Donna M. Kraus

Pharmacokinetics and Administration Regimens of Vancomycin in Neonates, Infants and Children

SummaryThe increased use of vancomycin in neonatal and paediatric patients has prompted numerous pharmacokinetic studies and the development of many empirical administration methods. The majority of dosage guidelines use the relationship between pharmacokinetic parameters and patient variables such as chronological age, body weight, and/or measures of renal function. Currently, those dosage guidelines which are based upon postconceptional age and body weight seem to provide the best options for empirical administration in neonates and infants. In addition, serum creatinine may prove to be a useful guide to the empirical administration of vancomycin in neonates older than 7 to 14 days.Several investigators have reported the individualisation of dosage regimens based on pharmacokinetic-based administration methods. The most common techniques employed have been Sawchuk-Zaske method and Bayesian forecasting. However, only a limited number of studies have evaluated either empirical administration or individualised administration techniques in patient populations outside those of the original reports; this makes choosing between the methods difficult.Pharmacokinetic data and administration recommendations have gradually become available in special paediatric patient populations. The majority of studies have focused on patients requiring cardiopulmonary bypass surgery or with burns, cancer or central nervous system infections. However, a limited amount of information is available regarding vancomycin disposition in children older than 1 year of age with and without end-stage renal failure.The monitoring of serum vancomycin concentrations may be useful in selected neonatal and paediatric patient populations, especially where large interpatient variability occurs and administration guidelines are not clearly established. Similar to the literature on adults, the lack of conclusive evidence concerning the relationship between serum vancomycin concentrations and therapeutic responses leaves this topic open to debate.

Valproic acid pharmacokinetics in children. IV. Effects of age and antiepileptic drugs on protein binding and intrinsic clearance

Pharmacokinetic data from 48 children who were taking valproic acid were analyzed by multiple step‐wise linear regression. Children who were receiving enzyme‐inducing antiepileptic drugs (n = 27) had greater (p < 0.01) clearances, elimination rates, and dosage requirements and greater (p < 0.05) variability in pharmacokinetic values than patients receiving monotherapy. Age and polytherapy explained most of the interpatient variability in total (r2 = 0.80; p < 0.001) and intrinsic (r2 = 0.77; p < 0.001) clearances and the elimination rate (r2 = 0.61; p < 0.002). Free fraction variability was related to valproate concentration and phenobarbital (r2 = 0.47; p < 0.001). Distribution volume variance was associated with free fraction (r2 = 0.48; p < 0.001). The effect of age and polytherapy on valproate clearance is primarily attributable to changes in metabolism rather than in protein binding. Valproic acid dosage requirements are greater and more variable for children who are receiving other enzyme‐inducing antiepileptic drugs.

Pharmacokinetics of Intravaginal Metronidazole Gel

The pharmacokinetics of a single 500 mg oral dose of metronidazole and 5 g of 0.75% metronidazole intravaginal gel (37.5 mg metronidazole) were compared in 12 adult volunteers in a randomized crossover manner. Serial serum samples were collected over a 48‐hour period and analyzed for metronidazole and hydroxymetronidazole. Metronidazole serum concentrations after intravaginal administration were only 2% of concentrations seen with the standard 500‐mg oral dose. The dose‐adjusted maximum serum concentration (898 ± 121 ng/mL vs. 237 ± 69 ng/mL) and area under the serum concentration—time curve (9362 ± 2873 ng * hr/mL vs. 4977 ± 2671 ng * hr/mL) were significantly greater for the oral versus intravaginal dose of metronidazole. The time to reach maximum concentration (1.4 ± 0.6 hr vs. 8.4 ± 2.2 hr) was significantly shorter for the oral compared with the intravaginal dose. The mean bioavailability for the intravaginal gel was 56%. Our results show that the 0.75% gel formulation may offer the advantage of fewer systemic adverse effects compared with other formulations for the treatment of bacterial vaginosis.

Bayesian forecasting of serum vancomycin concentrations in neonates and infants

A dynamic pharmacokinetic model for i.v. vancomycin administration was developed and tested in 47 neonates and infants. Twenty-nine patients (Group 1), having two or more concentrations, were used to estimate population parameters by nonlinear least-squares analysis. Multiple stepwise. linear regression techniques showed that estimated creatinine clearance, Clcr, and postnatal age were significant demographic factors related to vancomycin clearance (CL.) No strong associations were found for the apparent volume of distribution. A one-compartment model was constructed using the associations of CLcr and postnatal age with vancomycin CL. Eighteen patients (Group 2), receiving 35 courses of vancomycin therapy, with both initial and subsequent sets of peak and trough concentrations, were used to test the predictive performance of the model with and without the use of Bayesian forecasting. Using only population-based parameters, the respective mean error (ME) (bias) and mean absolute error (MAE) (precision) for predicting subsequent peak concentrations were – 1.20 and 3.89 mg/L and for trough concentrations, 0.83 and 2.23 mg/L, respectively. For the Bayesian method, these values were, respectively, 0.45 and 4.13 mg/L for peak concentrations and 1.55 and 2.40 mg/L for trough concentrations. When predicted concentrations occurred within 30 days of feedback concentrations, the Bayesian method tended to be slightly less biased and more precise than the population-based parameters. The opposite was true >30 days of the initial set of feedback concentrations. The use of population-specific pharmacokinetic parameters and Bayesian forecasting should allow accurate dosage regimen design as well as minimize the need for monitoring serum vancomycin concentrations in neonates and young infants.

Efficacy and Tolerability of Extended-Interval Aminoglycoside Administration in Pediatric Patients

Aminoglycosides are commonly used to treat serious Gram-negative infections in pediatric patients. An effort to improve the efficacy and tolerability of this antibiotic class has led to evaluation of extended-interval aminoglycoside administration (EIAA). EIAA is designed to achieve higher peak plasma aminoglycoside concentrations, with relatively undetectable trough concentrations, when compared with conventional aminoglycoside administration (CAA), and is therefore expected to be markedly effective and to reduce drug accumulation and prevent nephrotoxicity and ototoxicity.Clinical trials evaluating EIAA in neonates included patients with suspected Gram-negative infections requiring short courses of aminoglycoside therapy. Consequently, comparative efficacy of EIAA versus CAA could not be assessed. In addition, ototoxicity was often not assessed, and nephrotoxicity was virtually undetectable. Similarly, trials evaluating EIAA versus CAA in infants and children have not demonstrated a difference in outcomes.The use of EIAA in children with febrile neutropenia has been evaluated primarily with amikacin. The incidences of nephrotoxicity and ototoxicity were low, and were similar between EIAA and CAA. No deaths were reported in any of these studies; however, this could be related to the inclusion of patients with undocumented bacteremia. Further investigation of EIAA is necessary in patients with documented bacteremia, since plasma aminoglycoside concentrations were undetectable for most of the dosage interval in children with febrile neutropenia who were treated once daily.Overall, clinical studies suggest that EIAA has similar efficacy to, and no higher risk of toxicity than, CAA in neonates, infants, and children. A few evaluations have also demonstrated that EIAA is cost-effective in neonates and in children with febrile neutropenia. Future studies evaluating the efficacy and tolerability of EIAA in pediatric patients with documented systemic infections should be prospective, randomized, controlled trials with sample sizes sufficient to detect differences between administration methods. Further evaluations should also address the optimal dosage and cost-effectiveness of EIAA in infants and children.

Effectiveness and Infant Acceptance of the Rx Medibottle versus the Oral Syringe

Study Objective. To compare the effectiveness and infant acceptance of drug delivery of the Rx medibottle with the standard oral syringe.

Prediction of gentamicin concentrations in neonates and infants using a Bayesian pharmacokinetic model.

This study retrospectively characterized population-based pharmacokinetic parameters for gentamicin in neonates and young infants, and evaluated the predictive performance of these parameters in a Bayesian forecasting program. Population parameter estimates were determined from the serum concentration-time data of 19 neonates and infants using a one-compartment open infusion model and nonlinear least-squares regression analysis. Univariate and multiple stepwise linear regression analyses were used to determine significant relationships between demographic characteristics and gentamicin pharmacokinetic parameters. Creatinine clearance and postnatal age were the most significant predictors of weight-standardized gentamicin clearance (model r2 = 0.86). The relationships between patient characteristics and population-based parameters were incorporated into the one-compartment Bayesian forecasting model. A second group of 17 neonates and infants receiving 35 courses of gentamicin therapy were used to evaluate the predictive performance of the population-based parameters and a Bayesian forecasting model. The population parameters provided accurate prediction of steady state gentamicin concentrations throughout multiple courses of therapy within the same patient. Bayesian forecasting further minimized the mean prediction error (bias) once a set of steady state peak and trough serum gentamicin concentrations became available (peak concentrations: -0.062 vs. -0.273 mg/l; trough concentrations: -0.006 vs. -0.161 mg/l). The mean absolute error (accuracy) was similar for the two sets of parameters. The observed accuracy of both the population parameters and Bayesian forecasting suggests that monitoring of serum gentamicin concentrations can be kept to minimum in neonates and infants.

Bayesian forecasting of gentamicin pharmacokinetics in pediatric intensive care unit patients

The predictive performance of a one compartment Bayesian forecasting program was evaluated in pediatric intensive care unit patients with normal renal function. Gentamicin pharmacokinetic parameters were determined in 44 PICU patients (0.8 month to 14 years old) from all available serum concentrations and doses by nonlinear least squares regression. Population pharmacokinetic parameter estimates were established from 27 of the PICU patients. Mean prediction error (ME) and mean absolute error (MAE) for 2 future sets of peak and trough gentamicin serum concentrations with the use of the population parameter estimates with and without feedback were evaluated in the remaining 17 patients. Mean clearance (+/- SD) and volume of distribution for all 44 patients were 0.123 +/- 0.041 liter/hour/kg and 0.424 +/- 0.116 liter/kg, respectively. Bayesian forecasting of the second set of peak and trough concentrations with feedback from the first set of peak and trough concentrations resulted in smaller bias (peak ME, -0.15 mg/liter; trough ME, 0.13 mg/liter) and better accuracy (peak MAE, 0.91 mg/liter; trough MAE, 0.28 mg/liter) compared with the population parameter estimates alone (peak ME, 0.4 mg/liter; trough ME, 0.28 mg/liter; peak MAE, 1.21 mg/liter; trough MAE, 0.57 mg/liter). This study indicates that gentamicin volume of distribution in PICU patients is larger than non-PICU literature values. The Bayesian program, with specific population parameter estimates for PICU patients, provides accurate initial and subsequent predictions of gentamicin serum concentrations.

Morphine: An Effective Abortive Therapy for Pediatric Paroxysmal Sympathetic Hyperactivity After Hypoxic Brain Injury

Paroxysmal sympathetic hyperactivity (PSH) is a life-threatening condition characterized by hyperadrenergic activity and autonomic dysfunction. Also termed autonomic storms, PSH can occur after a variety of cerebral insults, most commonly traumatic brain injury. Limited pediatric literature is available, especially in patients with brain injury from hypoxia. No consensus exists for the terminology, diagnostic criteria, or treatment algorithm for PSH. Thus, the optimal management, including medication selection and dosing, remains unclear. We present the detailed treatment of a 9-year-old, African American male with hypoxic brain injury after pulseless arrest following status asthmaticus, who subsequently developed PSH. The patient began to experience episodes of tachycardia, hypertension, tachypnea, diaphoresis, rigidity, and dystonic posturing on hospital day 5. After ruling out other potential causes, a diagnosis of PSH was made. Episodes of PSH failed to respond to lorazepam or labetalol but were aborted successfully with morphine. Management of PSH after hypoxic brain injury required medications for acute treatment as well as for prevention of PSH. Morphine was found to be highly effective and safe for aborting the autonomic crises. Other agents more commonly described in the literature did not result in an adequate response and were associated with significant adverse effects. A combination of clonazepam, baclofen, and either propranolol or clonidine aided in reducing the frequency of episodes of PSH. We suggest using morphine for aborting severe episodes of PSH that do not respond to antihypertensive agents or benzodiazepines.

Pharmacokinetic evaluation of two theophylline dosing methods for infants.

Theophylline is often used in infants, yet few studies have evaluated the serum concentrations achieved with currently recommended dosing guidelines. Two theophylline dosing regimens, a postnatal age (PNA) equation and the Federal Drug Administration (FDA) dosing guidelines, were retrospectively evaluated in a group of infants, postconceptional age (PCA) 31–96 weeks, with known theophylline clearances. Large variations in theophylline concentrations were observed for both dosing regimens. Mean ± SD projected steady-state theophylline serum concentrations, Css, were 17.7 ± 7.6 μg/ml with the PNA equation (n = 40) and 5.6 ± 2.9 μg/ml with the FDA guidelines (n = 52). Over one-third of Css with the PNA equation were > 20 μg/ml. Using the FDA guidelines, 40% of Css were <5 μg/ml. The majority of infants <40 weeks PCA attained projected Css >20 μg/ml (21.7 ± 5.1 μg/ml) with the PNA equation, but <5 μg/ml (4.3 ± 1.4 μg/ml) with FDA guidelines. An age-related bias was also observed for each dosing method. For the PNA equation, projected Css were significantly higher in infants <40 weeks versus ≥40 weeks PCA (21.7 ± 5.1 versus 15.8 ± 7.9 μg/ml, p < 0.01). For FDA guidelines, projected Css were significantly lower in infants <40 weeks PCA versus older infants (4.3 ±1.4 versus 8.5 ± 4.3 μg/ml, p < 0.001). Clinical application of currently accepted theophylline dosing guidelines for infants results in a high frequency of Css, which are potentially toxic or sub therapeutic. The wide variability and age-related bias may be attributed to using PNA as the primary basis for theophylline dosing. Since recent studies suggest PCA as the major determinant of theophylline clearance in infants, new theophylline dosing guidelines, which take into account gestational as well as PNA, need to be developed and evaluated.