Population Pharmacokinetics of Vancomycin in Premature Malaysian Neonates: Identification of Predictors for Dosing Determination

Abstract

The present study determined the pharmacokinetic profile of vancomycin in premature Malaysian infants. A one-compartment infusion model with first-order elimination was fitted to serum vancomycin concentration data (n ‫؍‬ 835 points) obtained retrospectively from the drug monitoring records of 116 premature newborn infants. Vancomycin concentrations were estimated by a fluorescence polarization immunoassay. Population and individual estimates of clearance and distribution volume and the factors which affected the variability observed for the values of these parameters were obtained using a population pharmacokinetic modeling approach. The predictive performance of the population model was evaluated by visual inspections of diagnostic plots and nonparametric bootstrapping with replacement. Dosing guidelines targeting a value of >400 for the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC 24 /MIC ratio) were explored using Monte Carlo simulation. Body size (weight), postmenstrual age, and smallfor-gestational-age status are important factors explaining the between-subject variability of vancomycin pharmacokinetic parameter values for premature neonates. The typical population parameter estimates of clearance and distribution volume for a 1-kg premature appropriate-for-gestational-age neonate with a postmenstrual age of 30 weeks were 0.0426 liters/h and 0.523 liters, respectively. There was a 20% reduction in clearance for small-for-gestational-age infants compared to the level for the appropriate-for-gestational-age control. Dosage regimens based on a priori target response values were formulated. In conclusion, the pharmacokinetic parameter values for vancomycin in premature Malaysian neonates were estimated. Improved dosage regimens based on a priori target response values were formulated by incorporating body size, postmenstrual age, and small-for-gestational-age status, using Monte Carlo simulations with the modelestimated pharmacokinetic parameter values.Bacterial sepsis is a major cause of neonatal complications, prolonged hospital stay, and death in premature newborns, especially those in developing countries. Sepsis-related mortality and morbidity rates were even higher in extremely preterm neonates and intrauterine-growth-restricted infants because of their innate immunological immaturity (36). Because coagulase-negative staphylococcus (CoNS) is a common pathogen for late-onset (72-h-postbirth) septicemia, and because methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen (10), vancomycin continues to be widely prescribed in neonatal intensive care units.Kidney and vestibular/cochlear damage is a concern associated with vancomycin use. Very recently, it was shown that vancomycin trough concentrations were correlated with nephrotoxicity in hospitalized adult patients (27). Nonetheless, vancomycin-associated ototoxicity and nephrotoxicity among neonates are thought to be less frequent than those in adults (11), although more evidence-based i...

Reposicionando la cloxacilina como antibioticoterapia empírica inicial de la sepsis tardía neonatal

“…En el caso de los RNPret, la vida media de vancomicina es prolongada y variable e inversamente proporcional al peso, es así como, en el primer mes de vida en el neonato bajo 1.000 g llega aproximadamente a 10 h, lo que significa que el tiempo para alcanzar el estado de equilibrio podría ser de hasta 50 h 10,12 . En el mayor estudio de FK poblacional efectuado en 374 RN y niños bajo 2 años de edad, en el cual se midieron las concentraciones de vancomicina, se pudo establecer que la creatininemia estuvo fuertemente relacionada con la eliminación de vancomicina, siendo la edad cronológica y la prematuridad (< 28 semanas) predictores menos importantes que el clearance renal de vancomicina 22 . Sin embargo, aun cuando las variables más importantes (edad, peso y clearence de creatinina) son consideradas en los RN, la variabilidad inter-individual aún es elevada, siendo comparativamente entre los RNPret y RNT de 23% para el clearence de vancomicina y de 47% para el volumen de distribución 23 .…”

Determination of Vancomycin Pharmacokinetics in Neonates To Develop Practical Initial Dosing Recommendations

“…There is no evidence of correlation between serum vancomycin concentrations and clinical cure, microbiological cure, or nephrotoxicity in neonates (6)(7)(8). However, vancomycin trough concentrations are routinely monitored in neonates, and controversy exists with regard to the optimal target vancomycin trough levels, resulting in numerous different target trough concentration ranges being recommended in the literature for these patients (e.g., 5 to 10 mg/ liter, 5 to 12 mg/liter, 5 to 15 mg/liter, 5 to 20 mg/liter, or 12 to 15 mg/liter) (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In addition, the majority of the previous studies describing vancomycin pharmacokinetics in neonates have included small, heterogeneous groups with differing demographics, clinical conditions, lengths of infusion period, serum sampling times, and pharmacokinetic models (1-compartment versus 2-compartment models) (8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

“…However, vancomycin trough concentrations are routinely monitored in neonates, and controversy exists with regard to the optimal target vancomycin trough levels, resulting in numerous different target trough concentration ranges being recommended in the literature for these patients (e.g., 5 to 10 mg/ liter, 5 to 12 mg/liter, 5 to 15 mg/liter, 5 to 20 mg/liter, or 12 to 15 mg/liter) (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In addition, the majority of the previous studies describing vancomycin pharmacokinetics in neonates have included small, heterogeneous groups with differing demographics, clinical conditions, lengths of infusion period, serum sampling times, and pharmacokinetic models (1-compartment versus 2-compartment models) (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). As a result, the published data (8)(9)(10)(11)(12)(13)(14)(15)(16)(17) provide conflicting reports of significant covariates of clearance (CL) and do not provide practical dosing recommendations for the target trough concentrations used in practice today.…”

“…In addition, the majority of the previous studies describing vancomycin pharmacokinetics in neonates have included small, heterogeneous groups with differing demographics, clinical conditions, lengths of infusion period, serum sampling times, and pharmacokinetic models (1-compartment versus 2-compartment models) (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). As a result, the published data (8)(9)(10)(11)(12)(13)(14)(15)(16)(17) provide conflicting reports of significant covariates of clearance (CL) and do not provide practical dosing recommendations for the target trough concentrations used in practice today.…”

“…These guidelines acknowledge that data in children were limited. Two recent neonatal studies (15,18) assessed higher vancomycin target trough concentrations; however, the results from these studies highlight the continued question regarding appropriate vancomycin dosing in neonates and the lack of data to support practical initial dosing for vancomycin in neonates.…”