Vancomycin In Pediatric Patients Research Articles

Vancomycin in Pediatric Patients with Cystic Fibrosis: Dose Optimization Using Population Pharmacokinetic Approach.

An increase in Staphylococcus aureus infections has been reported in pediatric patients with cystic fibrosis (CF) over the last few years. This pathogen is commonly treated with vancomycin, an antibiotic for which therapeutic drug monitoring (TDM) is recommended. Updated guidelines were recently published regarding new targets of exposure for the TDM of vancomycin through a Bayesian approach, using population pharmacokinetic (popPK) models. This study aims to assess the predictive performance of vancomycin popPK models in pediatric patients with CF and to recommend optimal initial dosing regimens based on simulations. Patient data were collected from two centers in Canada, and a literature review was conducted to identify all published vancomycin popPK models for pediatric CF patients. External evaluation and simulations were performed according to patient and occasion of treatment. A total of 53 vancomycin concentrations were collected from six pediatric CF patients. Only two popPK models of vancomycin for pediatric CF patients were identified through the literature review. The external evaluation results for both centers combined revealed a population bias of 28.1% and an imprecision of 33.7%. A re-estimation of parameters was performed to improve predictive performance. The optimal initial dosing regimen was 15 mg/kg/dose administered every 6 hours according to the per occasion remodel. The predictive performance and identified optimal initial dosing regimens associated with the model were different depending on the data used, showing external evaluation's importance before implementing a model in clinical practice.

Recommended doses of endovenous vancomycin are insufficient to achieve therapeutic concentrations in paediatric patients

ObjectivesVancomycin therapeutic drug monitoring is challenging, especially in the paediatric population where evidence is scarce. The main objective of this study was to analyse the achievement of therapeutic concentrations of...

Population pharmacokinetic analysis for dose regimen optimization of vancomycin in Southern Chinese children.

Changes in physiological factors may result in large pharmacokineticvariability of vancomycin in pediatric patients, thereby leading to either supratherapeutic or subtherapeutic exposure and potentially affecting clinical outcomes. This study set out to characterize the disposition of vancomycin, quantify the exposure target and establish an optimal dosage regimen among the Southern Chinese pediatric population. Routine therapeutic drug monitoring data of 453 patients were available. We performed a retrospective population pharmacokineticanalysis of hospitalized children prescribed intravenous vancomycin using NONMEM® software. A one-compartment PPK model of vancomycin with body weight and renal functions as covariates based on a cutoff of 2 years old children was proposed in this study. Both internal and external validation showing acceptable and robust predictive performance of the model to estimate PK parameters. The value of area under the curve over 24 h to minimum inhibitory concentration ratio (AUC0-24/MIC) ≥ 260 was a significant predictor for therapeutic efficacy. Monte Carlo simulations served as a model-informed precision dosing approach and suggested that different optimal dose regimens in various scenarios should be considered rather than flat dosing. The evaluation of vancomycin exposure-efficacy relationship indicated that lower target level of AUC0-24/MIC may be needed to achieve clinical effectiveness in children, which was used to derive the recommended dosing regimen. Further prospective studies will be needed to corroborate and elucidate these results.

Population Pharmacokinetics and Dosage Optimization of Vancomycin in Pediatric Patients with Skin and Soft Tissue Infections, Bone, and Joint Infections.

Vancomycin is recommended for the treatment of skin and soft tissue infections (SSTI) and bone and joint infections (BJI). However, a detailed investigation of the pharmacokinetic profile and optimal dosing regimens of vancomycin in pediatric patients with SSTI and BJI is lacking. We successfully developed a new PopPK model of vancomycin in this population by using scavenged blood samples with the typical values for clearance (CL) of 0.14 L/h/kg and volume of distribution (V) of 0.5 L/kg. Body weight was confirmed as the significant covariate on CL and V. The optimal dosing regimens of 75 mg/kg/day and 80 mg/kg/day were recommended for this specific population.

Association of Vancomycin Trough Concentration and Clearance With Febrile Neutropenia in Pediatric Patients.

Febrile neutropenia promotes renal drug excretion. Adult and pediatric patients with febrile neutropenia exhibit a lower vancomycin concentration/dose (relative to bodyweight) ratio than those with other infections. In pediatric patients, renal function relative to bodyweight varies depending on age, and vancomycin clearance is age dependent. This study aimed to analyze the effects of febrile neutropenia on the pharmacokinetics of vancomycin in age-stratified pediatric patients. This retrospective, single-center, observational cohort study analyzed 112 hospitalized pediatric patients who met the selection criteria and intravenously received vancomycin at the Department of Pediatrics of the Oita University Hospital between April 2011 and October 2019. The febrile neutropenia (n = 46) cohort exhibited a significantly higher estimated glomerular filtration rate than the nonfebrile neutropenia (n = 66) cohort. Compared with those in the nonfebrile neutropenia cohort, the daily vancomycin dose relative to bodyweight and vancomycin clearance were significantly higher, and the vancomycin trough concentration and vancomycin concentration/dose ratio were significantly lower in the febrile neutropenia cohort. In the age groups of 1-6 and 7-12 years, compared with those in the nonfebrile neutropenia cohort, the vancomycin concentration/dose ratio was significantly lower, and vancomycin clearance was significantly higher in the febrile neutropenia cohort. Univariate and multivariate analyses identified febrile neutropenia as the independent factor influencing vancomycin concentration/dose ratio and clearance only in pediatric patients aged 1-6 years. Increased initial dosage and therapeutic drug monitoring-guided dose optimization are critical for the therapeutic efficacy of vancomycin in pediatric patients with febrile neutropenia, especially in those aged 1-6 years.

Population Pharmacokinetics and Pharmacodynamics of Vancomycin in Pediatric Patients With Various Degrees of Renal Function.

Although vancomycin dosage recommendations in the pediatric setting for methicillin-resistant Staphylococcus aureus (MRSA) infection indicate that ≥60 mg/kg/day is correlated to a desired area under the vancomycin concentration time curve from 0 to 24 hours to minimum inhibitory concentration ratio (AUC0-24 hr/MIC) ≥400, for some patients this dosage is inadequate or relates to toxicity. This study purposed to explore vancomycin dosing for pediatrics with various degrees of renal function. Routine monitoring data were retrospectively collected from patients, aged 1 month to 18 years. Population pharmacokinetic analysis was performed by using non-linear mixed-effect model with NONMEM software, and Monte Carlo simulation was conducted by using Crystal Ball software. Two hundred twelve patients with 348 vancomycin serum concentrations were included. Median age was 3.5 years (IQR, 0.9-10.9), median weight was 14.0 kg (IQR, 7.2-30.4), with baseline estimated glomerular filtration rate (eGFR) ranging from 15.5 to 359.3 mL/min/1.73 m2. A 1-compartment model with first-order elimination sufficiently described vancomycin PK. The dosing targeting AUC0-24hr/MIC ≥400 and AUC0-24hr <800 mg•h/L for pediatric patients with eGFRs of 15 to 29, 30 to 59, 60 to 89, 90 to 129, and 130 to 160 mL/min/1.73 m2 was 12.5, 25, 40, 60, and 70 mg/kg/day, respectively. All vancomycin dosing obtained >85% of the cumulative fraction of response across the MIC distribution of MRSA. Vancomycin dosing of 12.5, 25, 40, 60, and 70 mg/kg/day is suggested for pediatric patients with eGFRs of 15 to 29, 30 to 59, 60 to 89, 90 to 129, and 130 to 160 mL/min/1.73 m2, respectively.

1119. Assessment of Vancomycin Pharmacokinetic Parameters in Pediatric Patients After Liver Transplantation

BackgroundVancomycin is largely prescribed to treat gram-positive bacterial infections in pediatric patients after liver transplantation with the same empirical doses prescribed in other critical conditions due to the absence of pharmacokinetic studies in this population. The objective of this investigation was to describe the vancomycin pharmacokinetic parameters and to assess the vancomycin percentage of target attainment with empirical regimen.MethodsProspective and longitudinal study with pediatric post-liver transplantation patients who received at least 48 hours of vancomycin between January 2020 and May 2021. Patients with acute or chronic renal failure or receiving renal replacement therapy were excluded. Vancomycin therapy started with 40-60mg/kg daily, one-hour infusion. The pharmacokinetic parameters were determined by one-compartment model with first-order kinetics using near steady-state postdistributional peak and trough within the same dosing interval. Therapeutic target was defined as vancomycin 24-hour area under the curve/minimum inhibitory concentration (AUCss0-24/MIC) ≥ 400 and < 600. The study protocol was approved by the local ethics committee.ResultsWe included 18 sets of peak/trough serum concentrations obtained from 12 patients. The patients had median age of 11 (interquartile range [IQ] 8-16) months. The found vancomycin clearance, volume of distribution and half-life values were, respectively, 2.1 (IQ 1.4-2.8) mL/kg/min, 0.6 (IQ 0.5-0.7) L/kg and 3.2 (IQ 2.3-4.0) hours. After the initial dose regimen, 5 (42%) patients reached the therapeutic target.ConclusionUsing the one-compartment model, we evaluate the pharmacokinetic parameters of vancomycin in pediatric patients after liver transplantation. Most of patients did not reach the therapeutic target with empirical regimen, so it is prudent to monitor the exposure to vancomycin directly by AUC/MIC ratio to maximize antimicrobial efficacy.Disclosures All Authors: No reported disclosures

An Update on Population Pharmacokinetic Analyses of Vancomycin, Part II: In Pediatric Patients.

Vancomycin is widely used in pediatric patients, however, large inter- and intraindividual variability are observed in vancomycin pharmacokinetics, affecting proper therapeutic monitoring. This review aimed at providing a comprehensive synthesis of the population pharmacokinetic models of vancomycin in pediatric patients and identifying potential factors responsible for the variability observed in various subpopulations. We conducted a literature search of the PubMed and EMBASE databases to obtain population pharmacokinetic studies for vancomycin published between January 2011 and January 2020, which resulted in a total of 33 studies. Vancomycin pharmacokinetics were generally characterized using a one-compartment model (n=27), while a two-compartment model was used in six studies. The median (interquartile range) of the typical vancomycin clearance (CL) and the total volume of distribution adjusted to the median or mean body weight of the respective study was 0.103L/h/kg (0.071-0.125) and 0.64 L/kg (0.59-1.03), respectively. Median weight-adjusted CL between different child age groups, such as infants and adolescents, did not appear to vary significantly, although the sample size for many age groups was very small. Examples of the conditions with relatively abnormal vancomycin pharmacokinetic values include renal insufficiency, sepsis, hematological and solid malignancy, and hypothermia treatment. Factors influencing pediatric vancomycin pharmacokinetics after adjusting for size and maturation include various renal function descriptors and some case-specific variables such as dialysate flow rate, ultrafiltrate output, and hypothermia. This review was able to document possible variables explaining the high variability observed in certain subpopulations and contrast vancomycin pharmacokinetics in different pediatric subpopulations.

Population pharmacokinetics of vancomycin in paediatric patients with febrile neutropenia and augmented renal clearance: development of new dosing recommendations.

The purpose of this study was to evaluate the influence of augmented renal clearance (ARC) on vancomycin clearance and provide dosage recommendations for paediatric patients with febrile neutropenia following HSCT. A population pharmacokinetic analysis was performed based on a two-compartment model structure using a non-linear mixed-effect modelling approach. Monte Carlo simulations were conducted as a target attainment analysis of AUC between 400 mg·h/L and 650 mg·h/L for MRSA at an MIC of 1 mg/L. A total of 165 paediatric patients and 276 vancomycin serum concentrations were analysed in this study. Age, body weight, estimated glomerular filtration rate (eGFR) and fever (≥38.0°C) were identified as factors that significantly influenced vancomycin clearance. The median eGFR of the population was 143 mL/min/1.73 m2 and 34% of patients showed an eGFR ≥160 mL/min/1.73 m2, which may be classified as ARC. Our simulations showed that current dosing recommendations result in poor target attainment. In particular, children aged 6 months old to 6 years old with ARC require an initial vancomycin dose up to 35%-65% higher than the current dosing guidelines. ARC is frequently observed in paediatric patients with post-HSCT febrile neutropenia, resulting in a significant increase in vancomycin clearance. We propose a vancomycin dosing strategy for children with febrile neutropenia following HSCT based on eGFR, age, weight and body temperature.

Impact of the vancomycin and amikacin therapeutic monitoring in the optimization of antimicrobial dose in pediatric patients

The monitoring of antimicrobial therapy through plasma levels makes it possible to determine the optimal dosage of antimicrobials, an essential approach in pediatrics. To describe the monitoring of plasma antimicrobial levels and dose adjustment in the pediatric population to determine if the doses used reach therapeutic ranges. Retrospective, descriptive study using a database with measurement of plasma levels of amikacin and vancomycin in pediatric patients at San Borja Arriarán Hospital between 2015-2018. The number of patients who reached the therapeutic range with the initial dose, how many required adjustment and their characteristics were determined. 104 total levels were monitored. For vancomycin 65 plasmatic levels were baseline, being outside the therapeutic range 56.5%; 25% of those requiring adjustment were neonates with a higher probability of being out of range versus others (p = 0.022). For amikacin, Cpeak was in range in 60% of measurements; 15.4% required adjustment, including patients with cystic fibrosis and cancer, without adjustments in patients without comorbidity. Measurement of plasma levels is necessary to individually adjust the dose, especially in pediatric patients with cystic fibrosis, oncology and in neonatology where it is more likely not to reach a therapeutic range with initial doses.

Pharmacokinetics of Vancomycin in Pediatric Patients Receiving Intermittent Hemodialysis or Hemodiafiltration

IntroductionVancomycin is a common antibiotic used to treat hemodialysis (HD) or hemodiafiltration (HDF)-related infections in pediatric patients, but optimal dosing remains unknown. This is the first observational study to characterize the pharmacokinetics and evaluate dosing of vancomycin in this population.MethodsEligible patients received IV vancomycin 10 mg/kg per dose postdialysis followed by a series of serum vancomycin concentrations collected before, immediately after, 1 hour after, and 4 hours after dialysis. The pharmacokinetic parameters were estimated using 1- and 2-compartment models and a nonlinear least-squares algorithm.ResultsAmong 42 vancomycin courses in 16 patients, 1 compartment model had the best fit for observed data. The net drug removal was 43 ± 13% (39% for HD and 50% for HDF) from an average 3-hour HD/HDF session. The mean elimination constant was 0.28 h−1 (standard deviation [SD], 0.11 h−1) during the intradialytic period compared with 0.0049 h−1 (SD, 0.004 h−1) when off dialysis. The mean volume of distribution was 0.65 (SD, 0.19) L/kg. Duration of dialysis session and mode of dialysis (HD vs. HDF) were significant predictors of vancomycin pharmacokinetic parameters. Half-life was shorter for HDF compared with HD (2.1 vs. 3.5 hours).ConclusionsBased on the simulations, an initial vancomycin dose of 10 mg/kg per dose and redosing postdialysis was optimal to achieve a vancomycin concentration range of 5 to 12 mg/L at 4 hours postdialysis and 24-hour area under the curve over minimum inhibitory concentration of ≥400 hours. Therapeutic drug monitoring is necessary to account for residual variability in vancomycin elimination in pediatric patients receiving HD/HDF.

Dose Optimization of Vancomycin Using a Mechanism-based Exposure–Response Model in Pediatric Infectious Disease Patients

PurposeThis study aimed to determine the appropriate vancomycin dosage, considering patient size and organ maturation, by simulating the bacterial count and biomarker level for drug administration in pediatric patients with gram-positive bacterial (GPB) infections. MethodsNatural language processing for n-gram analysis was used to detect appropriate pharmacodynamic (PD) markers in infectious disease patients. In addition, a mechanism-based model was established to describe the systemic exposure and evaluate the PD marker simultaneously in pediatric patients. A simulation study was then conducted by using a mechanism-based model to evaluate the optimal dose of vancomycin in pediatric patients. Findings: C-reactive protein (CRP) was selected as a PD marker from an analysis of ~270,000 abstracts in PubMed. In addition, clinical results, including the vancomycin plasma concentrations and CRP levels of pediatric patients (n = 93), were collected from electronic medical records. The vancomycin pharmacokinetic model with allometric scaling and a maturation function was built as a one-compartment model, with an additional compartment for bacteria. Both the effects of vancomycin plasma concentrations on the destruction of bacteria and those of bacteria on CRP production rates were represented by using a maximum achievable effect model (Emax model). Simulation for dose optimization was conducted not only by using the final model but also by exploring the possibility of therapeutic failure based on the MICs of vancomycin for GPB. Clinical cure was defined as when the CRP level fell below the upper limit of the normal range. Our dose optimization simulations suggested a vancomycin dosage of 10 mg/kg every 8 h as the optimal maintenance dose for pediatric patients with a postconceptual age <30 weeks and 10 mg/kg every 6 h for older children, aged up to 12 years. In addition, the MIC of 3 μg/mL was assessed as the upper concentration limit associated with successful vancomycin treatment of GPB infections. ImplicationsThis study confirmed that the changes in bacterial counts and CRP levels were well described with mechanistic exposure–response modeling of vancomycin. This model can be used to determine optimal empiric doses of vancomycin and to improve therapeutic outcomes in pediatric patients with GPB.

Association of Initial Trough Concentrations of Vancomycin with Outcomes in Pediatric Patients with Gram-Positive Bacterial Infection.

Vancomycin is a glycopeptide antibiotic used for the treatment of Gram-positive infections. For adult patients, treatment with vancomycin requires effective therapeutic drug-monitoring (TDM) to achieve clinical outcomes and reduce the incidence of adverse effects. However, it remains still unclear whether the TDM with vancomycin is beneficial in yielding better clinical outcomes in pediatrics. The objective of our study was to evaluate whether the clinical response to treatment was associated with initial trough concentrations of vancomycin in pediatric patients. A retrospective observation study of 60 patients (age: 1 month-15 years) who had completed and qualified for analysis was conducted at Kyoto University Hospital. The response to treatment was assessed by the time to resolution of fever and time to 50% decline in C-reactive protein (CRP). In addition, we explored whether vancomycin trough level was associated with the baseline characteristics. Trend analysis showed that there were significant correlations between vancomycin trough level and age, body weight, estimated glomerular filtration rate, and serum albumin levels. The time to resolution of fever of the patients with higher initial trough level (≥ 5 µg/mL) was significantly lower than that of the patients with lower trough level (< 5 µg/mL). The higher vancomycin concentration tended to be associated with the shorter time to 50% decline in CRP. The findings suggest that initial trough concentration is important in achieving better outcomes with vancomycin treatment in pediatrics.

P01 An evaluation of vancomycin therapy in paediatric patients post guideline change

AimTo evaluate the prescribed dose of vancomycin as per local guideline and review the achieved therapeutic drug levels.MethodRetrospective data was collected from paediatric inpatients that were prescribed vancomycin for more than 24 hours during the audit period. Data was obtained from the Trust’s electronic prescribing system, LastWord. Measured standards included initial vancomycin dose, dose prescribed for renal impairment, time to first trough level and any required dose adjustments as per local guidance. The dose bands for each age group were1; birth - 6 months 15 mg/g 8 hourly; &gt;6 months -12 months 20 mg/kg 8 hourly; &gt;12 months – 12 years 25 mg/kg 8 hourly; &gt;12 years 20 mg/kg 8 hourly. The number of patients achieving therapeutic vancomycin trough levels was recorded. Safety data was collected, including reported adverse effects, infusion related reactions and renal impairment. Renal impairment was defined as an increase in creatinine by 50%. Data was collected from April 2018 for 6 months. Relevant data with regards to patient demographics, dosing and drug levels were collected and analysed using Microsoft Excel.Results12 patients received 15 doses of vancomycin over 6 months. 67% of initial vancomycin doses were prescribed as per local guideline, 60% of therapeutic trough levels were taken at the right time and 71% of patients that were prescribed the correct dose and had levels taken at the right time achieved therapeutic trough levels. 12 patients required dose adjustments. One patient with renal impairment was not prescribed the recommended dose as per local guidance. One patient reported an infusion related reaction, which was overcome by increasing the infusion time. Two patients who received therapy for &gt;7 days accumulated vancomycin and recorded high trough levels, with no adverse events. One patient reported an increase in creatinine by 50% over the treatment period.ConclusionsVancomycin has the potential to induce nephrotoxicity and ototoxicity when consistently at high serum drug levels. Due to its narrow therapeutic index, drug levels should be monitored to ensure the drug does not accumulate. The licensed dose and dose listed in the BNF for Children 2 3 has historically under dosed patients at our trust, leading to the risk of ineffective therapy and bacterial resistance. It is unclear from research what the optimal dose is for paediatric patients.More research is needed to determine the correct paediatric dose of vancomycin. Higher doses than currently recommended as per licence resulted in three quarters of patients achieving therapeutic levels, however 12 patients still required dose adjustment. No patients suffered irreversible adverse effects or toxicity, suggesting that higher doses are safe to use in the paediatric population. Further education is required for those involved in the prescribing, administering and monitoring of Vancomycin in paediatric patients to ensure its safe use. Additional monitoring is required for those receiving higher doses &gt;7 days to prevent drug accumulation, alternatively a loading dose followed by lower maintenance dose may be a more suitable dosing regimen.ReferencesHughes S, Crook J, Ross J. Vancomycin intravenous dosing guideline - paediatrics. Chelsea and Westminster Hospital; 2017.Stockman C, Sammons H, Stakey E, et al. Unanswered Questions Regarding Optimal Pediatric Vancomycin Use. Therapeutic Drug Monitoring 2016; 38:491–420.National Institute for Health and Care Excellence. Vancomycin. Available from https://bnfc.nice.org.uk/drug/vancomycin.html [Accessed 10th Oct 2018]

A Population Pharmacokinetics Model for Vancomycin Dosage Optimization Based on Serum Cystatin C.

Renal function has an important influence on the pharmacokinetics of vancomycin, and serum cystatin C (CysC) exhibits accurate predictive performance as a marker for renal function. This study aimed to develop a population pharmacokinetics (PopPK) model of vancomycin based on serum CysC in pediatric patients. In addition, vancomycin dosage was optimized with the area under the serum concentration-time curve over 24h (AUC0-24)/minimum inhibitory concentration (MIC) ratio in the target range of 400-700 and the steady-state trough concentration (Css,trough). Data were retrospectively obtained from pediatric patients aged 2-18years who received vancomycin treatment for infection from January 2014 to June 2019. PopPK analysis and Monte Carlo simulations were conducted using nonlinear mixed effects model (NONMEM) software. A total of 220 children were included. Serum CysC and age were significant covariates affecting the pharmacokinetics of vancomycin. The final typical value of clearance was 2.25L/h; the volume of distribution was 8.17L. The average probability of target attainment values of AUC0-24/MIC ratios within 400-700 in the 2-7, 7-12, and 12-18years age groups were 66.1%, 68.1% and 66.5%, respectively. The median Css,trough values of vancomycin for the 2-7, 7-12, and 12-18years age groups were 7.49-11.84, 5.98-11.32, and 5.15-11.39mg/L, respectively, and were highly correlated with AUC0-24/MIC ratios in the range of 400-700 when the MIC was 1mg/L. The pharmacokinetic parameters for vancomycin in pediatric patients were estimated using a serum CysC model. The simulated dosages provide a reference for vancomycin therapy.

Continuous Infusion Vancomycin in Pediatric Patients: A Critical Review of the Evidence.

To evaluate the use of continuous infusion vancomycin in pediatric patients. PubMed, Cochrane Library, International Pharmaceutical Abstracts, and Google Scholar were searched to identify relevant published articles (1977 to November 2019) using the following search terms: vancomycin, neonates, pediatrics, infusion, continuous, administration, children, nephrotoxicity, pharmacokinetics, and pharmacodynamics. All English-language primary references that evaluated continuous infusion vancomycin in pediatric patients were included in this review. Vancomycin is typically administered with intermittent infusions, but continuous infusion is an alternative delivery method used to improve achievement of target serum concentrations. Fifteen articles were reviewed that evaluated continuous infusion vancomycin in pediatric patients. Study data were heterogeneous with limited evidence to support improved clinical or microbiologic outcomes as compared with intermittent dosing. Potential benefits and limitations of continuous infusions are discussed. Currently available evidence is lacking to support routine implementation of continuous infusion vancomycin in pediatric patients. However, it is a therapeutic option in certain clinical conditions and could be beneficial for individuals with serious Gram-positive infections where rapid achievement of target serum concentrations is critical. Continuous infusions may also benefit individuals who do not achieve target concentrations or who experience significant red man syndrome with traditional dosing, particularly when high daily doses are required. Optimal dosing and ideal target serum concentrations have not been established and may vary for different populations. Future prospective randomized clinical trials should be performed to identify optimal dosing and monitoring regimens and determine comparative safety and efficacy with traditional intermittent dosing in various pediatric populations.

Population pharmacokinetic analysis of vancomycin in pediatric continuous renal replacement therapy.

Dosing of vancomycin in pediatric patients undergoing continuous venous-venous hemodiafiltration (CVVHDF) is challenging. Characterization of vancomycin pharmacokinetics can assist with dosing and attainment of goal serum concentrations. Patients less than 19years of age who received vancomycin and had post-dose vancomycin concentrations while undergoing CVVHDF were identified. Data collection included the following: patient demographics, vancomycin dosing and serum concentrations, CVVHDF variables, serum creatinine (SCR), blood urea nitrogen (BUN), albumin, hematocrit, and urine output. Fat-free mass was calculated. Data were summarized with descriptive statistical methods, and population pharmacokinetic analysis was performed with NONMEM 7.2 and PDx-Pop 5.2. Simulation was performed to identify dosing regimens with the highest percentage of goal serum concentration < 20mg/L and AUC0-24:MIC ≥ 400 attainment. A total of 138 patients met study criteria (45.6% male, median age 4.9years (IQR (1.0, 14.5))). Mean vancomycin dose was 14.3 ± 1.6mg/kg/dose (19.5 ± 3.0mg/kg/dose by FFM). Patients had a median of six (IQR 2, 12) vancomycin serum concentrations sampled 13.6 ± 8.4h after the dose, and the mean vancomycin serum concentration was 11.3 ± 3.4mg/L. Vancomycin pharmacokinetics were characterized by a two-compartment model with allometric scaling on fat-free mass and significant covariates of SCR, BUN, dialysate flow rate, and ultrafiltration rate on clearance. Simulation identified doses of 40-50mg/kg/day that divided every 8-12h had the highest percentage of patients with a serum concentration < 20mg/L and an AUC0-24:MIC ≥ 400. Vancomycin pharmacokinetics are characterized by fat-free mass, serum creatinine, blood urea nitrogen, dialysate flow rate, and ultrafiltration rate in the pediatric CVVHDF population. Dosing of 40-50mg/kg/day on fat-free mass divided every 8-12h with frequent vancomycin serum sampling is recommended.

Effective vancomycin concentrations in children: a cross-sectional study.

ABSTRACTObjective Analyze the microbiological effectiveness, based on the pharmacokinetics/pharmacodynamics correlation of vancomycin in pediatric patients, and to propose dose adjustment.Methods This is an observational, cross-sectional study, conducted in a pediatric hospital, over a 1-year period (2016 to 2017). Children of both sexes, aged 2 to 12 years, were included in the study; burn children, and children in renal replacement therapy were excluded. For the pharmacokinetic analysis, two samples of 2mL of whole blood were collected, respecting the 2-hour interval between each withdrawal.Results Ten pediatric patients with median age of 5.5 years and interquartile range (IQR) of 3.2-9.0 years, median weight of 21kg (IQR: 15.5-24.0kg) and median height of 112.5cm (IQR: 95-133cm), were included. Only one child achieved trough concentrations between 10µg/mL and 15µg/mL.Conclusion The empirical use of vancomycin in the children studied did not achieve the therapeutic pharmacokinetic/pharmacodynamic target for minimum inhibitory concentration of 1µg/mL.

How Much Vancomycin Dose Is Enough For The MRSA Infection in Pediatric Patients With Various Degrees of Renal Function?

Today, an increase in vancomycin dose has been proposed to ensure efficacy. However, the risk of nephrotoxicity will increase with the dose. The aim of this study was to evaluate the dosage regimens of vancomycin in pediatric patients based on pharmacokinetics/pharmacodynamics (PK/PD) and to optimize dosage individualization. Population pharmacokinetics analysis was performed on 155 Chinese children (aged 1 month to 16 years), which were divided into various renal function subpopulations. Monte Carlo simulation was carried to evaluate the efficacy and safety of vancomycin dosage regimens on each subpopulation. Compared with children with normal renal function as glomerular filtration rate (GFR) ≥ 90 mL/min·1.73 m2, the clearance of vancomycin decreased by 39.4% and the half life increased 1.74 fold respectively in children with moderate renal inadequacy (30 ≤ GFR < 60 mL/min·1.73 m2). When vancomycin was administered as conventional dosage (40-60mg·kg-1·d-1) to against methicillin-resistant staphylococcus aureus (MRSA) with higher MICs of 1-2 mg·L-1 for children with normal renal function, the probability of efficacy target attainment ( PTA) at AUC0-24h/MIC ≥ 400 (where AUC is the area under curve and MIC is the minimum inhibitory concentration) achieved ≤ 63.64%. While vancomycin dosage exceeded 70mg·kg-1·d-1 for children with normal renal function, 50mg·kg-1·d-1 for mild renal inadequacy (60 ≤ GFR < 90 mL/min·1.73 m2), 30 mg·kg-1·d-1 for moderate renal inadequacy respectively, the PTA at trough concentration above 20 mg·L-1 achieved > 20%, that not to be suggested for high risk of nephrotoxicity. Considering both efficacy and safety, the conventional vancomycin dosage is not enough and adjustable interval is narrow for pediatric patients with MIC 1-2 mg·L-1 MRSA infection and normal renal function.

LB12. Safety and Efficacy of Fidaxomicin and Vancomycin in Pediatric Patients with Clostridium difficile Infection: Phase III, Multicenter, Investigator-blind, Randomized, Parallel Group (SUNSHINE) Study

Background Clostridium difficile infection (CDI), a common cause of antibiotic-associated diarrhea, leads to substantial healthcare burden. In children and young adults, the incidence of CDI is increasing. Fidaxomicin (FDX) is a narrow-spectrum macrocyclic antibiotic treatment for CDI in adults, but pediatric data are limited. The primary objective of our study was to investigate safety and efficacy of FDX and vancomycin (VAN) in children.MethodsPatients aged <18 years with new laboratory-confirmed CDI and diarrhea (watery diarrhea for patients aged <2 years, and ≥3 unformed bowel movements in 24 hours for patients aged ≥2 years) were enrolled in a randomized, investigator-blinded study. Participants were randomized (2:1) to 10 days of treatment with either FDX (oral suspension 32 mg/kg/day or tablets 200 mg BID) or VAN (oral liquid 40 mg/kg/day or capsules 125 mg QID). Concurrent use of other antibiotic treatment for CDI was not permitted. Randomization was stratified by age group. The primary efficacy endpoint was confirmed clinical response (CCR) at Day 12 (absence of diarrhea for 2 consecutive days on treatment and remaining well until treatment discontinuation). Other efficacy endpoints were also evaluated.ResultsOf 142 patients in the full analysis set (FDX n = 98; VAN n = 44), 30 were aged <2 years, 48 were aged 2 to <6 years, 36 were aged 6 to <12 years and 28 were aged 12 to <18 years. At baseline, 28.6% of the FDX arm and 22.7% of the VAN arm had prior confirmed CDI. Overall, 73.5% of the FDX arm and 75.0% of the VAN arm had ≥1 treatment-emergent adverse event. There were three deaths in the FDX arm during the study and two deaths in the VAN arm after end of study (post-Day 40); none were related to treatment. There was a trend to improved CCR and other efficacy outcomes for FDX (figure) and this was statistically significant for global cure (adjusted difference 18.8%; 95% CI 1.5%, 35.3%).ConclusionsThere was a consistent trend for improved efficacy outcomes with FDX compared with VAN, as shown by the adjusted treatment differences, although the small sample size precluded conclusions on most outcome differences.Figure. Disclosures J. Wolf, Astellas Pharma: Consultant and Non-Financial Support, Consulting fee and This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas. . K. Kalocsai, Astellas Pharma: Non-Financial Support, This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas. . C. Fortuny, Astellas Pharma: Non-Financial Support, This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas. . S. Lazar, Astellas Pharma: Non-Financial Support, This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas. . S. Bosis, Astellas Pharma: Non-Financial Support, This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas. . B. Korczowski, Astellas Pharma: Non-Financial Support, This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas. . A. Petit, Astellas Pharma: Non-Financial Support, This study was initiated and sponsored by Astellas. Medical writing support was provided by Cello Health MedErgy and funded by Astellas. . D. Bradford, Astellas Pharma: Employee and Non-Financial Support, Medical writing support was provided by Cello Health MedErgy and funded by Astellas. and Salary. E. Incera, Astellas Pharma: Employee of Iqvia, a CRO contracted by Astellas, Medical writing support was provided by Cello Health MedErgy and funded by Astellas. . J. Melis, Astellas Pharma: Employee and Non-Financial Support, Medical writing support was provided by Cello Health MedErgy and funded by Astellas. and Salary. R. Van Maanen, Astellas Pharma: Employee and Non-Financial Support, Medical writing support was provided by Cello Health MedErgy and funded by Astellas. and Salary.