Vancomycin In Pediatric Patients Research Articles

Population Pharmacokinetics of Vancomycin in Pediatric Extracorporeal Membrane Oxygenation*

Describe the pharmacokinetics of vancomycin in pediatric patients undergoing extracorporeal membrane oxygenation and provide dosing recommendations to attain an area under the curve for 24 hours greater than 400 in this population. Retrospective, population pharmacokinetic analysis. PICU of a large tertiary care children's hospital. Population pharmacokinetic analysis and simulation were performed with NONMEM v7.3 (Icon, PLC, Dublin, Ireland). Patients less than 19 years old who received IV vancomycin and had serum vancomycin concentration monitoring while undergoing extracorporeal membrane oxygenation from January 1, 2011, to June 30, 2017. A total of 93 patients met study criteria (male 51%, median age 0.64 yr [interquartile range 0.07-6.7 yr]). Mean estimated creatinine clearance was 65 ± 47 mL/min/1.73 m. Patients received 1,116 vancomycin doses (14.6 ± 1.9 mg/kg/dose) and had 433 vancomycin serum concentrations (13.6 ± 6.9 mg/L) at 13.2 ± 10.7 hours after a dose. A two-compartment pharmacokinetic model with allometrically scaled weight on clearance (0.75) and volumes of distribution (1) was developed. Serum creatinine, postmenstrual age were significant covariates for clearance, patient age for central volume of distribution, and albumin for peripheral volume of distribution. Simulation identified a doses of 25-30 mg/kg/dose every 12-24 hours as having the highest percentage of patients with an area under the curve for 24 hours greater than 400 with the highest percentage trough concentrations in the less than 15 mg/L range. A vancomycin dose of 25-30 mg/kg/dose every 12-24 hours with serum concentration monitoring is a reasonable empiric dosing strategy to obtain an area under the curve for 24 hours greater than 400 in pediatric extracorporeal membrane oxygenation patients.

Therapeutic Drug Monitoring of Vancomycin in Pediatric Patients With Extracorporeal Membrane Oxygenation Support.

Determine pharmacokinetic (PK) parameters and optimal dosage of vancomycin for children on extracorporeal membrane oxygenation (ECMO). Retrospective PK study of vancomycin in pediatric patients on ECMO who received IV vancomycin 40 to 60 mg/kg/day every 6 hours. Patients were analyzed according to the presence of acute kidney injury (AKI) and requirement of renal replacement therapy (RRT). Data from 40 children, with a median age of 2.7 years of age (1 month to 14 years) were evaluated. Thirty-two patients (80%) received vancomycin. Vancomycin therapeutic drug monitoring was performed in 29 patients. The subgroup without AKI or RRT were 15. With initial doses, vancomycin trough levels were within therapeutic range in 53% of patients. After dose change, 93% of patients achieved therapeutic levels. The adjusted dose was 40 (34-60) mg/kg/day every 6 hours. Estimated PK parameters were clearance (CL) 1.67 (1-1.67) mL/kg/min; volume of distribution (Vd) 0.73 (0.7-0.9) L/kg; and half-life (t½) 6.2 (4.9-8.06) hours. In the AKI subgroup, 11 patients, the initial median dose was 40 (30-45) mg/kg/day every 8 (6-12) hours. Trough concentrations of vancomycin were within therapeutic range in 27% of patients. After dose modifications, 63% of patients achieved target trough concentration. The final adjusted dose was 20 mg/kg/day (15-30) every 12 (12-24) hours. Estimated PK parameters were Vd 1.16 (0.68-1.6) L/kg; CL 0.83 (0.38-1) mL/kg/min; and a t½ of 23.6 (16.2-31) hours. In patients without AKI or RRT, Vd of vancomycin was similar and CL was lower compared to pediatric critically ill patients without ECMO. Treatment could be started at 40 mg/kg/day every 6 hours. In patients with AKI, the use of lower doses should be used.

Factors affecting serum concentration of vancomycin in critically ill oliguric pediatric patients receiving continuous venovenous hemodiafiltration.

Vancomycin is known to be unintentionally eliminated by continuous renal replacement therapy, and the protein bound fraction of vancomycin is also known to be different in adults and children. However, there are only a few studies investigating the relationship between the dose of continuous venovenous hemodiafiltration (CVVHDF) parameters and serum concentration of vancomycin in pediatric patients. The aim of this study was to determine clinical and demographic parameters that significantly affect serum vancomycin concentrations. This retrospective cohort study was conducted at a pediatric intensive care unit in a tertiary university children’s hospital. Data from oliguric patients who underwent CVVHDF and vancomycin therapeutic drug monitoring were collected. The correlation between factors affecting serum concentration of vancomycin was analyzed using mixed effect model. A total of 177 serum samples undergoing vancomycin therapeutic drug monitoring were analyzed. The median age of study participants was 2.23 (interquartile range, 0.3–11.84) years, and 126 (71.19%) were male patients. Serum concentration of vancomycin decreased significantly as the effluent flow rate (EFR; P < 0.001), dialysate flow rate (DFR; P = 0.009), replacement fluid flow rate (RFFR; P = 0.008), the proportion of RFFR in the sum of DFR and RFFR (P = 0.025), and residual urine output increased. The adjusted R2 of the multivariate regression model was 0.874 (P < 0.001) and the equation was as follows: Vancomycin trough level (mg/L) = (0.283 × daily dose of vancomycin [mg/kg/d]) + (365.139 / EFR [mL/h/kg])–(15.842 × residual urine output [mL/h/kg]). This study demonstrated that the serum concentration of vancomycin was associated with EFR, DFR, RFFR, the proportion of RFFR, and residual urine output in oliguric pediatric patients receiving CVVHDF.

Vancomycin in Pediatric Patients with Solid or Hematological Malignant Disease: Predictive Performance of a Population Pharmacokinetic Model and New Optimized Dosing Regimens.

The application of population pharmacokinetic models and Bayesian methods offers the potential to develop individualized therapeutic approaches. The current study presents an external evaluation of a vancomycin pharmacokinetic model in a pediatric cancer population and proposes an easy-to-use chart for clinicians for a priori vancomycin schedule adaptation to achieve target concentration. External evaluation of a population pharmacokinetic model of vancomycin administered via continuous infusion was realized in a new retrospective dataset of pediatric patients with cancer. The published population pharmacokinetic model was implemented in NONMEM 7.3 with the structural and variance parameter values set equal to estimates previously reported. Predictive performance was assessed by quantifying bias and accuracy of model prediction. Normalized prediction distribution errors were also evaluated. Dosage simulations were performed according to the target concentration. A total of 77 patients were included in this study, representing 146 vancomycin courses and 289 concentrations. The model adequately predicted vancomycin concentrations (median prediction error % of - 9.4%, median |PE|% of 24.1%). Based on simulation results, vancomycin dosage (mg/kg) should be adapted for each child on the basis of body weight and cyclosporine coadministration. The model previously proposed by Guilhaumou et al. in pediatric patients with solid or hematological malignant disease was externally validated. Simulations have enabled the description of new dosage schedules and creation of a chart to help clinicians adapt vancomycin dosage.

Influence of pharmacokinetic/pharmacodynamic ratio on vancomycin treatment response in paediatric patients with Staphylococcus aureus bacteremia

Staphylococcus aureus is a frequent cause of hospital-acquired bacteremia in pediatric patients. Vancomycin is the drug of choice for the treatment of methicillin-resistant strains, although treatment failure is frequently observed. Area under the curve (AUC) of plasma concentrations over the minimum inhibitory concentration (MIC) has been proposed as the best index to predict treatment response, although information about its clinical impact on pediatric patients is scarce. The objective of this study is to determine if early recovery of an AUC/MIC>400 mg*h/L for vancomycin in pediatric patients with S. aureus bacteremia is associated with clinical and microbiological treatment response. Retrospective observational study. Pediatric patients younger than 3 years with vancomycin-treated S. aureus bacteremia were included. The pharmacokinetic parameters were calculated from the vancomycin value obtained in the first 72 hours of treatment, assuming a bicompartmental model. A multivariate analysis was performed to analyze factors associated with early clinical response, treatment failure, microbiological response and 30-day mortality. Fifty-one patients with S. aureus bacteremia were included in the study. In 18 patients (35.3%), strains with a MIC higher than 1.0 mg/L were isolated, being in eight (15.7%) greater than 1.5 mg/L. 22 (43.1%) patients did not reach an estimated AUC/MIC>400 during the first 72 hours. A significant association was observed between attainment of an AUC/MIC>400 and early clinical response (OR:3.23 [95% CI: 1.07-12.03]). No significant association was found between an AUC/MIC>400 and microbiological response or mortality. An AUC/MIC>400 is associated with early response to vancomycin in pediatric patients with S. aureus bacteremia.

An Educational Intervention to Improve the Use and Monitoring of Vancomycin in Pediatric Patients

An Educational Intervention to Improve the Use and Monitoring of Vancomycin in Pediatric Patients

A Multicenter, Randomized, Observer-blinded, Active-controlled Study Evaluating the Safety and Effectiveness of Ceftaroline Compared With Ceftriaxone Plus Vancomycin in Pediatric Patients With Complicated Community-acquired Bacterial Pneumonia.

The broad-spectrum cephalosporin ceftaroline, a metabolite of the prodrug ceftaroline fosamil, has shown in vitro activity against clinical isolates from pediatric patients. This multicenter, randomized, observer-blinded, active-controlled study (NCT01669980) assessed the safety and effectiveness of ceftaroline fosamil compared with ceftriaxone plus vancomycin in patients between 2 months and 17 years of age with complicated community-acquired bacterial pneumonia. Patients were randomized 3:1 (stratified by age cohort) to receive either ceftaroline fosamil or ceftriaxone plus vancomycin (comparator) as intravenous therapy for ≥3 days. Patients who met specific study criteria on or after Study Day 4 were permitted to switch to an oral study drug. Safety assessments were treatment-emergent adverse events, and the effectiveness of treatment was assessed by clinical and microbiologic outcomes. The median duration of intravenous treatment was 9.0 (range, 3.0-19.0) days in the ceftaroline fosamil group (N=30) and 7.5 (5.0-13.0) days in the comparator group (N=10). At least one treatment-emergent adverse event was experienced by 12/30 patients (40%) in the ceftaroline fosamil group and 8/10 (80%) in the comparator group; most treatment-emergent adverse events in both groups were mild to moderate in intensity. Clinical response rates in the modified intent-to-treat population were 52% (15/29 patients) in the ceftaroline fosamil group and 67% in the comparator group (6/9); clinical stability at Study Day 4 was 21% (6/29) and 22% (2/9), respectively. Ceftaroline fosamil was well tolerated and showed similar clinical response rates to ceftriaxone plus vancomycin in pediatric patients with complicated community-acquired bacterial pneumonia.

Safety of topical vancomycin for pediatric spinal deformity: nontoxic serum levels with supratherapeutic drain levels.

Retrospective cohort analysis. To establish if drain levels exceed the minimum inhibitory concentrations for common pathogens (methicillin-resistant Staphylococcus aureus, methicillin-sensitive Staphylococcus aureus, and Propionibacterium acnes-2 μg/mL; Staphylococcus epidermidis, Enterococcus faecalis-4 μg/mL). Evaluate the safety of topical vancomycin in pediatric patients undergoing spinal deformity surgery and determine if postoperative serum levels approach toxicity (25 μg/mL). The application of topical vancomycin powder has decreased postoperative wound infections in retrospective analyses in the adult population with minimal local and systemic risks. The safety and efficacy of vancomycin powder has not been completely evaluated in the pediatric population after deformity surgery. Topical vancomycin powder (1 g) was applied during wound closure after instrumented posterior spinal fusion. All patients received intravenous perioperative antibiotics and a subfascial drain was used. Serum and drain vancomycin levels were collected immediately postoperatively and during the first 2 postoperative days (PODs). Complications were recorded. The study population consisted of 25 patients with a mean age of 13.5 years (9.5-17.1 yr) and mean ± standard deviation body weight of 44.5 ± 18 kg. Underlying diagnoses included: adolescent idiopathic scoliosis (12), neuromuscular scoliosis (10), and kyphosis (3). Mean serum vancomycin levels trended downward from 2.5 μg/mL (POD 0) to 1.9 μg/mL (POD 1) to 1.1 μg/mL (POD 2). Mean drain levels also trended downward from 403 μg/mL (POD 0) to 251 μg/mL (POD 1) to 115 μg/mL (POD 2). No vancomycin toxicity or deep wound infections were observed. One patient with neuromuscular scoliosis developed a superficial wound dehiscence that was managed with dressing changes. Topical application of vancomycin powder in pediatric spinal deformity surgery produced local levels well above the minimum inhibitory concentration for common pathogens and serum levels below the toxicity threshold (25 μg/mL). There were no deep wound or antibiotic related complications. 3.

Improved Vancomycin Dosing in Children Using Area Under the Curve Exposure

: Our objectives were to (1) determine the pharmacokinetic indices of vancomycin in pediatric patients; and (2) compare attainment of 2 target exposures: area under curve (AUC) / minimum inhibitory concentration (MIC) ≥400 and trough concentration ≥15 mcg/mL. : The population-based pharmacokinetic modeling was performed using NONMEM 7.2 for children ≥3 months old who received vancomycin for ≥48 hours from 2003 to 2011. A 1-compartment model with first-order kinetics was used to estimate clearance, volume of distribution and AUC. Empiric Bayesian post hoc individual parameters and Monte Carlo simulations (N = 11,000) were performed. : Analysis included 702 patients with 1660 vancomycin serum concentrations. Median age was 6.6 (interquartile range 2.2-13.4) years, weight 22.7 (12.6-46) kg and baseline serum creatinine 0.40 (0.30-0.60) mg/dL. Final model pharmacokinetic indices were clearance (L/h) = 0.248 * Wt * (0.48/serum creatinine) * (ln(age)/7.8) and volume of distribution (L) = 0.636 * Wt. Using these parameters and the observed MIC distribution, Monte Carlo simulation indicated that the initial median dose of 44 (39-52) mg/kg/day was inadequate in most subjects. Regimens of 60 mg/kg/day for subjects ≥12 years old and 70 mg/kg/day for those <12 years old achieved target AUC/MIC in ~75% and trough concentrations ≥15 in ~45% of virtual subjects. An AUC/MIC ~400 corresponded to trough concentration ~8 to 9 mcg/mL. : Targeted exposure using vancomycin AUC/MIC, compared with trough concentrations, is a more realistic target in children. Depending on age, serum creatinine and MIC distribution, vancomycin in a dosage of 60 to 70 mg/kg/day was necessary to achieve AUC/MIC ≥ 400 in 75% of patients.

Clinical Characteristics, Outcomes, and Microbiologic Features Associated with Methicillin-Resistant Staphylococcus aureus Bacteremia in Pediatric Patients Treated with Vancomycin

Vancomycin is the first-line therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, but its efficacy in adult patients has been questioned. Less is known about the outcomes of MRSA bacteremia treated with vancomycin in pediatric patients. This study reviews the outcomes and clinical characteristics of MRSA bacteremia in children treated with vancomycin and characterizes the microbiologic and molecular features of the bloodstream isolates. A retrospective cohort study was conducted among pediatric patients with MRSA bacteremia treated with vancomycin for >5 days from 1 August 2005 to 31 May 2007 in a large tertiary care center. MRSA bloodstream isolates were characterized by antimicrobial susceptibility testing, PCR analysis of virulence genes, and Diversilab typing. Clinical records were reviewed for outcomes and comorbidities. A total of 22 pediatric patients with MRSA bacteremia were identified. Eleven cases (50.0%) were considered vancomycin treatment failures. Features significantly associated with vancomycin treatment failure were prematurity (P = 0.02) and isolates positive for Panton-Valentine leukocidin (PVL) (P = 0.008). Features typically associated with community-associated MRSA strains were identified in hospital-associated isolates. A dominant clone was not responsible for the high number of treatment failures. Further studies are needed to determine if vancomycin should be the first-line treatment for MRSA bacteremia in premature infants and for PVL-positive isolates.

A retrospective drug utilization evaluation of vancomycin usage in paediatric patients.

To evaluate the appropriateness of use of vancomycin in paediatric patients at KK Women's and Children's Hospital, the major paediatric hospital in Singapore to identify potential problems in prescribing practices that may necessitate intervention to optimize vancomycin usage. A retrospective drug utilization evaluation was performed for paediatric patients who received intravenous vancomycin from 1 June 1998 to 31 June 1999. The outcome measures were consistency of vancomycin indication with recommended guidelines, dosing regimens, microbiological data, monitoring of serum drug levels, renal function, clinical outcomes and adverse drug reactions (ADRs). A total of 96 cases was available for evaluation. Sixty-two (64.6%) courses of vancomycin were consistent with guidelines for indication of therapy. Eighty-six (89.6%) of the dosing regimen were consistent. All infusion times that were recorded (56.3%) were consistent with criteria. Of the patients treated with vancomycin for more than 1 day, peak and/or trough serum vancomycin levels were ordered for 70 cases. Of the 56 cases with paired levels ordered, 46 cases had at least one level that fell outside the therapeutic range. Nineteen (19.8%) cases of ADRs were documented. Fifty-eight (60.4%) cases received concurrent nephrotoxic drugs. However, a substantial portion of vancomycin courses were apparently not prescribed for appropriate indications, and there was poor recording of vancomycin administration information and sampling time. The majority of dosing regimens of vancomycin was consistent with guideline criteria. The most evident problem was the sub-optimal use of the monitoring of vancomycin serum levels. The information derived from this study may be used as a for further study and for the development of strategies for optimize vancomycin usage.

Caution needed for empiric use of vancomycin in paediatric patients?

Caution needed for empiric use of vancomycin in paediatric patients?

A population pharmacokinetic model for vancomycin in pediatric patients and its predictive value in a naive population.

The objectives of this study were to (i) construct a population pharmacokinetic (PK) model able to describe vancomycin (VAN) concentrations in serum in pediatric patients, (ii) determine VAN PK parameters in this population, and (iii) validate the predictive ability of this model in a naive pediatric population. Data used in this study were obtained from 78 pediatric patients (under 18 years old). PK analyses were performed using compartmental methods. The most appropriate model was chosen based on the evaluation of pertinent graphics and calculation of the Akaike information criterion test. The population PK analysis was performed using an iterative two-stage method. A two-compartment PK model using age, sex, weight, and serum creatinine as covariates was determined to be the most appropriate one to describe serum VAN concentrations. The quality of fit was very good, and the distribution of weighted residuals was found to be homoscedastic (Wilcoxon signed rank test). Fitted population PK parameters (mean +/- standard deviation) were as follows: central clearance (0.1 +/- 0.05 liter/h/kg), central volume of distribution (0.27 +/- 0.07 liter/kg), peripheral volume of distribution (0.16 +/- 0.07 liter/kg), and distributional clearance (0.16 +/- 0.07 liter/kg). The predictive ability of the developed model (including the above-mentioned covariates) was evaluated in a naive population of 19 pediatric patients. The predictability was very good. Precision (+/-95% confidence interval [CI]) (peak, 4.1 [+/-1.4], and trough, 2.2 [+/-0.7]) and bias (+/-95% CI) (peak, -0.58 [+/-2.2], and trough, 0.63 [+/-1.1] mg/liter) were significantly (P < 0.05) superior to those obtained using a conventional method (precision [+/-95% CI]: peak, 8.03 [+/-2. 46], and trough, 2.7 [+/-0.74]; bias: peak, -7.1 [+/-2.9], and trough, -1.35 [+/-1.2] mg/liter). We propose the use of this population PK model to optimize VAN clinical therapies in our institution and others with similar patient population characteristics.he object

A population PK model for vancomycin in pediatric patients and its predictive value in a naive population

A population PK model for vancomycin in pediatric patients and its predictive value in a naive population

Pharmacokinetics and Cerebrospinal Fluid (CSF) Concentrations of Vancomycin in Pediatric Patients Undergoing CSF Shunt Placement

Staphylococcus epidermidis has been established as the common pathogen causing cerebrospinal fluid shunt infections. In addition, clinical isolates of S. epidermidis from infected shunts are typically resistant to methicillin. Vancomycin is often used for neurosurgical prophylaxis due to its excellent in vitro activity against methicillin-resistant staphylococci. Limited data are available about the pharmacokinetics and cerebrospinal fluid concentrations of vancomycin in pediatric patients intraoperatively. The objectives of this study were to characterize the pharmacokinetics and determine the cerebrospinal fluid concentrations of vancomycin. Eight patients (mean age 8.3 +/- 7.0 years) received three doses of intravenous vancomycin, 15 mg/kg every 6 h. The first dose was administered 1 h prior to surgery. Blood samples were collected at 0, 0.5, 1, 2, 4, and 5 h after the end of the infusion. A cerebrospinal fluid sample was collected at the time of shunt insertion. Urine samples were collected over a 24-hour period. Vancomycin was measured with a fluorescence polarization immunoassay. The peak serum concentrations ranged from 15.6 to 33.7 micrograms/ml; cerebrospinal fluid concentrations ranged from less than 0.6 to 0.8 microgram/ml. The mean total clearance, renal clearance, apparent volume of distribution, and elimination half-life were 0.11 +/- 0.05 l/h/kg, 0.07 +/- 0.02 l/h/kg, 0.54 +/- 0.15 l/kg, and 4.8 +/- 4.0 h, respectively. Approximately 70% of total vancomycin dose was excreted in the urine. A 2- to 5-fold variation in total clearance and a 2.5-fold variability in renal clearance were observed. Low cerebrospinal fluid concentrations of vancomycin were present at the time of shunt insertion in these pediatric patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacology and efficacy of vancomycin in pediatric patients

The emergence of staphylococci resistant to multiple antibiotics and the lack of information on pharmacology, efficacy, and safety of vancomycin in pediatric patients prompted this study. In vitro susceptibility studies showed that 33 to 50% of staphylococci tested were resistant to nafcillin, methicillin, cephalothin, and gentamicin, whereas none were resistant to vancomycin. Pharmacokinetic data of vancomycin were evaluated in 55 pediatric patients and was characterized by the two-compartment open-system kinetic model. Mean peak serum concentrations in infants and children after 10 and 15 mg/kg doses ranged from 25.2 to 32.5 μg/ml. The 10 mg/kg dose in newborn infants resulted in substantially lower peak values. Mean serum elimination phase half-life values correlated inversely with gestational and chronologic age and ranged from 2.2 to 9.8 hours. The CSF penetration in three infants with staphylococcal ventriculoperitoneal shunt infections ranged from 7 to 21%. Sixteen patients with staphylococcal diseases were successfully treated with vancomycin. In these patients peak serum vancomycin concentrations greater than 25 μg/ml and trough concentrations less than 12 μg/ml produced satisfactory inhibitory and bactericidal titers. Laboratory studies and auditory function tests did not reveal any drug-related abnormalities. Dosage schedules were formulated from these data. Indications and precautions for vancomycin therapy in infants and children are presented. The emergence of staphylococci resistant to multiple antibiotics and the lack of information on pharmacology, efficacy, and safety of vancomycin in pediatric patients prompted this study. In vitro susceptibility studies showed that 33 to 50% of staphylococci tested were resistant to nafcillin, methicillin, cephalothin, and gentamicin, whereas none were resistant to vancomycin. Pharmacokinetic data of vancomycin were evaluated in 55 pediatric patients and was characterized by the two-compartment open-system kinetic model. Mean peak serum concentrations in infants and children after 10 and 15 mg/kg doses ranged from 25.2 to 32.5 μg/ml. The 10 mg/kg dose in newborn infants resulted in substantially lower peak values. Mean serum elimination phase half-life values correlated inversely with gestational and chronologic age and ranged from 2.2 to 9.8 hours. The CSF penetration in three infants with staphylococcal ventriculoperitoneal shunt infections ranged from 7 to 21%. Sixteen patients with staphylococcal diseases were successfully treated with vancomycin. In these patients peak serum vancomycin concentrations greater than 25 μg/ml and trough concentrations less than 12 μg/ml produced satisfactory inhibitory and bactericidal titers. Laboratory studies and auditory function tests did not reveal any drug-related abnormalities. Dosage schedules were formulated from these data. Indications and precautions for vancomycin therapy in infants and children are presented.