Amikacin pharmacokinetics and suggested dosage modifications for the preterm infant

Kenyon, Cynthia F.; Knoppert, David; Lee, Shoo Kim; Vandenberghe, Hilde; Chance, G. W.

doi:10.1128/aac.34.2.265

Cited by 46 publications

(48 citation statements)

References 9 publications

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“…To ensure the efficacy of amikacin treatment, we aimed to achieve a peak concentration/MIC ratio of at least 8 for MICs of 1 to 8 mg/liter, with minimum concentrations of less than 10 mg/liter, as recommended for adults and children (8,23,37,48). With a dose of 7.5 mg/kg given every 12 h in neonates and children and with a loading dose of 10 mg/kg in neonates, only 50% of patients had adequate plasma amikacin concentrations for MICs of 2 mg/liter.…”

Section: Discussionmentioning

confidence: 99%

“…For neonates, a loading dose of 10 mg/kg followed by a maintenance dose of 7.5 mg/kg every 12 h administered intravenously over 1 to 2 h has been recommended by the manufacturer, as V of amikacin is higher in neonates than in infants and children (26,45). 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).…”

Section: Methodsmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

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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“…However, in these studies, pre-and full-term neonates were included (10,18,30). There were as well conflicting data if postmenstrual (sum of gestational and neonatal) age was a good predictor of aminoglycoside CL (12,17,23,31). Considering the fact that the major changes in blood flow occur during the transition from the intrauterine to the extrauterine environment, it seems rational to observe gestational and neonatal age as independent factors since their influences on amikacin CL are different due to distinct causes (32,33).…”

Section: Discussionmentioning

confidence: 99%

“…High interindividual variability in amikacin pharmacokinetics was previously observed, and it was described in detail in pre-term neonates (9,11,22). In pre-term neonates, weight and gestational and/or neonatal age significantly contributed to amikacin pharmacokinetic variability (9,10,23). However, in fullterm patients, there were only few studies on amikacin pharmacokinetics (8,21).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Variability of Amikacin After Once-Daily and Twice-Daily Dosing Regimen in Full-Term Neonates

Vučićević¹,

Rakonjac

Miljković³

et al. 2014

J Pharmacol Sci

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Abstract. The purpose of the study was to compare peak (C peak ) and trough (C trough ) amikacin levels after twice-daily (TD) or once-daily dosing (OD) in full-term neonates. Additionally, the study aimed to address amikacin pharmacokinetics and its variability. Data included 31 patients born on term. Amikacin daily dose was 15 or 20 mg/kg depending on the neonate's age. Patients randomly received amikacin every 12 or 24 h. In all patients corresponding C peak and C trough were taken. Volume of distribution (Vd), clearance (CL) and half-life (t 1/2 ) were calculated. Mean C peak of 21.79 mg/ml in the TD group was statistically different from C peak of 36.39 mg/ml in the OD group. Average C trough in TD (5.67 mg/ml) was statistically different from the corresponding 3.99 mg/ml in the OD group. Mean amikacin Vd, CL, and t 1/2 were 0.78 ± 0.38 l/kg, 86.99 ± 48.22 ml/h•kg, and 6.81 ± 2.51 h, respectively. High interindividual pharmacokinetic variability was observed. Further analysis showed that neonatal age contributed to the pharmacokinetic parameters' values. Statistically significant difference in CL and t 1/2 was observed between patients age ≤ 2 and > 2 days on therapy initiation. As expected, amikacin given OD achieved higher C peak and lower C trough than TD. Based on the results, observed variability in amikacin pharmacokinetics was possibly due to the renal maturation process.

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“…1 They are almost exclusively eliminated renally, with a highly variable elimination half-life that is prolonged in neonates compared with children and adults. 2,3 In combination with ampicillin, an aminoglycoside is often initiated as empiric antibiotic therapy for neonatal earlyonset sepsis, or sepsis occurring within the first 3 days of life. In addition, aminoglycosides are also often initiated with vancomycin in neonatal late-onset sepsis, or sepsis occurring after the first 3 days of life.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Amikacin Pharmacokinetics in Neonates Following Implementation of a New Dosage Protocol

Hughes¹,

Johnson²,

Anderson³

et al. 2017

The Journal of Pediatric Pharmacology and Therapeutics

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OBJECTIVESThe primary aim was to compare attainment of goal serum amikacin concentrations using two dosage regimens in patients admitted to a neonatal intensive care unit. Secondary objectives included comparison of percentages of supratherapeutic trough concentrations, and subtherapeutic and supratherapeutic peak concentrations. METHODSThis was an Institutional Review Board-approved, retrospective study of neonates receiving amikacin during January-December 2013 (group 1) and January-December 2014 (group 2). Group 1 received amikacin dosage consistent with published recommendations, whereas group 2 was dosed using a modified protocol that was based on postmenstrual and postnatal age. Goal serum amikacin peak concentration was defined as 20 to 35 mg/L; hence, subtherapeutic and supratherapeutic peak concentrations were defined as <20 mg/L and >35 mg/L, respectively. Supratherapeutic trough concentrations were >8 mg/L. Between-group analysis was performed using Wilcoxon-Mann-Whitney test, Student t-test or χ 2 , or Fisher exact analysis as appropriate with a p value <0.05. RESULTSA total of 278 neonates were included (group 1: n = 144; group 2: n = 134). Most patients were male (60%) and were admitted for prematurity or respiratory distress (77%). The median gestational age in group 1 was 34.4 weeks (range, 30.0-37.9 weeks) versus group 2 at 36.9 weeks (range, 31.4-38.9 weeks), whereas the postnatal age was similar between both groups at 4 days. There was a significant increase in attaining goal peak amikacin concentrations between groups 1 and 2, 34% versus 84%, p < 0.001, and decrease in supratherapeutic peak concentrations, 65% versus 12%, p < 0.001. There was no significant difference in subtherapeutic peak or supratherapeutic trough concentrations.CONCLUSIONS A modified neonatal amikacin dosage protocol resulted in increased peak amikacin serum concentration compared with published dosage recommendations. Future research should focus on determination of the optimal dosage regimen in neonates.

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Amikacin pharmacokinetics and suggested dosage modifications for the preterm infant

Cited by 46 publications

References 9 publications

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

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

Pharmacokinetic Variability of Amikacin After Once-Daily and Twice-Daily Dosing Regimen in Full-Term Neonates

Comparison of Amikacin Pharmacokinetics in Neonates Following Implementation of a New Dosage Protocol

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