Extended-Interval Dosing of Gentamicin Aiming for a Drug-Free Period in Neonates: A Prospective Cohort Study
Erik M van Maarseveen1, Arwen Sprij, Daniel J Touw
1*Department of Clinical Pharmacy, University Medical Center Utrecht; †Department of Pediatrics, Haga Teaching Hospital, The Hague; and ‡Department of Hospital and Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, the Netherlands.
Insights
Extended interval gentamicin dosing achieved high target concentrations in neonatal sepsis patients. Lower gestational age and body weight predicted suboptimal levels, but the area under the curve remained unaffected, warranting further study.
Area of Science:
- Neonatal pharmacology
- Pediatric infectious diseases
- Clinical pharmacokinetics
Background:
- Gentamicin dosing in adults targets high peak concentrations (Cmax) and drug-free periods to ensure efficacy and prevent toxicity.
- Neonatal sepsis regimens often use lower peaks and higher troughs, increasing toxicity risk.
- This study aimed to evaluate a practical gentamicin dosing regimen for achieving drug-free periods in newborns.
Purpose of the Study:
- To assess the target attainment of a simple, extended-interval gentamicin dosing regimen in neonates.
- To identify factors predicting failure to achieve target gentamicin concentrations (Cmax >8 mg·L, Cmin <0.5 mg·L).
Main Methods:
- Prospective observational study of neonates with suspected early-onset sepsis receiving gentamicin 5 mg·kg every 36 hours.
- Dosing guided by therapeutic drug monitoring targeting Cmax >8 mg·L and Cmin <0.5 mg·L.
- Analysis of correlations between body weight (BW), gestational age (GA), and pharmacokinetic parameters, including logistic regression for target attainment failure predictors.
Main Results:
- 90.4% of 184 neonates achieved target Cmax and Cmin values.
- Significant correlations were found between GA and BW with both Cmax and Cmin.
- Gestational age (GA) was the sole independent predictor of underexposure during multivariate analysis.
Conclusions:
- Extended interval gentamicin dosing demonstrates high target attainment rates in a level II neonatal unit.
- Low GA and BW are confirmed predictors of suboptimal gentamicin peak and trough levels.
- The area under the curve (AUC) was not significantly affected by GA or BW, suggesting potential for AUC-guided dosing exploration in neonates.
Background:
Current gentamicin dosing algorithms in adult populations target a high peak concentration (Cmax) assuring efficacy and a drug-free period (concentration <0.5 mg/L) preventing toxicity. In contrast, gentamicin-based regimens in neonatal sepsis often aim for lower peak levels and trough concentrations of 0.5-2.0 mg·L. The latter concentrations are associated with an increased risk of aminoglycoside-related toxicity. Therefore, the primary aim of this study was to assess the target attainment of a simple and practical dosing regimen designed to attain drug-free periods in newborns.
Methods:
The study was of prospective observational design. Neonates admitted to a level II neonatal nursery diagnosed with (suspected) early-onset sepsis and commencing intravenous gentamicin therapy of 5 mg·kg every 36 hours were eligible for inclusion. Gentamicin dosing was guided by drug concentration monitoring targeting Cmax values >8 mg·L and estimated trough concentrations <0.5 mg·L. Relationships between body weight (BW), gestational age (GA), postnatal age, and pharmacokinetic parameters were analyzed using the Pearson correlation test, and univariate and multivariate logistic regression analyses were performed to identify covariates predictive of target attainment failure.
Results:
A total of 184 patients were included. 90.4% of patients (n = 166) achieved a Cmax value >8 mg·L with a Cmin value <0.5 mg·L. Subsequently, significant correlations were found between GA and Cmax (r = 0.58, P < 0.001) between GA and Cmin (r = 0.44, P < 0.001), between BW and Cmax (r = 0.50, P < 0.001), and between BW and Cmin (r = 0.42, P < 0.001). Correlations between area under the curve (AUC) and GA (r = 0.064, P = 0.4), and between AUC and BW (r = 0.028, P = 0.7) were not significant. During multivariate analysis, only GA (P < 0.001) was retained as an independent predictor of underexposure.
Conclusions:
Extended interval dosing of gentamicin resulted in high target attainment rates in neonates admitted to a level II unit. In line with previous reports, low GA and BW were predictive of subtherapeutic peak and toxic trough levels. The AUC, however, was unaffected by the interpatient variation in GA and BW. Since AUC-guided dosing is gaining interest worldwide, the latter finding deserves further exploration in other neonatal cohorts.
Related Concept Videos
01:15Determination of Multiple Dosing Parameters: Steady-State, Minimum and Maximum Concentrations
01:24Drug Accumulation During Multiple Dosing: Intermittent IV Infusions
01:26Pharmacokinetics in Pediatric Patients: Drug Excretion
01:20Estimation of k and VD of Aminoglycosides
01:29Drug Dosing: Infants and Children
01:19Dosage Interval and Administration Route: Determination Methods