Population Pharmacokinetics and Dosing Considerations for Gentamicin in Newborns with Suspected or Proven Sepsis Caused by Gram-Negative Bacteria

Bijleveld, Yuma A.; Heuvel, Maria E. van den; Hodiamont, Caspar J.; Mathôt, Ron A. A.; Haan, Timo R. de

doi:10.1128/aac.01304-16

Cited by 23 publications

(25 citation statements)

References 27 publications

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“…In four studies with newborns, the impact of serum creatinine concentrations on gentamicin Cl was demonstrated . In contrast, five other studies (with newborns, infants, and children) failed to demonstrate a significant association between serum creatinine concentration and gentamicin Cl . In addition, two studies tested the association between creatinine Cl (calculated by the bedside Schwartz equation) and gentamicin Cl, and both studies detected a significant correlation .…”

Section: Discussionmentioning

confidence: 92%

“…In addition, in some recent studies, the influence of postmenstrual age (PMA) on gentamicin Cl was demonstrated because it describes the maturation of GFR better than other age‐related covariates. Furthermore, in one study, the influence of postconceptional age (PCA) in combination with Apgar score at 5 minutes (Apgar5) was examined, and it was found that Cl was reduced in newborns with PCA ≤ 34 weeks and Apgar5 < 7.…”

Section: Discussionmentioning

confidence: 99%

“…For all the final PK models, the regression equations and typical values of Cl and Vd are presented in Table 2. When two-and three-compartment models were applied, 3,4,6,7,[16][17][18][19] the distribution clearance and volume of the peripheral compartments were estimated in addition to the total plasma clearance (Cl) and volume of the central compartment (Vc). The volume of the peripheral compartments and distribution clearance are not summarized in Table 2…”

Section: Clearance and Volume Of Distributionmentioning

confidence: 99%

“…TA B L E 3 Covariates studied for their influence on PK parameters of gentamicin 3,4,6,7,9,[16][17][18][19][20][21]23,25,26,39,46 Covariates with significant influence Abbreviations: (X/Y), the number of studies where they observed a significant influence of a covariate on a PK parameter versus the total number of studies, where the influence of the covariate was investigated; ALT, alanine aminotransferase; AST, aspartate aminotransferase; FFM, fat-free mass; GA, gestational age; PCA, post-conceptual age; PMA, postmenstrual age; PNA, post-natal age. a At least one of mentioned covariate.…”

Section: Ta B L E 2 (Continued)mentioning

confidence: 99%

“…17,19,20,25 In contrast, five other studies (with newborns, infants, and children) failed to demonstrate a significant association between serum creatinine concentration and gentamicin Cl. 4,7,9,18,26 In addition, two studies tested the association between creatinine Cl (calculated by the bedside Schwartz equation) and gentamicin Cl, and both studies detected a significant correlation. 3,16 Therefore, creatinine Cl seems to be a more reliable marker of renal function and more importantly related to gentamicin Cl than serum creatinine concentration.…”

Section: Parameters Of Renal Functionmentioning

confidence: 99%

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A review of population pharmacokinetic models of gentamicin in paediatric patients

2019

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What is known and objectives Gentamicin is often used for the treatment of Gram‐negative infections. Due to pharmacokinetic variability in paediatric patients, appropriate dosing of gentamicin in the paediatric population is challenging. This article reviews published population pharmacokinetic models of gentamicin in paediatric patients, identifies covariates that significantly influence gentamicin pharmacokinetics, and determines whether there is a consensus on proposed dosing for intravenous gentamicin in this population. Methods The PubMed database was searched for articles published until the end of 2017. If the articles described population pharmacokinetic models of gentamicin in the paediatric population (after intravenous administration of gentamicin), the following data were extracted: type of study, year of publication, population characteristics and number of patients, gentamicin dosing, total number of gentamicin (serum and/or plasma) concentrations, type of population modelling approach, developed model with pharmacokinetic parameters and covariates included. Results and discussion In most of the studies, one‐ or two‐compartment modelling was applied. The mean estimated gentamicin clearance for newborns, infants and the complete paediatric population was 0.048, 0.13 and 0.067 L/h/kg, respectively, and the mean predicted volume of distribution was 0.475, 0.35 and 0.33 L/kg, respectively. The values reflect differences in body composition and kidney maturation within the different paediatric populations. Gentamicin pharmacokinetics were most influenced by age, body size and renal function. What is new and conclusion Based on our review, the authors agree on a prolonged dosing interval for preterm and term newborns (up to 48 hours). However, there was no agreement on proposed dosing with respect to gestational age. In general, the proposed daily doses were lower compared to those initially applied for preterm newborns and comparable to those for term newborns. For infants and children, the dosing interval remained unchanged (24 hours), but the proposed daily doses were higher than actually applied. When differences in the paediatric population are considered and an appropriate population PK model with applicable covariates is applied, dosing can be individualized. In the future, studies of gentamicin pharmacokinetics in paediatric patients should focus on currently underestimated covariates, such as fat‐free mass, concomitantly administered drugs, body temperature and critical illness because these can change gentamicin PK considerably. Consequently, different dosing is required and TDM becomes even more important.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Clearance and Volume Of Distributionmentioning

confidence: 99%

Section: Ta B L E 2 (Continued)mentioning

confidence: 99%

Section: Parameters Of Renal Functionmentioning

confidence: 99%

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A review of population pharmacokinetic models of gentamicin in paediatric patients

2019

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Predictors of gentamicin therapy failure in neonates with sepsis

Singu,

Pieper,

Verbeeck

et al. 2024

Pharmacology Res & Perspec

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Sepsis is a common disease with high morbidity and mortality among newborns in intensive care units world‐wide. Gram‐negative bacillary bacteria are the major source of infection in neonates. Gentamicin is the most widely used aminoglycoside antibiotic in empiric therapy against early‐onset sepsis. However, therapy failure may result due to various factors. The purpose of this study was to identify predictors of gentamicin therapy failure in neonates with sepsis. This was a prospective cross‐sectional study at the Neonatal Intensive Care Unit at Windhoek Central Hospital over a period of 5 months in 2019. Neonates received intravenous gentamicin 5 mg/kg/24 h in combination with either benzylpenicillin 100 000 IU/kg/12 h or ampicillin 50 mg/kg/8 h. Logistic regression modeling was performed to determine the predictors of treatment outcomes. 36% of the 50 neonates were classified as having gentamicin treatment failure. Increasing treatment duration by 1 day resulted in odds of treatment failure increasing from 1.0 to 2.41. Similarly, one unit increase in CRP increases odds of gentamicin treatment failure by 49%. The 1 kg increase in birthweight reduces the log odds of treatment failure by 6.848, resulting in 99.9% decrease in the odds of treatment failure. One unit increase in WBC reduces odds of gentamicin treatment failure by 27%. Estimates of significant predictors of treatment failure were precise, yielding odds ratios that were within 95% confidence interval. This study identified the following as predictors of gentamicin therapy failure in neonates: prolonged duration of treatment, elevated C‐reactive protein, low birthweight, and low white blood cell count.

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Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review

et al. 2022

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Gentamicin is an aminoglycoside antibiotic with a small therapeutic window that is currently used primarily as part of shortterm empirical combination therapy. Gentamicin dosing schemes still need refinement, especially for subpopulations where pharmacokinetics can differ from pharmacokinetics in the general adult population: obese patients, critically ill patients, paediatric patients, neonates, elderly patients and patients on dialysis. This review summarizes the clinical pharmacokinetics of gentamicin in these patient populations and the consequences for optimal dosing of gentamicin for infections caused by Gram-negative bacteria, highlighting new insights from the last 10 years. In this period, several new population pharmacokinetic studies have focused on these subpopulations, providing insights into the typical values of the most relevant pharmacokinetic parameters, the variability of these parameters and possible explanations for this variability, although unexplained variability often remains high. Both dosing schemes and pharmacokinetic/pharmacodynamic (PK/PD) targets varied widely between these studies. A gentamicin starting dose of 7 mg/kg based on total body weight (or on adjusted body weight in obese patients) appears to be the optimal strategy for increasing the probability of target attainment (PTA) after the first administration for the most commonly used PK/PD targets in adults and children older than 1 month, including critically ill patients. However, evidence that increasing the PTA results in higher efficacy is lacking; no studies were identified that show a correlation between estimated or predicted PK/PD target attainment and clinical success. Although it is unclear if performing therapeutic drug monitoring (TDM) for optimization of the PTA is of clinical value, it is recommended in patients with highly variable pharmacokinetics, including patients from all subpopulations that are critically ill (such as elderly, children and neonates) and patients on intermittent haemodialysis. In addition, TDM for optimization of the dosing interval, targeting a trough concentration of at least < 2 mg/L but preferably < 0.5-1 mg/L, has proven to reduce nephrotoxicity and is therefore recommended in all patients receiving more than one dose of gentamicin. The usefulness of the daily area under the plasma concentration-time curve for predicting nephrotoxicity should be further investigated. Additionally, more research is needed on the optimal PK/PD targets for efficacy in the clinical situations in which gentamicin is currently used, that is, as monotherapy for urinary tract infections or as part of short-term combination therapy.

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Population Pharmacokinetics and Dosing Considerations for Gentamicin in Newborns with Suspected or Proven Sepsis Caused by Gram-Negative Bacteria

Cited by 23 publications

References 27 publications

A review of population pharmacokinetic models of gentamicin in paediatric patients

A review of population pharmacokinetic models of gentamicin in paediatric patients

Predictors of gentamicin therapy failure in neonates with sepsis

Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review

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