Serum Vancomycin Concentrations Research Articles

Comparison of the Areas Under the Curve of Vancomycin Continuous vs. Intermittent Infusion in Critically Ill Pediatrics: A Randomized Clinical Trial

Background: Providing data on the superior efficacy of vancomycin administered based on the area under the curve over 24 hours to the minimum inhibitory concentration of vancomycin (AUC24/MIC) is crucial. However, data on dosing and monitoring of vancomycin pharmacokinetics in the pediatric population are limited. Previous findings have suggested that intermittent infusion of vancomycin (IIV) may not achieve the desired levels. Continuous infusions of vancomycin (CIV) reach the desired serum concentration faster than IIV and are associated with reduced nephrotoxicity. Objectives: This study aimed to compare the concentrations, AUC24, clinical variables, and adverse effects of two vancomycin administration methods in the pediatric population. Methods: This study was a double-blind, randomized, controlled clinical trial conducted at a tertiary children's teaching hospital. Inclusion criteria were age between 2 months and 15 years and weight less than 67 kilograms, with exclusion criteria including renal impairment. Participants were divided into CIV and IIV groups following distinct administration protocols. Demographic, clinical, and laboratory data, including vancomycin serum concentrations, were compiled. Assessments included pediatric mortality risk, pediatric sequential organ failure assessment, and regular temperature monitoring. Pharmacokinetic analysis was conducted using Monolix software 2023R1. Primary endpoints were vancomycin serum levels and AUC24 between cohorts on day three, with nephrotoxicity and additional adverse drug responses evaluated. Results: Sixty-eight patients in the pediatric intensive care unit (PICU) were allocated to either CIV (33) or IIV (35) for vancomycin treatment. In the CIV group, 82% of patients achieved an AUC24 ≥ 400 mg.h/L, compared to 23% in the IIV group. Continuous infusions of vancomycin demonstrated a greater AUC24 (587.7 ± 184.4 mg.h/L vs. 361.9 ± 113.2 mg.h/L, P < 0.05) compared to IIV. Two cases of nephrotoxicity were reported, one in each group, with mortality and adverse events being comparable between the two groups. Conclusions: This study demonstrated that continuous vancomycin infusion has a higher success rate in safely achieving therapeutic vancomycin levels in PICU patients compared to intermittent vancomycin infusion.

Association between trough serum vancomycin concentration and vancomycin-associated acute kidney injury and 30-day mortality in critically ill elderly adults

BackgroundVancomycin-associated acute kidney injury (VA-AKI) is the most clinically relevant side effect of vancomycin. The objective of this study was to investigate the association between VTC and VA-AKI as well as 30-day mortality in critically ill elderly adults.MethodElderly patients with trough serum vancomycin concentration records(VTC) in the Medical Information Mart-IV (MIMIC-IV) and eICU databases were retrospectively studied.ResultsA total of 3,146 critically ill elderly adults were finally enrolled. The incidence of VA-AKI in the elderly population was 76.5%. Logistic regression analysis revealed significant relationships between VA-AKI and various factors, including VTC, comorbidities, and laboratory indicators, and SOFA, and GCS score. For each mg/L increase, the OR for VA-AKI increased by 2.5%. The association between VTC and 30-day mortality was found to be statistically significant (odds ratio (OR): 1.021, 95% CI: 1.010–1.031), P < 0.001). The Restricted cubic splines (RCS) curves revealed that VTC ranged of 19.67 to 35.72 mg/l for AKI and 19.17 to 42.86 mg/l for 30-day mortality exhibit OR with 95% CI above 1, indicating statistically significant associations with an increased risk of AKI and 30-day mortality, respectively. In the subgroup analysis, VTC was identified as a risk factor for VA-AKI in specific patient groups, including white individuals, female patients, those with shock, patients with SOFA > 6, patients with baseline creatinine > 1.2 mg/dl and patients with or without exposed to other nephrotoxic medications.ConclusionThis study found the significant association between VTC and the incidence of VA-AKI and 30-day mortality in critically ill elderly adults. The RCS curves indicated concentration ranges for AKI (19.67–35.72 mg/L) and 30-day mortality (19.17–42.86 mg/L), signifying increased risk.

Development of a model to predict vancomycin serum concentration during continuous infusion of vancomycin in critically ill pediatric patients.

Vancomycin is a frequently used antibiotic in intensive care units, and the patient's renal clearance affects the pharmacokinetic characteristics of vancomycin. Several advantages have been reported for vancomycin continuous intravenous infusion, but studies on continuous dosing regimens based on patients' renal clearance are insufficient. The aim of this study was to develop a vancomycin serum concentration prediction model by factoring in a patient's renal clearance. Children admitted to our institution between July 1, 2021, and July 31, 2022 with records of continuous infusion of vancomycin were included in the study. Sex, age, height, weight, vancomycin dose by weight, interval from the start of vancomycin administration to the time of therapeutic drug monitoring sampling, and vancomycin serum concentrations were analyzed with the linear regression analysis of the mixed effect model. Univariable regression analysis was performed using the vancomycin serum concentration as a dependent variable. It showed that vancomycin dose (p < 0.001) and serum creatinine (p = 0.007) were factors that had the most impact on vancomycin serum concentration. Vancomycin serum concentration was affected by vancomycin dose (p < 0.001) and serum creatinine (p = 0.001) with statistical significance, and a multivariable regression model was obtained as follows: Vancomycin serum concentration (mg/l) = -1.296 + 0.281 × vancomycin dose (mg/kg) + 20.458 × serum creatinine (mg/dl) (adjusted coefficient of determination, R2 = 0.66). This prediction model is expected to contribute to establishing an optimal continuous infusion regimen for vancomycin.

Impact of physical build on serum vancomycin concentrations of patients undergoing hemodialysis: A retrospective cohort study at an acute care hospital

IntroductionEstimating the serum vancomycin (VCM) concentrations of lean and patients with obesity is challenging. Additionally, VCM dosing for Japanese patients undergoing hemodialysis remains particularly unclear. This study aimed to determine the impact of the physical build on serum VCM concentrations of Japanese patients undergoing hemodialysis. MethodsThis retrospective cohort study included hospitalized patients undergoing hemodialysis, who received treatment with VCM between May 1, 2019, and December 31, 2021, at Kansai Rosai Hospital, which is a 642-bed acute care hospital in Japan. Patients were divided into the following three groups based on their body mass index (BMI): lean group (≤18.5 kg/m2), normal group (18.5–25 kg/m2), and obese group (≥25 kg/m2). The VCM dose and predialysis serum VCM concentration (PVC) were compared. ResultsThis study included 191 patients. There were 50 patients in the lean group, 85 in the normal group, and 56 in the obese group. The median loading doses per body weight were 24.0, 22.1, and 21.2 mg/kg for the lean, normal, and obese groups, respectively. The VCM dose per body weight decreased significantly with increasing BMI. The median PVCs of the lean and normal groups were approximately 15 mg/L (not significantly different). However, the median PVC of the obese group was 18.3 mg/L, which was significantly higher (P < 0.001). ConclusionsThe VCM dose per body weight for Japanese patients undergoing hemodialysis should be adjusted based on the BMI.

Model-Informed Precision Dosing Improves Outcomes in Patients Receiving Vancomycin for Gram-Positive Infections.

Consensus guidelines for dosing and monitoring of vancomycin recommend collection of 2 serum concentrations to estimate an area under the curve/minimum inhibitory concentration ratio (AUC/MIC). Use of Bayesian software for AUC estimation and model-informed precision dosing (MIPD) enables pre-steady state therapeutic drug monitoring using a single serum concentration; however, data supporting this approach are limited. Adult patients with culture-proven gram-positive infections treated with vancomycin ≥72 hours receiving either trough-guided or AUC-guided therapy were included in this retrospective study. AUC-guided therapy was provided using MIPD and single-concentration monitoring. Treatment success, vancomycin-associated acute kidney injury (VA-AKI), and inpatient mortality were compared using a desirability of outcome ranking analysis. The most desirable outcome was survival with treatment success and no VA-AKI, and the least desirable outcome was death. The study population (N = 300) was comprised of an equal number of patients receiving AUC-guided or trough-guided therapy. More patients experienced the most desirable outcome in the AUC-guided group compared to the trough-guided group (58.7% vs 46.7%, P = .037). Rates of VA-AKI were lower (21.3% vs 32.0%, P = .037) and median hospital length of stay was shorter (10 days [interquartile range {IQR}, 8-20] vs 12 days [IQR, 8-25]; P = .025) among patients receiving AUC-guided therapy. AUC-guided vancomycin therapy using MIPD and single-concentration monitoring improved outcomes in patients with culture-proven gram-positive infections. Safety was improved with reduced incidence of VA-AKI, and no concerns for reduced efficacy were observed. Moreover, MIPD allowed for earlier assessment of AUC target attainment and greater flexibility in the collection of serum vancomycin concentrations.

Association of piperacillin and vancomycin exposure on acute kidney injury during combination therapy.

Acute kidney injury (AKI) is a well-documented adverse effect observed with piperacillin/tazobactam in combination with vancomycin. The pharmacokinetics of these antibiotics when given in combination have not been previously evaluated. The purpose of this study was to compare the exposure of vancomycin + piperacillin/tazobactam in patients with and without AKI. Ninety adult patients, who received at least 72 h of vancomycin + piperacillin/tazobactam combination therapy and had available serum concentrations of vancomycin and piperacillin were included in the study. Nephrotoxicity was defined as a 1.5-fold increase in serum creatinine within 7 days from baseline. Median daily AUCs were calculated in those with nephrotoxicity (vancomycin + piperacillin/tazobactam 'N') versus those without nephrotoxicity (vancomycin + piperacillin/tazobactam 'WN') during the first 7 days of combination therapy. The overall incidence of AKI in those receiving vancomycin + piperacillin/tazobactam was 20% (18/90). The median daily vancomycin AUCs did not differ between the vancomycin + piperacillin/tazobactam 'WN' and vancomycin + piperacillin/tazobactam 'N' groups. Although not statistically significant, the median daily vancomycin AUCs in the vancomycin + piperacillin/tazobactam 'N' group were numerically greater on Day 5 and trended downwards thereafter. For the piperacillin group, the median daily AUCs did not vary between groups, except on Day 7 where the vancomycin + piperacillin/tazobactam 'WN' group had statistically greater median piperacillin AUC than the vancomycin + piperacillin/tazobactam 'N' group (P = 0.046). Utilizing serum creatinine-defined AKI, our study did not find any significant differences in vancomycin and piperacillin/tazobactam exposure between the groups with and without nephrotoxicity. These data indicate that vancomycin + piperacillin/tazobactam should not be avoided due to the risk of overexposure; instead, clinicians should continue to use these therapies cautiously.

Toward Model-Based Informed Precision Dosing of Vancomycin in Hematologic Cancer Patients: A First Step.

There is no consensus on the optimal vancomycin dose to achieve pharmacokinetic/pharmacodynamic (PK/PD) target in patients with hematologic cancer or in hematopoietic stem cell transplant (HSCT) recipients. A 24-h area under the concentration-time curve (AUC) >400 mg*h/L must be achieved early for successful treatment of severe methicillin-resistant Staphylococcus aureus (MRSA) infections. Current nomograms derived from general population data are not sufficiently accurate to allow AUC-based model-informed precision dosing. The objective of this study was to characterize vancomycin PK in patients with hematologic cancer or in HSCT recipients and to develop a model-informed dosing tool based on PK/PD target requirements. Pooled retrospective and prospective vancomycin serum concentrations were analyzed using NONMEM® to evaluate the performance of previously published population PK (popPK) models built from hematologic cancer datasets and to develop a novel Bayesian PK model. Patients' characteristics and clinical data were tested as potential covariates. The popPK model was validated internally and externally. Predictions of vancomycin concentrations for different dosing regimens were made using Monte-Carlo simulations, and a nomogram strategy was proposed according to selected probability of target attainment (PTA). The predictive performance of the published popPK models was found to be suboptimal for our population. A novel popPK model was developed using 240 vancomycin concentrations (60 patients). A two-compartment structural model with an additive error model best described the data. Ideal body weight and estimated glomerular filtration rate (eGFR) [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)] were selected as covariates for volume of distribution (V) and clearance (CL). Bootstrapping confirmed the stability and precision of the popPK parameters. The volume of distribution was V1=46.8 L and V2=56.1L, while CL=5.63L/h. External validation using 107 vancomycin concentrations (24 patients) demonstrated the predictivity of the model. A nomogram was developed to reach minimally PTA >50% for 400 < AUC < 600 mg*h/L. To our knowledge, this study provides the first model-informed AUC-based strategy in North American hematologic cancer patients with or without HSCT. The resulting nomogram generated provides a simplified approach to improving the accuracy of initial vancomycin dosing in this population.

Model-Informed Vancomycin Dosing Optimization to Address Delayed Renal Maturation in Infants and Young Children with Critical Congenital Heart Disease.

Ensuring safe and effective drug therapy in infants and young children often requires accounting for growth and organ development; however, data on organ function maturation are scarce for special populations, such as infants with congenital diseases. Children with critical congenital heart disease (CCHD) often require multiple staged surgeries depending on their age and disease severity. Vancomycin (VCM) is used to treat postoperative infections; however, the standard pediatric dose (60-80 mg/kg/day) frequently results in overexposure in children with CCHD. In this study, we characterized the maturation of VCM clearance in pediatric patients with CCHD and determined the appropriate dosing regimen using population pharmacokinetic (PK) modeling and simulations. We analyzed 1,254 VCM serum concentrations from 152 postoperative patients (3 days-13 years old) for population PK analysis. The PK model was developed using a two-compartment model with allometrically scaled body weight, estimated glomerular filtration rate (eGFR), and postmenstrual age as covariates. The observed clearance in patients aged ≤ 1 year and 1-2 years was 33% and 40% lower compared with that of non-CCHD patients, respectively, indicating delayed renal maturation in patients with CCHD. Simulation analyses suggested VCM doses of 25 mg/kg/day (age ≤ 3 months, eGFR 40 mL/min/1.73 m2 ) and 35 mg/kg/day (3 months < age ≤ 3 years, eGFR 60 mL/min/1.73 m2 ). In conclusion, this study revealed delayed renal maturation in children with CCHD, could be due to cyanosis and low cardiac output. Model-informed simulations identified the lower VCM doses for children with CCHD compared with standard pediatric guidelines.

Vancomycin removal and pharmacokinetics during accelerated venovenous hemofiltration.

Vancomycin pharmacokinetics are affected by renal replacement therapy and physiologic changes in critically ill patients. Literature regarding vancomycin removal and pharmacokinetics during accelerated venovenous hemofiltration (AVVH), a form of prolonged intermittent renal replacement therapy, is limited. To describe the removal and pharmacokinetics of vancomycin during AVVH. Eighteen critically ill adults receiving vancomycin and AVVH were included. Vancomycin serum concentrations were obtained within 4 h before and 2-6 h after the AVVH session. Patients' serum concentrations were plotted against time, and individual pharmacokinetic parameters were determined by a one-compartmental analysis. Continuous data are reported as a median (interquartile range [IQR]) and categorical data as a percentage. The median AVVH effluent rate was 39.3 mL/kg/h (IQR 35.5-48 mL/kg/h) for a duration of 9 h (IQR 8-9.75 h). AVVH decreased vancomycin concentrations by 29.8% (IQR 24.9%-35.9%), at a rate of 3.4% per hour (IQR 3.1%-4.3% per hour) of AVVH. The vancomycin elimination rate constant and half-life were 0.039 h-1 (IQR 0.036-0.053 h-1 ) and 17.6 h (IQR 13.1-18.8 h), respectively. The area under the curve during AVVH was 171.7 mg*h/L (IQR 149.1-190 mg*h/L). The volume of distribution in 10 patients was 1 L/kg (IQR 0.73-1.1 L/kg). After AVVH, vancomycin 1000 mg (IQR 750-1000 mg) was needed to maintain a serum trough concentration ≥15 mg/L. Vancomycin is significantly removed by AVVH, which requires supplemental dosing after completion of the AVVH session to maintain desired serum concentrations. Therapeutic drug monitoring of vancomycin serum concentrations is recommended for patients undergoing AVVH.

Comparison of Vancomycin Trough-Based and 24-Hour Area Under the Curve Over Minimum Inhibitory Concentration (AUC/MIC)-Based Therapeutic Drug Monitoring in Pediatric Patients.

Vancomycin 24-hour area under the curve over minimum inhibitory concentration (AUC/MIC) monitoring has been recommended over trough-based monitoring in pediatric patients. This study compared the proportion of target attainment between vancomycin AUC/MIC and trough-based methods, and identified risk factors for subtherapeutic initial extrapolated targets. This was a retrospective, observational study conducted at KK Women's and Children's Hospital (KKH), Singapore. Patients aged 1 month to 18 years with stable renal function who received intravenous vancomycin between January 2014 and October 2017, with at least 2 vancomycin serum concentrations obtained after the first dose of vancomycin, were included. Using a pharmacokinetic software, namely Adult and Pediatric Kinetics (APK), initial extrapolated steady-state troughs and 24-hour AUC were determined by using a one-compartmental model. Statistical tests included Wilcoxon rank sum test, McNemar test, logistic regression, and classification and regression tree (CART) analysis. Of the 82 pediatric patients included, a significantly larger proportion of patients achieved therapeutic targets when the AUC/MIC-based method (24, 29.3%) was used than with the trough-based method (9, 11.0%; p < 0.01). Patients with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 or with age <13 years had an increased risk of obtaining subtherapeutic targets. However, empiric vancomycin doses of 60 mg/kg/day would be sufficient to achieve serum therapeutic targets, using the AUC/MIC-based method. The AUC/MIC-based vancomycin monitoring may be preferred because a larger proportion of patients could achieve initial therapeutic targets. Future prospective studies with larger sample size will be required to determine the optimal vancomycin strategy for pediatric patients.

Effectiveness of a low trough serum concentration of vancomycin on acute kidney injury in infants and toddlers in the paediatric intensive care unit

ObjectiveThis study aimed to assess the effectiveness of a low trough serum concentration of vancomycin on acute kidney injury in infants and toddlers in the paediatric intensive care unit (PICU).MethodsA...

Vancomycin and daptomycin dosing recommendations in patients receiving home hemodialysis using Monte Carlo simulation

BackgroundFew drug dosing recommendations for patients receiving home hemodialysis (HHD) have been published which has hindered the adoption of HHD. HHD regimens vary widely and differ considerably from conventional, thrice weekly, in-center hemodialysis in terms of treatment frequency, duration and blood and dialysate flow rates. Consequently, vancomycin and daptomycin clearances in HHD are also likely to be different, consequently HHD dosing regimens must be developed to ensure efficacy and minimize toxicity when these antibiotics are used. Many HHD regimens are used clinically, this study modeled ten common HHD regimens and determined optimal vancomycin and daptomycin dosing for each HHD regimen.MethodsMonte Carlo simulations using pharmacokinetic data derived from the literature and demographic data from a large HHD program treating patients with end stage kidney disease were incorporated into a one-compartment pharmacokinetic model. Virtual vancomycin and daptomycin doses were administered post-HHD and drug exposures were determined in 5,000 virtual patients receiving ten different HHD regimens. Serum concentration monitoring with subsequent dose changes was incorporated into the vancomycin models. Pharmacodynamic target attainment rates were determined for each studied dose. The lowest possible doses that met predefined targets in virtual patients were chosen as optimal doses.ResultsHHD frequency, total dialysate volumes and HHD durations influenced drug exposure and led to different dosing regimens to meet targets. Antibiotic dosing regimens were identified that could meet targets for 3- and 7-h HHD regimens occurring every other day or 4–5 days/week. HHD regimens with 3-day interdialytic periods required higher doses prior to the 3-day period. The addition of vancomycin serum concentration monitoring allowed for calculation of necessary dosing changes which increased the number of virtual subjects meeting pharmacodynamic targets.ConclusionsDoses of vancomycin and daptomycin that will meet desired pharmacodynamic targets in HHD are dependent on patient and HHD-specific factors. Doses used in conventional thrice weekly hemodialysis are unlikely to meet treatment goals. The antibiotic regimens paired with the HHD parameters studied in this analysis are likely to meet goals but require clinical validation.

Vancomycin dosing in high-intensity continuous renal replacement therapy: A retrospective cohort study.

An inverse relationship exists between vancomycin serum concentrations and the intensity of continuous renal replacement therapy (CRRT), reflected through the dialysate flow rate (DFR). There remains a lack of evidence to guide initial vancomycin dosing in the setting of high-intensity CRRT (i.e., DFR >30 mL/kg/h). Additionally, recommendations for pharmacokinetic monitoring of vancomycin have transitioned from a trough-based to area under the curve (AUC)-based dosing strategy to optimize efficacy and safety. Therefore, an improved understanding of the impact of CRRT intensity on AUC/MIC (minimum inhibitory concentration) has the potential to enhance vancomycin dosing in this patient population. The goal of this study is to evaluate current vancomycin dosing strategies and achievement of pharmacokinetic targets in patients on high-intensity CRRT. This was a single-center, retrospective cohort study of adult critically ill patients admitted to Houston Methodist Hospital between May 2019 and October 2021 and received vancomycin therapy while on high-intensity CRRT. High-intensity CRRT was defined by a DFR that was both ≥3 L/h and >30 mL/kg/h. Depending on the initial vancomycin dosing strategy, patients were stratified into either the traditional (15 mg/kg/day) or enhanced (≥15 mg/kg/day) dosing group. The primary outcome was the percent of patients who attained steady-state AUC24 /MIC ≥400 mg*h/L at the first obtained vancomycin level in the enhanced group compared with the traditional group. A total of 125 patients were included in the final analysis, 56 in the traditional and 69 in the enhanced dosing group. The primary end point occurred in 74% and 54% of patients in the enhanced and traditional dosing groups, respectively (p = 0.029). Therapeutic vancomycin trough levels (10-20 μg/mL) were more commonly achieved in the enhanced dosing group compared with the traditional dosing group (66.7% vs. 45%, p = 0.013). As DFR rose, increasingly higher doses of vancomycin, up to 27 mg/kg/day, were required to achieve the therapeutic targets. This is the first study to evaluate the influence of variable CRRT intensities on vancomycin AUC/MIC. Our findings suggest that vancomycin doses of ≥15 mg/kg/day are needed to achieve early therapeutic targets in patients on high-intensity CRRT.

Vancomycin population pharmacokinetics analysis in Chinese paediatric patients with varying degrees of renal function and ages: development of new practical dosing recommendations.

To describe the pharmacokinetics of vancomycin in a large Chinese paediatric cohort with varying degrees of renal function and ages and to develop practical dosing guidelines. We conducted a retrospective population pharmacokinetic study using data from paediatric patients who received vancomycin between June 2013 and June 2022. A non-linear mixed-effect modelling approach with a one-compartment model structure was applied. Monte Carlo simulations were used to stimulate an optimal dosage regimen to achieve the target of AUC24/MIC between 400 and 650. We analysed a total of 673 paediatric patients and 1547 vancomycin serum concentrations. Covariate analysis revealed that physiological maturation, renal function, albumin and cardiothoracic surgery (CTS) significantly affected vancomycin pharmacokinetics. The typical clearance and volume of distribution, standardized to 70 kg, were 7.75 L/h (2.3% relative standard error, RSE) and 36.2 L (1.7% RSE), respectively. Based on the model, we proposed an optimal dosing regimen that considers the patient's age and estimate glomerular filtration rate (eGFR) to achieve a target AUC24/MIC for CTS and non-CTS patients. We also found that a loading dose of 20 mg/kg can help patients with an eGFR of <60 mL/min/1.73 m2 achieve the target AUC on the first day of treatment. We established vancomycin pharmacokinetic parameters in Chinese paediatric patients and proposed a dosing guideline integrating eGFR, age and CTS status, potentially improving clinical outcomes and reducing nephrotoxicity risk.

Performance of Bayesian Area Under the Concentration-Time Curve-Based Pharmacokinetic Dosing Based on a One-Compartment Model and Trough-Only Monitoring for Vancomycin.

A novel Bayesian method was developed to interpret serum vancomycin concentrations (SVCs) following the administration of one or more vancomycin doses with potential varying doses and intervals based on superposition principles. The method was evaluated using retrospective data from 442 subjects from three hospitals. The patients were required to receive vancomycin for more than 3 days, have stable renal function (fluctuation in serum creatinine of ≤0.3 mg/dL), and have at least 2 trough concentrations reported. Pharmacokinetic parameters were predicted using the first SVC, and the fitted parameters were then used to predict subsequent SVCs. Using only covariate-adjusted population prior estimates, the first two SVC prediction errors were 47.3 to 54.7% for the scaled mean absolute error (sMAE) and 62.1 to 67.8% for the scaled root mean squared error (sRMSE). "Scaled" refers to the division of the MAE or RMSE by the mean value. The Bayesian method had minimal errors for the first SVC (by design), and for the second SVC, the sMAE was 8.95%, and the sRMSE was 36.5%. The predictive performance of the Bayesian method did degrade with subsequent SVCs, which we attributed to time-dependent pharmacokinetics. The 24-h area under the concentration-time curve (AUC) was determined from simulated concentrations before and after the first SVC was reported. Prior to the first SVC, 170 (38.4%) patients had a 24-h AUC of <400 mg · h/L, 186 (42.1%) had a 24-h AUC within the target range, and 86 (19.5%) had a 24-h AUC of >600 mg · h/L. After the first SVC was reported, 322 (72.9%) had a 24-h AUC within the target range, 68 (15.4%) had low values, and 52 (11.8%) had high values based on the model simulation. Target attainments were 38% before the first SVC and 73% after the first SVC. The hospitals had no policies or procedures in place for targeting 24-h AUCs, although the trough target was typically 13 to 17 mg/L. Our data provide evidence of time-dependent pharmacokinetics, which will require regular therapeutic drug monitoring regardless of the method used to interpret SVCs.

Acute supratherapeutic vancomycin serum concentration in a premature neonate: a case report 

Vancomycin, a glycopeptide, is a first-line agent in the neonatal population for the treatment of suspected or confirmed Gram-positive infections, including methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative Staphylococci (CoNS).1,2 Vancomycin dosing strategies vary greatly and are generally based on factors such as post-menstrual age (PMA), post-natal age (PNA), and serum creatinine (SCr). Recommended starting doses can range from 10 to 15 mg/kg/dose every 6 to 48 hours, depending upon infection site, suspected organism, desired serum vancomycin trough concentration/area under the curve (AUC), and/or minimal inhibitory concentration (MIC) to vancomycin. Nephrotoxicity in patients receiving vancomycin has been systematically documented in adults and less often in neonates, with a reported occurrence of 1-9% when receiving recommended dosing.1 Risk of toxicity can be minimized through dosage modifications and close monitoring of SCr and urine output at baseline and throughout therapy.2 This case report describes the use of vancomycin, dosed at 10 mg/kg, in a premature infant born at 26 weeks and 4 days gestation for CoNS pneumonia. The infant showed signs of renal dysfunction, prompting a pre-steady state vancomycin serum concentration lab draw, resulting in a concentration of 102.2 µg/mL. Serial repeat vancomycin serum concentrations showed a linear excretion pattern and an ARCHITECT iVancomycin assay completed by medical laboratory scientists confirmed the concentration of the vancomycin aliquot prepared by the inpatient pharmacy department. Renal ultrasound established return to normal renal function; however, the infant failed routine newborn hearing screening upon NICU (neonatal intensive care unit) discharge due to suspected vancomycin-induced ototoxicity.

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...

Evaluation of Dosing Regimens of Vancomycin and Aminoglycosides in Pediatric Patients on Continuous Renal Replacement Therapy.

To determine the optimal empiric dosing regimen to achieve therapeutic serum concentrations of vancomycin and aminoglycosides in pediatric patients who are receiving continuous renal replacement therapy (CRRT). This retrospective study investigated pediatric patients (<18 years old) who received at least one dose of an aminoglycoside and/or vancomycin while on CRRT and who had at least one serum concentration assessed during the study period. Rates of culture clearance and discontinuation of renal replacement therapy, pharmacokinetic variables (i.e., volume of distribution [Vd], half-life [t½], rate of elimination [ke]), and correlations between patient's age and weight in regard to the empiric dosing regimen were evaluated. Forty-three patients were included in this study. The median dose required to reach therapeutic serum concentrations for vancomycin was 17.6 mg/kg (12.8-20.4 mg/kg) every 12 hours (6-30 hours) in continuous venovenous hemodialysis (CVVHD) patients and 16.3 mg/kg (13.9-21.4 mg/kg) every 12 hours (6-24 hours) in continuous venovenous hemodiafiltration (CVVHDF) patients. The median dose for aminoglycosides was unable to be determined. In CVVHD patients, the median vancomycin ke was 0.04 hr-1, t½ was 18 hours, and Vd was 1.6 L/kg. In CVVHDF patients, the median vancomycin ke was 0.05 hr-1, t½ was 14 hours, and Vd was 0.6 L/kg. No correlation was found between age and weight with regard to effective dosing regimen. To achieve therapeutic trough concentrations in pediatric patients on CRRT, vancomycin should be dosed at approximately 17.5 mg/kg administered every 12 hours.

Predicting the Area under the Plasma Concentration-Time Curve (AUC) for First Dose Vancomycin Using First-Order Pharmacokinetic Equations.

To treat critically ill patients, early achievement of the target area under the plasma concentration-time curve/minimum inhibitory concentration (AUC/MIC) in the first 24 h is recommended. However, accurately calculating the AUC before steady state is an obstacle to this goal. A first-order pharmacokinetic equation to calculate vancomycin AUC after a first dose of vancomycin has never been studied. We sought to estimate AUC using two first-order pharmacokinetic equations, with different paired concentration time points, and to compare these to the actual first dose vancomycin AUC calculated by the linear-log trapezoid rule as a reference. The equations were validated using two independent intensive first dose vancomycin concentration time data sets, one from 10 adults and another from 14 children with severe infection. The equation with compensation for the alpha distribution phase using a first vancomycin serum concentration from 60 to 90 min and the second concentration from 240 to 300 min after the completed infusion showed good agreement and low bias of calculated AUC, with mean differences <5% and Lin's correlation coefficient >0.96. Moreover, it gave an excellent correlation with Pearson's r > 0.96. Estimating the first dose vancomycin AUC calculated using this first-order pharmacokinetic equation is both reliable and reproducible in clinical practice settings.

Pharmacokinetics of vancomycin and meropenem during continuous online hemodiafiltration: A case report

The pharmacokinetics of vancomycin and meropenem in patients treated with continuous online hemodiafiltration (OL-HDF) are not well understood. We evaluated dialytic clearance and serum concentrations of vancomycin and meropenem by OL-HDF in a critically ill patient with soft tissue infection. The mean clearance of OL-HDF and mean serum concentrations during continuous OL-HDF were 155.2 mL/min and 23.1 µg/mL for vancomycin and 145.6 mL/min and 22.7 µg/mL for meropenem. Vancomycin and meropenem showed high clearance rates during continuous OL-HDF. However, continuous infusion of these agents at high doses maintained therapeutic serum concentrations.