Vancomycin Pharmacokinetics Research Articles

The pharmacokinetics of vancomycin during the initial loading dose in patients with septic shock.

ObjectiveTo characterize the pharmacokinetics (PK) of vancomycin in patients in the initial phase of septic shock.MethodsTwelve patients with septic shock received an intravenous infusion of vancomycin 30 mg/kg over 2 h. The vancomycin PK study was conducted during the first 12 h of the regimen. Serum vancomycin concentration–time data were analyzed using the standard model-independent analysis and the compartment model.ResultsFor the noncompartment analysis the mean values ± standard deviation (SD) of the estimated clearance and volume of distribution of vancomycin at steady state were 6.05±1.06 L/h and 78.73±21.78 L, respectively. For the compartmental analysis, the majority of vancomycin concentration–time profiles were best described by a two-compartment PK model. Thus, the two-compartmental first-order elimination model was used for the analysis. The mean ± SD of the total clearance (3.70±1.25 L/h) of vancomycin was higher than that obtained from patients without septic shock. In contrast, the volume of the central compartment (8.34±4.36 L) and volume of peripheral compartment (30.99±7.84 L) did not increase when compared with patients without septic shock.ConclusionThe total clearance of vancomycin was increased in septic shock patients. However, the volume of the central compartment and peripheral compartment did not increase. Consequently, a loading dose of vancomycin should be considered in all patients with septic shock.

Population Pharmacokinetics of Vancomycin in Postoperative Neurosurgical Patients and the Application in Dosing Recommendation

Our previous study indicates that cerebrospinal fluid (CSF) albumin level is a determinant of CSF vancomycin concentration for postoperative neurosurgical patients. We aimed to develop an improved vancomycin population pharmacokinetic model with incorporation of more covariates, and to provide dosing guidance for clinicians. Vancomycin was administered intravenously to 20 patients with external ventricular drains after neurosurgical operation. Blood and CSF were collected and vancomycin concentrations were measured by HPLC. A separate CSF compartment was considered, and was linked to the central compartment by a first-order process (QCSF). The clearance of the CSF compartment (ClCSF) was used to characterize vancomycin elimination from CSF through external ventricular drain. Nonlinear mixed-effects modeling approach was used to develop the model. The CSF albumin level (mg/dL) was the covariate influencing QCSF: QCSF=0.0049+0.000021×(CSF albumin−279). The effect of body weight (BW, kg) was significant on central volume (VC): VC=27.84+0.96×(BW−69). All parameters were estimated with an acceptable precision (relative standard error: RSE% < 30.26). The performance of the final model was acceptable with our previous dataset. A simple to use dosage regimen table was created to guide clinicians with vancomycin dosing. This model incorporates variables of both CSF albumin and BW, which offers improvements to the previous pharmacokinetics model.

A Population Pharmacokinetic Model for Vancomycin in Adult Patients Receiving Extracorporeal Membrane Oxygenation Therapy.

The literature on the pharmacokinetics of vancomycin in patients undergoing extracorporeal membrane oxygenation (ECMO) therapy is sparse. A population pharmacokinetic (PK) model for vancomycin in ECMO patients was developed using a nonlinear mixed effects modeling on the concentration–time profiles of 14 ECMO patients who received intravenous vancomycin. Model selection was based on log‐likelihood criterion, goodness of fit plots, and scientific plausibility. Identification of covariates was done using a full covariate model approach. The pharmacokinetics of vancomycin was adequately described with a two‐compartment model. Parameters included clearance of 2.83 L/hr, limited central volume of distribution 24.2 L, and low residual variability 0.67%. Findings from the analysis suggest that standard dosing recommendations for vancomycin in non‐ECMO patients are adequate to achieve therapeutic trough concentrations in ECMO patients. This further shows that ECMO minimally affects the PK of vancomycin in adults including in higher‐weight patients.

Comparison of the pharmacokinetics of vancomycin in neurosurgical and non-neurosurgical patients

Although vancomycin concentrations in neurosurgical patients tend to be lower following standard dosing compared with other patient populations, factors influencing vancomycin pharmacokinetics in neurosurgical patients are poorly understood. In this study, pharmacokinetic (PK) parameters in neurosurgical and non-neurosurgical patients were compared. Furthermore, factors influencing vancomycin PK alterations, including those known to augment renal clearance, were determined. Routine therapeutic drug monitoring data from neurosurgical and non-neurosurgical patients were retrospectively collected. Vancomycin PK parameters were estimated using non-linear mixed-effects modelling (NONMEM v.7.2.0); analyses were performed for the entire population and for neurosurgical patients only. Furthermore, the final models performed a bootstrap, visual predictive check and external validation. A total of 359 serum vancomycin concentration data variables from 132 patients were used to execute the PK modelling. Neurosurgical patient factor, the early phase of treatment, underlying liver cirrhosis, co-administration of a nephrotoxic drug and estimated creatinine clearance influenced vancomycin clearance (CL). However, other factors known to augment renal clearance did not affect vancomycin pharmacokinetics. Vancomycin CL was significantly higher in neurosurgical patients than in controls (0.104 ± 0.036 L/h/kg vs. 0.073 ± 0.042 L/h/kg; P < 0.01). Augmented vancomycin CL should be considered when determining vancomycin dosages in neurosurgical patients.

AUC-Guided Vancomycin Dosing in Adolescent Patients With Suspected Sepsis.

Vancomycin is a first-line treatment for β-lactam-resistant Gram-positive bacterial infections. Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of vancomycin in an adolescent population is of clinical importance in this often overlooked pediatric population. This retrospective study investigated vancomycin PK-PD in an adolescent cohort (12 to 18 years of age) of 463 patients (57% male, 81% white) admitted to the Intermountain Healthcare System between January 2006 and December 2013. Population PK modeling was performed in NONMEM 7.3. Vancomycin PK was well described with a 1-compartment model that identified both body weight (WT) and creatinine clearance (CRCL) as covariates significantly impacting vancomycin disposition. The model was then utilized to determine dosing strategies that achieved the targeted area under the 24-hour time curve vs minimum inhibitory concentration (AUC0-24 /MIC) ratio of ≥400. Additionally, these data were correlated with minimum steady-state concentrations (Css,min ) to find an acceptable target trough concentration range in adolescents. This analysis demonstrated that Css,min ranging from 10 to 12.5 mg/L were highly predictive of achieving an AUC0-24 /MIC ≥400 when the MIC was ≤1 mg/L. These results suggest that the target trough concentration for adolescents may be lower than that for adults.

Pharmacokinetics of Vancomycin in Elderly Patients Aged over 80 Years.

Since the 1950s, vancomycin has remained a reference treatment for severe infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus Vancomycin is a nephrotoxic and ototoxic drug mainly eliminated through the kidneys. It has a large interindividual pharmacokinetic variability, which justifies monitoring its plasma concentrations in patients. This is especially important in patients aged over 80 years, who frequently have renal impairment. However, the pharmacokinetics of vancomycin in this population is very poorly described in the literature. The objective of this work was to propose a model able to predict the pharmacokinetics of vancomycin in very elderly people. First, a population pharmacokinetic model was carried out using the algorithm NPAG (nonparametric adaptive grid) on a database of 70 hospitalized patients aged over 80 years and treated with vancomycin. An external validation then was performed on 41 patients, and the predictive capabilities of the model were assessed. The model had two compartments and six parameters. Body weight and creatinine clearance significantly influenced vancomycin volume of distribution and body clearance, respectively. The means (± standard deviations) of vancomycin volume of distribution and clearance were 36.3 ± 15.2 liter and 2.0 ± 0.9 liter/h, respectively. In the validation group, the bias and precision were -0.75 mg/liter and 8.76 mg/liter for population predictions and -0.39 mg/liter and 2.68 mg/liter for individual predictions. In conclusion, a pharmacokinetic model of vancomycin in a very elderly population has been created and validated for predicting plasma concentrations of vancomycin.

Clinical Utility and Safety of a Model-Based Patient-Tailored Dose of Vancomycin in Neonates.

Pharmacokinetic modeling has often been applied to evaluate vancomycin pharmacokinetics in neonates. However, clinical application of the model-based personalized vancomycin therapy is still limited. The objective of the present study was to evaluate the clinical utility and safety of a model-based patient-tailored dose of vancomycin in neonates. A model-based vancomycin dosing calculator, developed from a population pharmacokinetic study, has been integrated into the routine clinical care in 3 neonatal intensive care units (Robert Debré, Cochin Port Royal, and Clocheville hospitals) between 2012 and 2014. The target attainment rate, defined as the percentage of patients with a first therapeutic drug monitoring serum vancomycin concentration achieving the target window of 15 to 25 mg/liter, was selected as an endpoint for evaluating the clinical utility. The safety evaluation was focused on nephrotoxicity. The clinical application of the model-based patient-tailored dose of vancomycin has been demonstrated in 190 neonates. The mean (standard deviation) gestational and postnatal ages of the study population were 31.1 (4.9) weeks and 16.7 (21.7) days, respectively. The target attainment rate increased from 41% to 72% without any case of vancomycin-related nephrotoxicity. This proof-of-concept study provides evidence for integrating model-based antimicrobial therapy in neonatal routine care.

The Pharmacokinetics of Vancomycin Calculated Using the Sawchuk-Zaske Method in Patients Undergoing Continuous Hemodiafiltration

The Pharmacokinetics of Vancomycin Calculated Using the Sawchuk-Zaske Method in Patients Undergoing Continuous Hemodiafiltration

In silico Analysis of Clostridium difficile Biofilm Metabolism and Treatment

Abstract: Clostridium difficile is an anaerobic bacterium responsible for recurring infections in the gastrointestinal tracts of patients previously treated with oral antibiotics that disrupt the healthy gut microbiome. Recent in vitro experiments have demonstrated the ability of C. difficile to form biofilms on surfaces. We developed a metabolic model of C. difficile biofilms to investigate the effects of biofilm formation on antibiotic treatment in vivo. The model was formulated by combining a genome-scale reconstruction of C. difficile primary metabolism with reaction-diffusion type equations for key nutrients (glucose and six essential amino acids) and the common oral antibiotic vancomycin. A very simple model of vancomycin pharmacokinetics was used to predict the efficacy of a typical treatment schedule under the assumption of a fixed thickness of the mature biofilm. Our model predicted that vancomycin will effectively eradicate biofilms of sufficiently small thickness. Once the thickness passed a critical threshold, the model predicted vancomycin treatment would fail catastrophically due to insufficient antibiotic penetration into the biofilm caused by the combination of limited diffusion and vancomycin binding to cell wall precursors. This critical biofilm thickness was shown to be very sensitive to model parameters associated with the vancomycin stool levels and killing efficiency.

Pharmacokinetic Characteristics and Clinical Outcomes of Vancomycin in Young Children With Various Degrees of Renal Function.

Although vancomycin pharmacokinetics are affected by age and renal function in adults and older children, its pharmacokinetics in children aged 1month to 2 years remained unclear. We investigated clinical outcome and nephrotoxicity in younger children with renal insufficiency who were treated with vancomycin. One hundred and ten children aged 1 month to 2 years were enrolled, and they were divided into 3 groups: normal renal function (group A), mild renal insufficiency (group B), and moderate renal insufficiency (group C). A population pharmacokinetic model was established. Significant differences were observed for trough concentration, AUC0-24h , CL, and t1/2 in the 3 groups. When given at 40 mg/kg per day, 36.4%, 62.5%, and 85.0% of children achieved the target of AUC/MIC ≥ 400, and 47.0%, 70.8%, and 95% of children obtained early good clinical outcomes in groups A, B, and C (P<.05), respectively. One child in group A and 4 children in group C suffered from acute kidney injury. These results indicated that children with renal insufficiency readily achieved the target AUC/MIC but were at increased risk of nephrotoxicity. Vancomycin clearance and creatinine clearance were not correlated with each other in children with renal insufficiency, indicating that both renal function and serum concentration should be monitored during vancomycin therapy.

Pharmacokinetics of vancomycin and dosing recommendations for trauma patients.

The objectives of this study were to characterize the population pharmacokinetics of vancomycin in trauma patients and to propose dosing schemes to optimize therapy. Trauma patients from Hospital Universitario Severo Ochoa (Spain) receiving intravenous vancomycin and routine therapeutic drug monitoring were included. Concentrations and time data were retrospectively collected, and population modelling was performed with NONMEM 7.2; internal and external validations were performed to probe the final model. Finally, several simulations were executed to propose dosing guidelines to reach expected vancomycin concentrations. A total of 118 trauma patients were included; the population was 45% males, with a mean age of 77 years (range 37-100 years) and a mean total body weight (TBW) of 72 kg (range 38-110 kg). The pharmacokinetics of vancomycin was best described by a two-compartment open model; creatinine clearance (CLCR) was related to vancomycin clearance (0.49 ± 0.04 L/h), being diminished by the presence of furosemide (0.34 ± 0.05 L/h). TBW influenced both the central volume of distribution (V1 = 0.74 ± 0.1 L/kg) and peripheral volume of distribution (V2 = 5.9 ± 2 L/kg), but patients with age >65 years showed a larger V1 (1.07 ± 0.1 L/kg). Bootstrapping was performed to internally validate the stability of the final model. External validation was developed using an alternate population of 40 patients with the same characteristics. The validated model was compared with population pharmacokinetic models previously published and showed better predictive performance for trauma patients than the current one. This final model allowed us to propose a new practical dose guideline to reach higher trough concentrations (15-20 mg/L) and AUC0-24/MIC ratios of more than 400 after 4 days of vancomycin treatment. A new population model was described for trauma patients to optimize vancomycin therapy, showing precise predictive performance to be applied for therapeutic drug monitoring and providing a new practical dose guideline that considers CLCR and concomitant administration of furosemide for these patients.

Population Pharmacokinetics of Vancomycin in Postoperative Neurosurgical Patients

Neurosurgical procedures may damage the blood-brain barrier to allow more vancomycin distribution into the cerebrospinal fluid (CSF) from blood after intravenous administration. However, a large intersubject variability in CSF vancomycin concentration was observed. We aimed to develop a population pharmacokinetic model to guide vancomycin dosing in patients after neurosurgical operation. Blood and CSF samples were collected and determined from postoperative neurosurgical patients after vancomycin administration. A three-compartment (central, peripheral, and CSF) model was proposed to characterize the pharmacokinetics of vancomycin. A nonlinear mixed-effects modeling approach was applied to fit the blood and CSF data simultaneously. The covariate analysis found that the CSF albumin level was strongly associated with the clearance between central and CSF compartment. Visual predictive check indicated that the proposed population pharmacokinetic model agrees well with the observed vancomycin concentrations. Individualized vancomycin dosage regimens could be developed for postoperative neurosurgical patients with different CSF albumin levels through model simulations. The CSF albumin level is a determinant of CSF vancomycin concentration.

Prophylactic Vancomycin Drops Reduce the Severity of Early Bacterial Keratitis in Keratoprosthesis.

BackgroundArtificial cornea transplantation, keratoprosthesis, improves vision for patients at high risk of failure with human cadaveric cornea. However, post-operative infection can cause visual loss and implant extrusion in 3.2–17% of eyes. Long-term vancomycin drops are recommended following keratoprosthesis to prevent bacterial keratitis. Evidence, though, in support of this practice is poor. We investigated whether prophylactic vancomycin drops prevented bacterial keratitis in an animal keratoprosthesis model.MethodologyTwenty-three rabbits were assigned either to a prophylactic group (n = 13) that received vancomycin 1.4% drops 5 times/day from keratoprosthesis implantation to sacrifice, or a non-prophylactic group (n = 10) that received no drops. All rabbits had Staphylococcus aureus inoculation into the cornea at 7–12 days post-implantation and were sacrificed at predetermined time-points. Prophylactic and non-prophylactic groups were compared with slit-lamp photography (SLP), anterior segment optical coherence tomography (AS-OCT), and histology, immunohistochemistry and bacterial quantification of excised corneas. Corneal vancomycin pharmacokinetics were studied in 8 additional rabbits.ResultsOn day 1 post-inoculation, the median SLP score and mean±SEM AS-OCT corneal thickness (CT) were greater in the non-prophylactic than the prophylactic group (11 vs. 1, p = 0.049 and 486.9±61.2 vs. 327.4±37.1 μm, p = 0.029 respectively). On days 2 and 4, SLP scores and CT were not significantly different. Immunohistochemistry showed a greater CD11b+ve/non-CD11b+ve cell ratio in the non-prophylactic group (1.45 vs. 0.71) on day 2. Bacterial counts were not significantly different between the two groups. Corneal vancomycin concentration (2.835±0.383 μg/ml) exceeded minimum inhibitory concentration (MIC) for Staphylococcus aureus only after 16 days of vancomycin drops. Two of 3 rabbits still developed infection despite bacterial inoculation after 16 days of prophylactic drops.ConclusionsProphylactic vancomycin drops provided short-term benefit, but did not prevent infection. Achieving MIC in the cornea was not sufficient to prevent Staphylococcus aureus keratitis. Patients should continue to be counselled regarding the risk of infection following keratoprosthesis.

A Larger Dose of Vancomycin Is Required in Adult Neurosurgical Intensive Care Unit Patients Due to Augmented Clearance.

The objective of this study was to explore the pharmacokinetics of vancomycin and determine an appropriate dosage regimen for vancomycin in adult neurosurgical intensive care unit (ICU) patients. First, a 20-month therapeutic drug monitoring database at a medical center was used to retrospectively analyze the pharmacokinetic parameters of vancomycin in adult neurosurgical patients. Significant covariates were selected through Pearson or Spearman correlation tests and multiple linear regressions. Pharmacokinetic models were built using significant covariates to predict vancomycin clearance. Second, a 12-month prospective cohort of neurosurgical ICU patients was recruited to validate the models. Urine and cerebrospinal fluid samples were collected, and vancomycin concentrations were determined using a high-performance liquid chromatography assay. The relation between the model-predicted and observed pharmacokinetic parameters was assessed by Pearson correlation. In the retrospective cohort, 98 sets of peak/trough serum concentrations obtained from 73 patients were analyzed. These patients had a mean age of 54 ± 16 years, an estimated creatinine clearance (eClCr) of 83 ± 29 mL/min, a total vancomycin clearance (ClVan) of 101 ± 41 mL/min, and a volume of distribution (Vd) of 0.93 ± 0.27 L/kg. In a subgroup analysis, the ClVan of ICU patients was higher than the ClVan of non-ICU patients (1.57 ± 0.34-fold versus 1.16 ± 0.32-fold of eClCr, P < 0.05). Fifteen patients enrolled in the prospective cohort had an average age of 67 ± 12 years, an eClCr of 108 ± 44 mL/min, a ClVan of 112 ± 29 mL/min, and a Vd of 1.03 ± 0.55 L/kg. Adult neurosurgical ICU patients have a significantly elevated ClVan. In this study, 2 dosing equations were derived to achieve optimal serum vancomycin concentrations for this special population.

A Bayesian Model to Describe Factors Influencing Trough Levels of Vancomycin in Hemodialysis Patients

Background/Aims: In hemodialysis patients, there is a marked inter-individual variability in the pharmacokinetics of vancomycin. This retrospective study was carried out to design a model describing the parameters that may influence the trough concentrations of vancomycin (TCV) in hemodialysis patients. Methods: A Bayesian model was constructed from data obtained during 314 hemodialysis sessions performed in 31 hemodialysis patients receiving vancomycin. The model's validity was assessed by goodness of fit. A bootstrap resampling method was used to calculate bias and accuracy for 80 predicted and observed TCV. Results: A total of 31 patients underwent dialysis 3 times a week for a mean duration of 4 h. Their mean age was 69 ± 12 years. The vancomycin infusion was started 30 min before the scheduled end of the dialysis session at a flow rate of 1,000 mg/h. The mean TCV of the study population was 16.1 ± 3.2 mg/l. The area under receiver operating characteristic curve of the constructed model was 95.2%. In the validation sample (80 randomly selected TCV), the observed mean TCV was 15.8 ± 3.6 mg/l, whereas the mean TCV predicted by the model was 15.7 ± 3.0 mg/l. If the mean bias was low between the predicted and observed TCV (-0.1 mg/l), SD was high (3.43 mg/l). The variables most closely linked to TCV were in descending order: weight after dialysis, weight before dialysis, the dose of vancomycin administered during the previous dialysis session and creatinine concentration before dialysis. Conclusion: This simple model describes patient-related and dialysis-related parameters that mainly influence TCV. Before its use in clinical practice, this model should be validated prospectively.

Enhanced oral bioavailability of vancomycin in rats treated with long-term parenteral nutrition.

Long-term parenteral nutrition (PN) can induce intestinal atrophy, leading to a loss of epithelial integrity in the small intestines. This change may alter the intestinal permeability of vancomycin (VCM), a non-absorbable antibiotic. The aim of the present study was to investigate the effect of PN on the pharmacokinetics of VCM in rats. VCM was intravenously (5 mg/kg) or intraduodenally (20 mg/kg) administered to control and PN rats, which were prepared by administration of PN for 9 days. After intravenous administration, there were no significant differences in any of the VCM pharmacokinetic parameters between the control and PN rats. However, after intraduodenal administration, the maximum concentration and area under the plasma concentration–time curve of VCM in PN rats was approximately 2.4- and 2.6-fold higher, respectively, than in the control rats; the calculated bioavailability was approximately 0.5 and 1.3 % in control and PN rats, respectively. These results indicated that PN administration did not affect VCM disposition, but enhanced VCM absorption; however, the enhanced oral VCM bioavailability was statistically, not clinically, significant. Therefore, while long-term PN administration may play a role in the enhancement of VCM bioavailability, this effect may be negligible without any complications.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1228-8) contains supplementary material, which is available to authorized users.

Single-dose pharmacokinetics of vancomycin in porcine cancellous and cortical bone determined by microdialysis

High treatment failure rates and the need for prolonged antimicrobial therapy for osteomyelitis and implant-associated infections suggest that antimicrobial bone penetration may be incomplete. Assessment of the bone pharmacokinetics of antimicrobials is challenged by a lack of validated methods. In this study, 1000mg of vancomycin was administered as a single dose over 100min to eight female pigs. Plasma, subcutaneous adipose tissue (SCAT) and bone pharmacokinetics were investigated over 12h. Microdialysis was applied for collection of samples in bone and SCAT. The vancomycin concentration in microdialysates was determined using ultra-high performance liquid chromatography, whilst the free plasma concentration was determined using Cobas c501. The mean (95% CI) area under the concentration–time curve (AUC0–last; minμg/mL) was 9375 (7445–11304), 9304 (7374–11233), 5998 (3955–8040) and 3451 (1522–5381) for plasma, SCAT, and cancellous and cortical bone, respectively (ANOVA P-value <0.001). Both cortical and cancellous bone AUC0–last were lower than that of free plasma (P<0.01). Peak drug concentrations (Cmax) in cortical and cancellous bone were also significantly lower than that of free plasma (P<0.001). Moreover, both AUC0–last and Cmax were significantly lower in cortical bone than in cancellous bone (P<0.025). Bone penetration of vancomycin was found to be incomplete and delayed. Significant differences in pharmacokinetics between cancellous and cortical bone suggest that bone may not be considered as one compartment. Future studies should focus on validating the applicability of microdialysis for assessment of antimicrobial bone pharmacokinetics.

A reference for clinical practice of vancomycin according to pharmacokinetic modeling based on plasma concentration monitoring in children

Objective To investigate the trough and peak vancomycin plasma concentrations in steady-state following regular dosage and to improve dosing regimen based on pharmacokinetic modeling, providing reference for clinical practice in children. Methods We retrospectively analyzed pharmacokinetics of vancomycin in 50 cases admitted in our PICU who had been confirmed or suspected with gram-positive bacterial infections following regular dosage[40 mg/(kg·d)]. Then we tried to optimize dosing regimens with Monte Carlo simulation to evaluate different dosing regimens of vancomycin in children. Results With regular dosage of vancomycin, mean trough concentrations of vancomycin were (11.02±4.44) mg/L, trough concentrations higher than 15 mg/L accounted for only 12%.In the actual program, the extension of a single intravenous infusion to 3 hours after administration would result in 26% of trough concentrations distributing in the range above 15 mg/L.If we increased daily dose to 50 mg/kg and 60 mg/kg with simulation, the trough concentration distribution frequency above 15 mg/L would increase from 12% to 32% and 40%.If minimum inhibitory concentration of vancomycin to pathogenic bacteria(Staphylococcus aureus) was 1 mg/L, the probabilities of target attainment for pharmacokinetic/pharmacodynamic evaluation were 51.73%, 76.54% and 87.5% for three dosages[40 mg/(kg·d), 50 mg/(kg·d) and 60 mg/(kg·d)] of vancomycin, respectively.We suspected that dosage of 60 mg/(kg·d) was a good choice.With this dosage regimen, we could achieve a substantial increase in the probability of target attainment. Conclusion Following regular dosages, trough concentration distribution frequency from 15 to 20 mg/kg is low.The extension of a single intravenous infusion time can not achieve a good result.According to the result of pathogenic bacteria and antimicrobial susceptibility tests, increasing daily dosage of vancomycin to 60 mg/(kg·d) will help to improve the trough concentration and get more clinic achievements. Key words: Vancomycin; Plasma concentration; Pharmacokinetics; Children

Vancomycin pharmacokinetics and predicted dosage requirements in pediatric cancer patients.

To determine the pharmacokinetic parameters and compare pharmacodynamic target attainment at different dosing strategies of vancomycin in pediatric cancer patients. Pediatric patients who received vancomycin and had at least two steady-state concentrations taken within the same dosing interval were identified. Vancomycin minimum inhibitory concentrations (MICs) for methicillin resistant staphylococcus aureus (MRSA) isolates from our institution were determined using E-test. The population-based pharmacokinetic modeling was performed using NONMEM 7.2. A one-compartment model with first-order kinetics was used to estimate clearance (CL) and volume of distribution (Vd). Monte Carlo simulations (N = 9800) were performed to compare area-under-the-curve over 24 h (AUC24)/MIC and trough concentration at different doses. Forty-nine patients, with 120 vancomcyin serum concentrations, were included in the analysis, mean age was 6 ± 2.5 (SD) years, mean weight was 19.6 ± 6.9(SD) kg, mean baseline serum creatinine was 0.4 ± 0.11(SD) mg/dl, and mean initial vancomycin dose was 205 mg/day (range 100-460). Final model pharmacokinetic parameters were: CL (L/h) = 0.381 × weight(0.75) and Vd (L) = 0.663 × weight. Mean baseline (±SD) vancomycin CL was 0.20 ± 0.07 L/h/kg and Vd 0.66 ± 0.001 L/kg. . Renal function, sex, age, stay in the intensive care unit, and co-administration of nephrotoxic medications did not have an effect on the calculated parameters. Using Monte Carlo simulation with reported MICs, a dose of 60 mg/kg/day achieved AUC24/MIC ≥400 and trough concentration ≥15 mcg/mL in only 21.5% and 11% of virtual subjects, respectively. Higher than usual vancomycin doses may be required to treat serious MRSA infections in pediatric patients. The currently recommended dose of 60 mg/kg/day is unlikely to achieve the targets in most subjects. The optimal vancomycin dosing in pediatric cancer patients requires further investigations.

Predictive Performance of a Vancomycin Population Pharmacokinetic Model in Neonates.

IntroductionThe pharmacokinetics of vancomycin are highly variable among neonates, which makes dosing challenging in this population. However, adequate drug exposure is critical, especially when treating methicillin-resistant Staphylococcus aureus (MRSA) infections. Utilization of population pharmacokinetic models and Bayesian methods offers the potential for developing individualized therapeutic approaches. To meet this need, a neonatal vancomycin population pharmacokinetic model was recently published. The current study sought to externally evaluate the predictive performance and generalizability of this model.MethodsA retrospective chart review of neonates who received vancomycin and had ≥1 peak and ≥1 trough concentrations at five Intermountain Healthcare neonatal intensive care units from 2006 to 2013 was performed and served as the external validation cohort. The published population pharmacokinetic model was implemented in NONMEM 7.2 with the structural and variance parameter values set equal to the estimates reported previously. The model was then used to predict the first peak and trough concentration for each neonate in the validation cohort and the model prediction error and absolute prediction error were calculated. Normalized prediction distribution errors (NPDE) were also evaluated.ResultsA total of 243 neonates were studied with a median postmenstrual age of 33 (range: 23–54) weeks and a median weight of 1.6 (range: 0.4–6.8) kg. The model predicted the observed vancomycin concentrations with reasonable precision. For all vancomycin concentrations, the median prediction error was −0.8 (95% CI: −1.4 to −0.4) mg/L and the median absolute prediction error was 3.0 (95% CI: 2.7–3.5) mg/L. No trends in NPDE across weight, postmenstrual age, serum creatinine, or time after dose were observed.ConclusionAn evaluation of a recently published neonatal vancomycin population pharmacokinetic model in a large external dataset supported the predictive performance and generalizability of the model. This model may be useful in evaluating neonatal vancomycin dosing regimens and estimating the extent of drug exposure.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-015-0067-9) contains supplementary material, which is available to authorized users.