Gentamicin dosing and pharmacokinetics in low birth weight infants.

Nakae, Shingi; Yamada, Masaaki; Ito, Takeshi; Chiba, Yuji; Sasaki, Etsuko; Sakamoto, Masahiro; Tada, Kazuhiro; Yamada, Takeo; Mori, Shigeru

doi:10.1620/tjem.155.213

Cited by 7 publications

(3 citation statements)

References 27 publications

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“…In total, 38 and 44 publications that included reported CL values were identified for gentamicin and midazolam, respectively. These papers reported a total of 66 and 57 CL values for gentamicin and midazolam, respectively.…”

Section: Resultsmentioning

confidence: 99%

Scaling clearance in paediatric pharmacokinetics: All models are wrong, which are useful?

Germovsek

Barker

Sharland

et al. 2016

Brit J Clinical Pharma

113

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Linked ArticlesThis article is commented on in the editorial by Holford NHG and Anderson BJ. Why standards are useful for predicting doses. Br J Clin Pharmacol 2017; 83: 685–7. doi: 10.1111/bcp.13230 AimWhen different models for weight and age are used in paediatric pharmacokinetic studies it is difficult to compare parameters between studies or perform model‐based meta‐analyses. This study aimed to compare published models with the proposed standard model (allometric weight0.75 and sigmoidal maturation function).MethodsA systematic literature search was undertaken to identify published clearance (CL) reports for gentamicin and midazolam and all published models for scaling clearance in children. Each model was fitted to the CL values for gentamicin and midazolam, and the results compared with the standard model (allometric weight exponent of 0.75, along with a sigmoidal maturation function estimating the time in weeks of postmenstrual age to reach half the mature value and a shape parameter). For comparison, we also looked at allometric size models with no age effect, the influence of estimating the allometric exponent in the standard model and, for gentamicin, using a fixed allometric exponent of 0.632 as per a study on glomerular filtration rate maturation. Akaike information criteria (AIC) and visual predictive checks were used for evaluation.ResultsNo model gave an improved AIC in all age groups, but one model for gentamicin and three models for midazolam gave slightly improved global AIC fits albeit using more parameters: AIC drop (number of parameters), –4.1 (5), –9.2 (4), –10.8 (5) and –10.1 (5), respectively. The 95% confidence interval of estimated CL for all top performing models overlapped.ConclusionNo evidence to reject the standard model was found; given the benefits of standardised parameterisation, its use should therefore be recommended.

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Section: Resultsmentioning

confidence: 99%

Scaling clearance in paediatric pharmacokinetics: All models are wrong, which are useful?

Germovsek

Barker

Sharland

et al. 2016

Brit J Clinical Pharma

113

View full text Add to dashboard Cite

show abstract

“…We also searched the reference lists in identified papers. The authors of the publications that met the inclusion criteria (n ϭ 8) (11,15,21,22,(28)(29)(30)(31) were then invited to contribute their data.…”

Section: Methodsmentioning

confidence: 99%

“…We received no response from four authors (11,(28)(29)(30), and, although an initial response was received from two authors (22,31), no data were actually shared. Additionally, we obtained some previously unpublished data taken during a PK study of ampicillin and penicillin (32).…”

Section: Patientsmentioning

confidence: 99%

Development and Evaluation of a Gentamicin Pharmacokinetic Model That Facilitates Opportunistic Gentamicin Therapeutic Drug Monitoring in Neonates and Infants

Germovsek

Kent

Metsvaht

et al. 2016

Antimicrob Agents Chemother

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T he aminoglycoside antibiotic gentamicin is the most commonly used antimicrobial in neonatal units (1, 2) and is effective against Gram-negative bacteria. Gentamicin use is limited by its narrow therapeutic index and risk of toxicity, specifically, nephro-and ototoxicity (3). It is not metabolized in the liver (4) and is almost entirely eliminated by the kidneys; clearance therefore depends on renal function. During the first 2 weeks of life, renal and intrarenal blood flow increase rapidly, causing a steep rise in the glomerular filtration rate (GFR) (5, 6).Therapeutic drug monitoring (TDM) is required to ensure maximal efficacy and, in particular, minimal toxicity, particularly in the neonatal population, where the variability in pharmacokinetic (PK) parameters is large. Dose individualization approaches focus on toxicity (7, 8) and include single-level methods and nomograms (9, 10), area under the curve (AUC) methods (11), and Bayesian methods (12). The use of nomograms is limited as they cannot readily incorporate covariates affecting PK parameters. AUC methods use a simplified 1-compartment PK model and require at least two gentamicin measurements, which is not appropriate in neonates with limited blood volumes. These drawbacks make Bayesian approaches the most attractive for newborn infants.Deriving a Bayesian prior for TDM requires a nonlinear mixed-effect PK model, and several such studies of neonatal gentamicin were previously published (13-24). However, those studies were limited by their heterogeneity and use of sparse data (often identifying only a 1-compartment model, whereas gentamicin follows multicompartment kinetics [25,26]) and failed to account for age-related differences in creatinine levels during the immediate newborn period. Although gentamicin is not a new drug, its dosing and monitoring are still current issues as identified in the United Kingdom National Patient Safety alert (http://www.nrls .npsa.nhs.uk/alerts/?entryid45ϭ66271) and in a recent publication by Valitalo et al. (27), who used simulations to define dosing guidelines.We aimed to investigate whether opportunistic sampling can predict trough gentamicin concentrations so that standard TDM can be performed using a blood sample taken for other purposes Citation Germovsek E, Kent A, Metsvaht T, Lutsar I, Klein N, Turner MA, Sharland M, Nielsen EI, Heath PT, Standing JF, the neoGent Collaboration. 2016. Development and evaluation of a gentamicin pharmacokinetic model that facilitates opportunistic gentamicin therapeutic drug monitoring in neonates and infants.

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Pharmacokinetics and Pharmacodynamics of Antibacterials, Antifungals, and Antivirals Used Most Frequently in Neonates and Infants

et al. 2014

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Antimicrobials and antivirals are widely used in young infants and neonates. These patients have historically been largely excluded from clinical trials and, as a consequence, the pharmacokinetics and pharmacodynamics of commonly used antibacterials, antifungals, and antivirals are incompletely understood in this population. This review summarizes the current literature specific to neonates and infants regarding pharmacokinetic parameters and changes in neonatal development that affect antimicrobial and antiviral pharmacodynamics. Specific drug classes addressed include aminoglycosides, aminopenicillins, cephalosporins, glycopeptides, azole antifungals, echinocandins, polyenes, and guanosine analogs. Within each drug class, the pharmacodynamics, pharmacokinetics, and clinical implications and future directions for prototypical agents are discussed. β-Lactam antibacterial activity is maximized when the plasma concentration exceeds the minimum inhibitory concentration for a prolonged period, suggesting that more frequent dosing may optimize β-lactam therapy. Aminoglycosides are typically administered at longer intervals with larger doses in order to maximize exposure (i.e., area under the plasma concentration-time curve) with gestational age and weight strongly influencing the pharmacokinetic profile. Nonetheless, safety concerns necessitate therapeutic drug monitoring across the entire neonatal and young infant spectrum. Vancomycin, representing the glycopeptide class of antibacterials, has a long history of clinical utility, yet there is still uncertainty about the optimal pharmacodynamic index in neonates and young infants. The high degree of pharmacokinetic variability in this population makes therapeutic drug monitoring essential to ensure adequate therapeutic exposure. Among neonates treated with the triazole agent fluconazole, it has been speculated that loading doses may improve pharmacodynamic target attainment rates. The use of voriconazole necessitates therapeutic drug monitoring and dose adjustments for patients with hepatic dysfunction. Neonates treated with lipid-based formulations of the polyene amphotericin B may be at an increased risk of death, such that alternative antifungal agents should be considered for neonates with invasive fungal infections. Alternative antifungal agents such as micafungin and caspofungin also exhibit unique pharmacokinetic considerations in this population. Neonates rapidly eliminate micafungin and require nearly three times the normal adult dose to achieve comparable levels of systemic exposure. Conversely, peak caspofungin concentrations have been reported to be similar among neonates and adults. However, both of these drugs feature favorable safety profiles. Recent studies with acyclovir have suggested that current dosing regimens may not result in therapeutic central nervous system concentrations and more frequent dosing may be required for neonates at later postmenstrual ages. Though ganciclovir and valganciclovir demonstrate excellent activity against cytomegaloviru...

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Gentamicin dosing and pharmacokinetics in low birth weight infants.

Cited by 7 publications

References 27 publications

Scaling clearance in paediatric pharmacokinetics: All models are wrong, which are useful?

Scaling clearance in paediatric pharmacokinetics: All models are wrong, which are useful?

Development and Evaluation of a Gentamicin Pharmacokinetic Model That Facilitates Opportunistic Gentamicin Therapeutic Drug Monitoring in Neonates and Infants

Pharmacokinetics and Pharmacodynamics of Antibacterials, Antifungals, and Antivirals Used Most Frequently in Neonates and Infants

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