Momograms for Extended-Dosing Intervals for Gentamicin in Neonates
Momograms for Extended-Dosing Intervals for Gentamicin in Neonates
Purpose: The development of two nomograms to predict dosing intervals for gentamicin in neonates based on one gentamicin concentration is described.
Methods: Pooled data from three retrospective studies on neonates age seven days or younger were used to create nomograms that would predict dosing intervals for gentamicin. The population volume of distribution (0.45 L/kg) and a determined half-life were used to create nomogram cutoff concentrations that could select a dosing inter-val for neonates to achieve steady-state trough concentrations of ≤0.5 or ≤1 mg/L. A dose of 4 mg/kg was used to simulate concentration-versus-time profiles for included neonates based on their individual pharmacokinetic data. Predicted concentrations from hours 6 to 22, at one-hour intervals, for each neonate were compared against the nomograms and evaluated for the number of correct interval predictions. The nomograms were considered to have failed at any time point where they indicated an interval that would not have achieved the desired trough concentration of ≤0.5 or ≤1 mg/L or if the interval chosen was longer than necessary.
Results: The 0.5- and 1-mg/L nomograms predicted correct dosing intervals for 81-92% of neonates for postinfusion hours between 15 to 21 and 86-93% for postinfusion hours of 13 and 21, respectively. Accuracy of the nomograms to predict correct dosing intervals improved as the postinfusion time before the next concentration measurement increased.
Conclusion: Using the two nomograms may help predict the correct extended-dosing intervals of gentamicin administration for neonates. Prospective evaluation and validation of the nomograms may be necessary for their wider use as a clinical tool.
Aminoglycosides are used for patient populations across the age spectrum, but there is no simple method to consistently determine dosing regimens and intervals for neonates without measuring more than one concentration. The standard approach used to adjust doses and dosing intervals involves collecting both serum or plasma peak and trough concentrations of an amino-glycoside. This approach, while reasonably accurate, relies on the collection of two concentrations that coincide closely with the administration of one or two doses and therefore can lead to errors because of the need for additional blood collections and often short windows of time in which to collect these samples. However, the practice of taking only one sample during the middle of a dosing interval could reduce costs and the potential for a sampling error.
As aminoglycosides may cause nephrotoxicity and ototoxicity associated with prolonged exposure to the drug or exposure to high concentrations of the drug, dosing regimens are often designed to attain trough concentrations below 2 mg/L in adults (sometimes even <1 mg/L) before subsequent doses are given, to minimize an accumulation of the drug in the body. To date, there is no clear consensus on the ideal trough concentration or trough range for gentamicin in neonates.
Doses of aminoglycosides in the neonate population have traditionally averaged around 2.5 mg/kg and have been given in 12-, 18-, or 24-hour intervals based on gestational or post-conception age. Large-dose extended-interval (LDEI) dosing protocols for gentamicin are frequently used in adults and have been increasingly used for neonates. Such protocols for neonates suggest administering a larger weight-based dose than previously used in an effort to attain a peak aminoglycoside concentration of ≥5-10 mg/L. This dose is given at extended intervals of 24 hours or longer so that the patient has very low drug concentrations before the next dose is administered. A higher peak concentration is advocated due to the concentration-dependent killing exhibited by aminoglycosides and the potential for treatment failures associated with an insufficient peak concentration. The long interval is considered acceptable in part because aminoglycosides also exhibit a postantibiotic effect. Although LDEI aminoglycoside protocols are increasingly used for neonates, the best approaches to monitoring the dosing and concentration outcomes have not been clearly identified for pediatric patients.
The purpose of this study was to create two nomograms for neonates age seven days or younger that practitioners could use to quickly and accurately determine a dosing interval of ≥24 hours to achieve desired trough concentrations by analyzing one measured concentration after an initial dose. In addition, the time points after the first administration of gentamicin for collecting concentrations that would yield a high percentage of accurate dosing intervals were to be determined.
Abstract and Introduction
Abstract
Purpose: The development of two nomograms to predict dosing intervals for gentamicin in neonates based on one gentamicin concentration is described.
Methods: Pooled data from three retrospective studies on neonates age seven days or younger were used to create nomograms that would predict dosing intervals for gentamicin. The population volume of distribution (0.45 L/kg) and a determined half-life were used to create nomogram cutoff concentrations that could select a dosing inter-val for neonates to achieve steady-state trough concentrations of ≤0.5 or ≤1 mg/L. A dose of 4 mg/kg was used to simulate concentration-versus-time profiles for included neonates based on their individual pharmacokinetic data. Predicted concentrations from hours 6 to 22, at one-hour intervals, for each neonate were compared against the nomograms and evaluated for the number of correct interval predictions. The nomograms were considered to have failed at any time point where they indicated an interval that would not have achieved the desired trough concentration of ≤0.5 or ≤1 mg/L or if the interval chosen was longer than necessary.
Results: The 0.5- and 1-mg/L nomograms predicted correct dosing intervals for 81-92% of neonates for postinfusion hours between 15 to 21 and 86-93% for postinfusion hours of 13 and 21, respectively. Accuracy of the nomograms to predict correct dosing intervals improved as the postinfusion time before the next concentration measurement increased.
Conclusion: Using the two nomograms may help predict the correct extended-dosing intervals of gentamicin administration for neonates. Prospective evaluation and validation of the nomograms may be necessary for their wider use as a clinical tool.
Introduction
Aminoglycosides are used for patient populations across the age spectrum, but there is no simple method to consistently determine dosing regimens and intervals for neonates without measuring more than one concentration. The standard approach used to adjust doses and dosing intervals involves collecting both serum or plasma peak and trough concentrations of an amino-glycoside. This approach, while reasonably accurate, relies on the collection of two concentrations that coincide closely with the administration of one or two doses and therefore can lead to errors because of the need for additional blood collections and often short windows of time in which to collect these samples. However, the practice of taking only one sample during the middle of a dosing interval could reduce costs and the potential for a sampling error.
As aminoglycosides may cause nephrotoxicity and ototoxicity associated with prolonged exposure to the drug or exposure to high concentrations of the drug, dosing regimens are often designed to attain trough concentrations below 2 mg/L in adults (sometimes even <1 mg/L) before subsequent doses are given, to minimize an accumulation of the drug in the body. To date, there is no clear consensus on the ideal trough concentration or trough range for gentamicin in neonates.
Doses of aminoglycosides in the neonate population have traditionally averaged around 2.5 mg/kg and have been given in 12-, 18-, or 24-hour intervals based on gestational or post-conception age. Large-dose extended-interval (LDEI) dosing protocols for gentamicin are frequently used in adults and have been increasingly used for neonates. Such protocols for neonates suggest administering a larger weight-based dose than previously used in an effort to attain a peak aminoglycoside concentration of ≥5-10 mg/L. This dose is given at extended intervals of 24 hours or longer so that the patient has very low drug concentrations before the next dose is administered. A higher peak concentration is advocated due to the concentration-dependent killing exhibited by aminoglycosides and the potential for treatment failures associated with an insufficient peak concentration. The long interval is considered acceptable in part because aminoglycosides also exhibit a postantibiotic effect. Although LDEI aminoglycoside protocols are increasingly used for neonates, the best approaches to monitoring the dosing and concentration outcomes have not been clearly identified for pediatric patients.
The purpose of this study was to create two nomograms for neonates age seven days or younger that practitioners could use to quickly and accurately determine a dosing interval of ≥24 hours to achieve desired trough concentrations by analyzing one measured concentration after an initial dose. In addition, the time points after the first administration of gentamicin for collecting concentrations that would yield a high percentage of accurate dosing intervals were to be determined.
Source...