasma is associated with a significant decrease in the rate of mortality due to infection in critically ill patients (2, 36, 37), and a relationship has also been found between the minimum plasma amikacin concentration and renal toxicity (20,49). Interindividual variability in the pharmacokinetics of amikacin may therefore make it difficult to achieve safe and effective treatment. The pharmacokinetics of aminoglycosides have been shown to be highly variable in neonates and children. Several factors account for the pharmacokinetic variabilities of other aminoglycosides in this population (50). The pharmacokinetics of netilmicin and gentamicin depend on gestational age, postnatal age, weight, renal clearance, and Apgar score (6,9,11,12,14,18,21,43,46,47,(51)(52)(53). Very few data are available concerning the effects of clinical and biological covariates on the pharmacokinetics of amikacin in neonates and the changes in the pharmacokinetic profile of amikacin that occur from birth into infancy. The lack of data on the pharmacokinetics of many drugs in neonates and children is related to blood sampling limitations for this population. One way around this problem is to collect a few samples from many individuals and analyze the...

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Section: Methodsmentioning

confidence: 99%

Nonparametric Population Pharmacokinetic Analysis of Amikacin in Neonates, Infants, and Children

Tréluyer

Merlé

Tonnelier

et al. 2002

Antimicrob Agents Chemother

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“…A PMA-based dosing chart was implemented in 2002 based on the suggestions of Langhendries et al (16) as follows: PMA of Ͻ28 weeks, 20 mg/kg/42 h; PMA of 28 to 30 weeks, 20 mg/kg/36 h; PMA of 31 to 33 weeks, 18.5 mg/kg/30 h; PMA of 34 to 37 weeks, 17 mg/kg/24 h; and PMA of Ͼ37 weeks, 15.5 mg/kg/24 h, with an additional dosing interval increase of 6 h if ibuprofen was coadministered or if neonates had suffered asphyxia or hypoxia (1). Amikacin (Amukin, 50-mg/ml pediatric vial; Bristol Myers Squibb Belgium) was given as an intravenous infusion over 20 min via syringe driver (SIMS; Graseby, Watford, United Kingdom).…”

Section: Methodsmentioning

confidence: 99%

Cerebrospinal Fluid Compartmental Pharmacokinetics of Amikacin in Neonates

Allegaert

Scheers²,

Adams³

et al. 2008

Antimicrob Agents Chemother

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The incidence of early-onset bacterial infection in the neonate varies from 0.5 to 1% of the total number of deliveries but is significantly higher in preterm neonates, where infection is causally linked with premature delivery in ca. 50% of cases (14). Late-onset, nosocomial bacterial infections occur in a significant number of preterm and term neonates during their stay in the neonatal intensive care unit. Bacteremia, pneumonia, necrotizing enterocolitis, and meningitis are the most frequent loci for infection in neonates. Empirical treatment for suspected infection in early neonatal life consists of combination therapy based on a time-dependent (beta-lactamase) and a concentration-dependent (aminoglycoside) antibiotic coverage (e.g., Streptococcus agalactiae and Escherichia coli), whereas in late neonatal life coagulase-negative Staphylococcus should also be covered.The bactericidal effectiveness of amikacin is linked to intermittent, discontinuous peak concentrations, whereas renal side effects and ototoxicity relate to the average serum concentration that contributes to the saturation of renal and cochlear cell binding sites. The combination of bactericidal effect and toxicity data has resulted in the concept of administration of relative larger doses with extended dosing intervals between consecutive doses. The safety and effectiveness of extended interval dosing of aminoglycosides in neonates has been reviewed (19). After the first few days of postnatal life, size, postmenstrual age (PMA), renal function, and ventilation contribute to renal drug clearance variability in neonates and subsequent serum concentration (1, 2, 3).The effectiveness of amikacin for treating meningitis depends on the concentrations in the central nervous system, and this compartment is separated from the blood by the bloodbrain barrier (BBB). Access of aminoglycosides to the central nervous compartment is limited in healthy children and adults (8,26,28), but cerebrospinal fluid (CSF) aminoglycoside exposure after systemic administration is more extended in children with meningitis than in those without meningitis (24). Correlations between antibiotic concentration and CSF glucose content, CSF leukocytosis, or CSF protein concentrations have been investigated (12,13,15,26,27). Ototoxicity relates to the mean aminoglycoside concentration in the central nervous system compartment, but a genetic predisposition to develop aminoglycoside-related ototoxicity has also been documented (4,10,17,23).Observations on maturational amikacin CSF disposition in neonates are therefore of relevance (17,19). However, data on amikacin CSF concentrations are limited in neonates, and amikacin CSF time-concentration profiles in preterm neonates have not been reported (9). In the present study, time-concentration profiles of amikacin in serum and single CSF samples were collected to evaluate the relationship between serum and CSF concentration and to explore the impact of CSF inflammatory markers (leuko-, gluco-, and protidorhachia) on this relationship du...

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“…One concern is that the higher initial peak concentration with EID may be accompanied with more toxicities, especially ototoxicity. It was demonstrated that due to saturation of binding site of AGs in renal and cochlear tissues, transiently higher concentration of AGs does not cause additional nephrotoxicity or ototoxicity (9). Increasing the dose to improve the peak concentration for better killing would be accompanied with higher trough levels if the interval would not be extended over traditionally eight hours (10).…”

Section: Rational Of Single Daily Dosingmentioning

confidence: 99%

Extended-Interval Dosing of Aminoglycosides in Pediatrics: A Narrative Review

Salehifar¹,

Rafati

2015

J Pediatr Rev

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Aminoglycosides (AGs) are frequently used in pediatric settings, especially for empiric treatment of early-onset neonatal sepsis. Although AGs are used for several decades, the optimum method of administration and their dosing schemes needs more clarification. The risks of ototoxicity and nephrotoxicity, two main toxicities associated with AGs, have been contributed to the peak and trough plasma levels, respectively. One approach to decrease these potential toxicities of AGs is to administer higher doses with a prolonged interval, named extended-interval dosing (EID). Post-antibiotic effect (PAE) and concentration-dependent killing of AGs provide rational basis for the efficacy of EID. PAE refers to the extended bactericidal activity of AGs against many Gram-negative organisms after the drug was removed by metabolism. One concern is that the higher initial peak concentration with EID may be accompanied with more toxicities, especially ototoxicity. It was demonstrated that due to saturation of binding site of AGs in renal and cochlear tissues, transiently higher concentration of AGs does not cause additional nephrotoxicity or ototoxicity. Experience and clinical evidence regarding EID in pediatrics is suboptimal. In this review, we presented the rational and studies focusing on EID in pediatric setting. The overall finding of trials is that in pediatric setting, EID is a safe and effective dosing method. The risk of serum drug concentration outside the therapeutic range is lower in neonates treated with EID, leading to less need of therapeutic drug monitoring (TDM) with EID. Moreover, there are evidences supporting lower chance of bacterial resistance with EID compared with traditional dosing approach.

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Adaptation in Neonatology of the Once-Daily Concept of Aminoglycoside Administration: Evaluation of a Dosing Chart for Amikacin in an Intensive Care Unit

Cited by 67 publications

References 25 publications

Nonparametric Population Pharmacokinetic Analysis of Amikacin in Neonates, Infants, and Children

Nonparametric Population Pharmacokinetic Analysis of Amikacin in Neonates, Infants, and Children

Cerebrospinal Fluid Compartmental Pharmacokinetics of Amikacin in Neonates

Extended-Interval Dosing of Aminoglycosides in Pediatrics: A Narrative Review

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