Vancomycin Plasma Concentrations Research Articles

Safety and efficacy of intrawound vancomycin powder in the prevention of lumbar surgical site infection: A prospective, double-blind, randomized controlled study.

To evaluate the safety and efficacy of intra-wound vancomycin powder in reducing surgical site infections (SSIs) after spine surgery. A prospective, double-blind, randomized controlled study. Patients who underwent posterior lumbar interbody fusion (PLIF) surgery from May 2021 to September 2022. Patients who underwent posterior lumbar interbody fusion (PLIF) surgery between May 2021 and September 2022 were included. Participants were randomized to the vancomycin treatment or control groups using block randomization (block size 4). Except for baseline and surgical data, the plasma levels of white blood cells, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), aspartate aminotransferase, alanine aminotransferase, and serum vancomycin concentration in the groups were analyzed on postoperative days (PODs) 1, 3, and 5. Vancomycin concentration was measured daily until the drainage tubes were removed. The primary outcomes were the 90-day vancomycin-related adverse reactions and SSI rates. Secondary outcomes were perioperative hematological parameters and vancomycin serum (drain) concentrations. A total of 156 participants (78 each in each group) were analyzed by an independent researcher. The follow-up rate was 91%. All participants were followed up for at least 90 days. The 90-day SSI rate in the vancomycin group was 1.3% (1/78), comprising one case of superficial infection. The SSI rate in the control group was 10.3% (8/78), comprising seven cases of superficial infection and one case of deep infection. Compared with that in the control group, the SSI rate in the vancomycin group was decreased by 87.5%, with a statistically significant difference (RR=0.125, 95% CI=0.016-0.976). Additionally, the vancomycin group demonstrated a statistically significant decrease in serum ESR on POD 3 (P=0.039) and CRP on POD 5 (P=0.024) compared to the control group. The local plasma concentration of vancomycin remained elevated for at least 4 days postoperatively, while the serum concentration of vancomycin remined low. Vancomycin-associated adverse reactions were not observed. Intra-wound application of vancomycin powder is a safe and effective procedure for reducing the risk of SSI during PLIF surgery.

Case analysis of hepatotoxicity caused by vancomycin

BackgroundAlthough the correlation between liver toxicity and vancomycin is generally considered low, it has been observed that the use of vancomycin can lead to abnormal liver function indicators, such as elevated aspartate aminotransferase, alanine aminotransferase, alpha fetoprotein, and jaundice. To further understand the clinical features associated with vancomycin-induced liver toxicity and to provide clinical guidance, we conducted an analysis of the characteristics and clinical manifestations of vancomycin-induced liver injury.MethodsPatients with liver function injury who received vancomycin treatment at the Third Xiangya Hospital of Central South University and Hunan Maternal and Child Health Hospital between 2016 and 2021 were selected for retrospective analysis of their general characteristics, vancomycin course, dose, liver function index, severity of liver injury, and concomitant medications.ResultsOf the 4562 patients who received vancomycin, 17 patients were finally included, with an incidence rate of 0.37%. Of these patients, 12 were male (70.6%) and 5 were female (29.4%), ranging in age from 17 to 84 years with a mean average age of 45.41 ± 20.405 years. All patients were evaluated using Naranjo’s score, with score ≥ 3. The dosage, time, and plasma concentration of vancomycin were analyzed and it was found that nine patients (52.94%) had abnormal liver function when initially given a dose of 1 g every 12 hours. In total, 14 patients (82.35%) with liver injury were taking vancomycin in combination with two to four drugs, and severe liver injury occurred in patients taking vancomycin in combination with two drugs. The occurrence time of liver injury was 2–12 days after starting vancomycin, with a mean of 4.53 ± 2.401 days. Of these patients, 16 patients (94.1%) showed liver function abnormalities within 7 days of taking the drug, and 2 patients with grade 3–4 liver injury both showed liver function abnormalities within 3 days of taking the drug. Only 4 of the 17 patients (23.53%) had vancomycin blood concentrations within the normal range, and there was no correlation found between blood concentration and severity of liver injury. Analysis of the correlation between the severity of liver injury and vancomycin showed that none of the patients had allergies such as rash, two patients (11.76%) had jaundice, and fatigue occurred in five patients (29.41%). The remaining ten patients (58.82%) had no symptoms related to liver injury. All 17 patients had abnormal aspartate aminotransferase/alanine aminotransferase levels and 9 patients also had abnormal bilirubin levels. In 15 patients (88.24%), the severity of liver injury was grade 1, indicating mild liver injury, and no correlation was observed between the severity of liver injury and creatinine. Of the 17 patients, 1 patient received no intervention, 4 patients stopped taking vancomycin after developing liver injury, 1 patient reduced the dose, and 11 patients (64.7%) were treated with hepatic protectant.ConclusionAlthough the study concluded that the incidence of liver injury was not high, the liver toxicity of vancomycin should still be considered and liver function indicators should be monitored during the clinical use of vancomycin.

The association between vancomycin trough concentrations and nephrotoxicity in the paediatric intensive care unit

Objective: To analyze and describe the pharmacokinetic aspects of vancomycin usage in a cohort of critically ill children and to construct a pharmacokinetic model for this population. Method: We conducted an observational study in a pediatric intensive care unit from September 2017 to March 2019. Children receiving vancomycin with at least one serum measurement were included. Variables with a p-value lower than 0.2 in univariate analysis, and biologically plausible for inducing nephrotoxicity and not correlated with other predictors, were incorporated into logistic regression. Additionally, pharmacokinetic modeling was performed using the PMETRICS® package for patients with creatinine clearance (CLCR) > 30 mL/min. Result: The study included 70 children, with an average vancomycin dose of 60 mg/kg/day. Only eleven children achieved vancomycin levels within the target range (15-20 mg/L). No significant differences in doses/mg/kg/day were observed among children above, within, or below the vancomycin target range. In the multivariate model, children above the recommended serum range had an odds ratio of 4.6 [95% CI 1.4 – 17.2] for nephrotoxicity. A pharmacokinetic model was proposed using data from 15 children, estimating PK parameters for CLCR and V as 0.94 L/h and 5.71 L, respectively. Conclusion: Nephrotoxicity was associated with vancomycin plasma concentrations equal to or exceeding 15 mg/L. The developed model enhanced understanding of the drug’s behavior within this population, potentially aiding clinical practice in dose calculations and estimation of the area under the curve – a recommended parameter for vancomycin monitoring.

Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia.

Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment. Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed-effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400-600 mg*h/L was used as target range. Sixteen patients received vancomycin (median gestational age: 41 [range: 38-42] weeks, postnatal age: 4.4 [2.5-5.5] days, birth weight: 3.5 [2.3-4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1-compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5kg without perinatal asphyxia (range: 0.20-0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment. Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model-informed precision dosing.

Population pharmacokinetics and target attainment analysis of vancomycin after intermittent dosing in adults with cystic fibrosis.

Vancomycin is the first-line agent to treat pulmonary infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis (PwCF). However, there is no consensus on vancomycin initial dosing in this population among health institutions, and there is a large variability in initial dosing across the United States. In this study, we characterized the pharmacokinetics (PK) of vancomycin in PwCF using a population PK approach. The clinical PK data to develop the population PK model were obtained from vancomycin therapeutic monitoring data from PwCF undergoing treatment for infections due to MRSA. The population PK model was then used to perform comprehensive Monte Carlo simulations to evaluate the probability of target attainment (PTA) of 12 different initial dosing scenarios. The area under the curve to minimum inhibitory concentration (MIC) ratio ≥400 mg*h/L and <650 mg*h/L were used as efficacy and toxicity targets for PTA analysis. A total of 181 vancomycin plasma concentrations were included in the analysis. A one-compartment model with first-order elimination best described the data. Weight significantly influenced the vancomycin PK (P < 0.05). In the final model, clearance was estimated as 5.52 L/h/70 kg, and the volume of distribution was 31.5 L/70 kg. The PTA analysis showed that at MIC = 1 µg/mL, doses 1,500 q8h and 2,000 q12h showed the highest %PTA in achieving both efficacy and toxicity targets. The PTA results from this study may potentially inform the initial dosing regimens of vancomycin to treat pulmonary infections due to MRSA in PwCF.

Model-informed precision dosing of antimicrobial drugs in pediatrics: experiences from a pilot scale program.

Antibiotics are among the most utilized drugs in pediatrics. Nonetheless, there is a lack in pharmacokinetics information for this population, and dosing criteria may vary between healthcare centers. Physiological variability associated with maturation in pediatrics makes it challenging to reach a consensus on adequate dosing, which is further accentuated in more vulnerable groups, such as critically ill or oncology patients. Model-informed precision dosing is a useful practice that allows dose optimization and attainment of antibiotic-specific pharmacokinetic/pharmacodynamic targets. The aim of this study was to evaluate the needs of model-informed precision dosing of antibiotics in a pediatrics unit, at a pilot scale. Pediatric patients under antibiotic treatment were monitored with either a pharmacokinetic/pharmacodynamic optimized sampling scheme or through opportunistic sampling. Clindamycin, fluconazole, linezolid, meropenem, metronidazole, piperacillin, and vancomycin plasma concentrations were quantified through a liquid chromatography coupled to mass spectrometry method. Pharmacokinetic parameters were estimated using a Bayesian approach to verify pharmacokinetic/pharmacodynamic target attainment. A total of 23 pediatric patients aged 2 to 16years were included, and 43 dosing regimens were evaluated; 27 (63%) of them required adjustments as follows: 14 patients were underdosed, 4 were overdosed, and 9 patients needed infusion rate adjustments. Infusion rate adjustments were mostly recommended for piperacillin and meropenem; daily doses were augmented for vancomycin and metronidazole, meanwhile linezolid was adjusted for under- and overdosing. Clindamycin and fluconazole regimens were not adjusted at all. Conclusion: Results showcase a lack of antibiotic pharmacokinetic/pharmacodynamic target attainment (particularly for linezolid, vancomycin, meropenem, and piperacillin), and the need for model-informed precision dosing in pediatrics. This study provides pharmacokinetic evidence which can further improve antibiotic dosing practices. What is Known: • Model-informed precision dosing is performed in pediatrics to optimize the treatment of antimicrobial drugs such as vancomycin and aminoglycosides, while its usefulness is debated for other groups (beta-lactams, macrolides, etc.). What is New: • Vulnerable pediatric subpopulations, such as critically ill or oncology patients, can benefit the most from model-informed precision dosing of antibiotics. • Model-informed precision dosing of linezolid, meropenem, piperacillin, and vancomycin is particularly useful in pediatrics, and further research mayimprove dosing practices altogether.

External validation of population pharmacokinetic models of vancomycin in postoperative neurosurgical patients.

Vancomycin is commonly used in the prevention and treatment of intracranial infections in postoperative neurosurgical patients with narrow therapeutic window and large pharmacokinetic variations. Several population pharmacokinetic (PPK) models of vancomycin have been established for neurosurgical patients. But comprehensive external evaluation has not been performed for almost all models. The objective of this study was to evaluate the predictive ability of published vancomycin PPK models in adult postoperative neurosurgical patients using an independent dataset. PubMed, Embase and China National Knowledge Internet databases were searched to identify published vancomycin PPK models in adult postoperative neurosurgical patients. Prediction-based and simulation-based diagnostics were used to evaluate model predictability. Bayesian forecasting was used to assess the influence of prior concentration on model prediction performance. A total of 763 vancomycin plasma concentrations from 493 postoperative neurosurgical patients were included in the external dataset. Eight population pharmacokinetic models of vancomycin in postoperative neurosurgical patients were included and evaluated. The model by Zhang et al. exhibited the best predictive performance in prediction-based diagnostics and prediction-corrected visual predictive checks, followed by the model by Shen et al. The predictive performance of other models was not satisfactory. The normalized predictive distribution error test shows that none of the models is suitable to describe our data. The predictive performance of vancomycin models was obviously improved by maximum a posteriori Bayesian forecasting. The published PPK models for adult postoperative neurosurgical patients show extensive variation in predictive performance in our patients. Although it is challenging to recommend initial doses of vancomycin from these predictive models, the combination of model-based prediction and therapeutic drug monitoring can be used for dose optimization.

Pharmacokinetic and Biomarker Quantification Studies on Vancomycin-Loaded PEGylated Liposomes and Its Potential to Reduce Vancomycin-Induced Kidney Injury: A Rat Study.

Vancomycin is a commonly used antibiotic in hospital settings, especially against Methicillin-resistant staphylococcus aureus (MRSA). One of the major adverse events of vancomycin use in adults is kidney injury. The drug concentration, specifically the area under the concentration curve, predicts kidney injury in adults receiving vancomycin. To attempt to reduce vancomycin-induced nephrotoxicity, we have successfully encapsulated vancomycin in polyethylene glycol-coated liposomes (PEG-VANCO-lipo). We have previously carried out in vitro cytotoxicity studies on kidney cells using PEG-VANCO-lipo and found it to be minimally toxic compared to the standard vancomycin. In this study, we have dosed male adult rats with PEG-VANCO-lipo or vancomycin HCl and compared plasma vancomycin concentrations and KIM-1 as an injury biomarker in rat urine. Male Sprague Dawley rats (350 ± 10 g) were administered vancomycin (n = 6) or PEG-VANCO-lipo (n = 6) 150 mg/kg/day for three days using an IV infusion in the left jugular vein catheter. Blood was collected for plasma at 15, 30, 60, 120, 240, and 1440 min after the first and the last IV dose. Urine was collected 0-2, 2-4, 4-8, and 8-24 h after the first and the last IV infusions using metabolic cages. The animals were observed for three days after the last compound administration. Vancomycin was quantified in plasma by LC-MS/MS. Urinary KIM-1 analysis was done by using an ELISA kit. Three days after the last dose, under terminal anesthesia with IP ketamine (65-100 mg/kg) and xylazine (7-10 mg/kg), rats were euthanized. Vancomycin urine and kidney concentrations and KIM-1 were lower on day three in the PEG-Vanco-lipo group compared to the vancomycin group (p < 0.05, ANOVA and/or t-test). There was a significant reduction in plasma vancomycin concentration on day one and day three (p < 0.05, t-test) in the vancomycin group compared to the PEG-VANCO-lipo group. Vancomycin-loaded PEGylated liposomes resulted in lower levels of kidney injury, as noted by a decrease in KIM-1 values. Moreover, longer circulation in plasma with increased concentration in plasma as opposed to the kidney was observed with the PEG-VANCO-lipo group. The results indicate the high potential of PEG-VANCO-lipo in decreasing the nephrotoxicity of vancomycin clinically.

Population Pharmacokinetics of Vancomycin in Patients Receiving Hemodialysis in a Malian and a French Center and Simulation of the Optimal Loading Dose.

Vancomycin dosing remains challenging in patients receiving intermittent hemodialysis, especially in developing countries, where access to therapeutic drug monitoring and model-based dose adjustment services is limited. The objectives of this study were to describe vancomycin population PK in patients receiving hemodialysis in a Malian and French center and examine the optimal loading dose of vancomycin in this setting. Population pharmacokinetic analysis was conducted using Pmetrics in 31 Malian and 27 French hemodialysis patients, having a total of 309 vancomycin plasma concentrations. Structural and covariate analyses were based on goodness-of-fit criteria. The final model was used to perform simulations of the vancomycin loading dose, targeting a daily area under the concentration-time curve (AUC) of 400-600 mg.h/L or trough concentration of 15-20 mg/L at 48 hours. After 48 hours of therapy, 68% of Malian and 63% of French patients exhibited a daily AUC of <400. The final model was a 2-compartment model, with hemodialysis influencing vancomycin elimination and age influencing the vancomycin volume distribution. Younger Malian patients exhibited a lower distribution volume than French patients. Dosing simulation suggested that loading doses of 1500, 2000, and 2500 mg would be required to minimize underexposure in patients aged 30, 50, and 70 years, respectively. In this study, a low AUC was frequently observed in hemodialysis patients in Mali and France after a standard vancomycin loading dose. A larger dose is necessary to achieve the currently recommended AUC target. However, the proposed dosing algorithm requires further clinical evaluation.

Changes in the Use of Antibiotics for Methicillin-Resistant Staphylococcus aureus Bloodstream Infections in Children: A 5-Year Retrospective, Single Center Study

Monitoring antibiotic use in the pediatric population is a challenge, especially when determining a relationship between specific pathogens, infections, and antibiotic use. We retrospectively analyzed the consumption of anti-methicillin-resistant Staphylococcus aureus (MRSA) drugs from 2017 to 2021 at Istituto Giannina Gaslini by means of defined daily dose (DDD) adopted for adults by World Health Organization. We observed a statistically significant increase in the use of daptomycin and ceftaroline, combined with a decrease in the use of vancomycin. In the same period, we observed an increase in the proportion of bloodstream infections due to MRSA with vancomycin minimally inhibitory concentration (MIC mg/L) = 1, that represented the 100% of cases in 2021. This aspect was combined with the observation that in the 59% of cases, where vancomycin plasma concentrations were evaluated, it was not possible to achieve a ratio of the 24-h area under the concentration-time curve and MIC (AUC0-24/MIC) of vancomycin ≥ 400 mg/L. This study confirms that DDD can be used in pediatrics to monitor antibiotic consumption in relationship with infections epidemiology. Moreover, it describes the presence of vancomycin MIC creep for MRSA also in pediatrics and the difficulties in obtaining effective vancomycin plasma concentrations in children.

Comparison of the mathematical equation and trapezoidal approach for 24 h area under the plasma concentration-time curve calculation in patients who received intravenous vancomycin in an acute care setting.

The current recommendation for therapeutic monitoring of vancomycin has recently suggested AUC-guided dosing in patients with serious methicillin-resistant Staphylococcus aureus infections. The study objective was to evaluate mathematical equations and trapezoidal methods for calculating the 24 h area under the plasma vancomycin concentration-time curve (AUC24). The analysis of plasma vancomycin concentrations was performed in 20 adult patients treated with intravenous vancomycin. For each patient, AUC24 was estimated using two methods including, equation and trapezoidal calculation. The AUC24 from two methods was analyzed for correlation. The correlation between the equation and trapezoidal methods was strong. The coefficient of determination (R2 ) values was greater than .99. The two plasma vancomycin concentrations to achieve the highest correlation were concentration at 2.5 to 3h after starting the infusion and concentration at 1h before the next dose. Moreover, the AUC24 calculation from trapezoidal and equation methods showed that 19 out of 20 patients (95%) had AUC24 of more than 400 mg·h/L, and more than 50% in this group had AUC24/MIC greater than 600. Of those patients with AUC-trapezoidal >600, 15.38% of patients had trough under 15 mg/L, 15.38% of patients had trough in the range 15 to 20 mg/L and 69.23% of patients had trough more than 20 mg/L. The results of AUC-equation were similar to those of the AUC-trapezoidal method. Our study confirmed that the AUC monitoring is more appropriate than the trough vancomycin concentration. Given these considerations, the AUC-equation method is better and more practical to use in part of a point-of-care treatment, especially in the part of the Bayesian program is not available. The best sampling time point of the peak concentration was 0.5-1h after 2-h infusion.

Population pharmacokinetic model of vancomycin in postoperative neurosurgical patients.

Objective: Vancomycin is commonly used in postoperative neurosurgical patients for empirical anti-infective treatment due to the low success rate of bacterial culture in cerebrospinal fluid (about 20%) and the high mortality of intracranial infection. At conventional doses, the rate of target achievement for vancomycin trough concentration is low and the pharmacokinetics of vancomycin varies greatly in these patients, which often leads to treatment failure. The objective of this study was to establish a population pharmacokinetic (PPK) model of vancomycin in postoperative neurosurgical patients for precision medicine. Method: A total of 895 vancomycin plasma concentrations from 560 patients (497 postoperative neurosurgical patients) were retrospectively collected. The model was analyzed by nonlinear mixed effects modeling method. One-compartment model and mixed residual model was employed. The influence of covariates on model parameters was tested by forward addition and backward elimination. Goodness-of-fit, bootstrap and visual predictive check were used for model evaluation. Monte Carlo simulations were employed for dosing strategies with AUC24 targets 400–600. Result: Estimated glomerular filtration rate (eGFR), body weight (BW) and mannitol had significant influence on vancomycin clearance (CL). , for female, a = 0.7, Scr 0.7 mg/dl, b = −0.329, Scr 0.7 mg/dl, b = −1.209; for male, a = 0.9, Scr 0.9 mg/dl, b = −0.411, Scr 0.9 mg/dl, b = −1.210. Vancomycin clearance was accelerated when co-medicated with mannitol and increased with eGFR and BW. In the final model, the population typical value is 7.98 L/h for CL and 60.2 L for apparent distribution volume, , where A = 0.13 when co-medicated with mannitol, otherwise A = 0. The model is stable and effective, with good predictability. Conclusion: In postoperative neurosurgical patients, a higher dose of vancomycin may be required due to the augmented renal function and the commonly used mannitol, especially in those with high body weight. Our vancomycin PPK model could be used for individualized treatment in postoperative neurosurgical patients.

An updated vancomycin dosing protocol for initiating therapy in patients undergoing intermittent high-flux hemodialysis.

To design an updated vancomycin dosing protocol for initiating therapy in patients undergoing chronic intermittent high-flux hemodialysis (iHFHD) that is congruent with the revised 2020 consensus guidelines for therapeutic drug monitoring (TDM). Monte Carlo simulation methods were used to study vancomycin dosing for patients on iHFHD. Vancomycin regimens were constructed as intravenous infusions (for intradialytic administration) of a loading dose and maintenance doses 3 times weekly during subsequent dialysis sessions. Vancomycin plasma concentrations were simulated, and the probability of target attainment (PTA) for a 24-hour area under the time-concentration curve (AUC24) of 400 to 700 mg · h/L was determined. Standardized weight-based (ie, dose-banding) regimens were investigated, and an optimized protocol was selected based on TDM target attainment and practical considerations for use in the dialysis setting. The proposed vancomycin dosing protocol (for intradialytic administration) specifies 3 regimens: (1) a 1,500-mg loading dose and 750-mg maintenance doses for patients weighing 50 kg to 69 kg; (2) a 2,000-mg loading dose and 1,000-mg maintenance doses for patients weighing 70 kg to 89 kg; and (3) a 2,500-mg loading dose and 1,250-mg maintenance doses for patients weighing 90 kg to 110 kg. In a simulated hemodialysis population (n = 5,000), the proposed protocol delivered median (interquartile range [IQR]) loading and maintenance doses of 25.0 (23.4-26.6) mg/kg and 12.5 (11.8-13.3) mg/kg, respectively. The PTA for an AUC24 of 400 to 700 mg · h/L was 74.7% on day 1 and 70.8% on day 8, with less than 10% of values exceeding the target range. Our proposed dosing protocol for patients undergoing iHFHD offers an updated and practical approach for initiating vancomycin therapy that can be optimized with early TDM.

1104. Comparison of Antibiotic Sampling Techniques: Predicting Plasma Vancomycin Concentrations Using Volumetric Absorptive Microsampling (VAMS) from Capillary and Venous/Arterial Whole Blood

BackgroundTherapeutic drug monitoring (TDM) is paramount to optimize the safety and efficacy of vancomycin (VAN). In children, TDM is challenged by difficulty in obtaining venous samples, impeding timely sampling. We assessed the ability of volumetric absorptive microsampling (VAMS) as a novel, whole blood sampling technique to predict plasma VAN concentrations in plasma.MethodsWe conducted a prospective pilot study among critically ill children prescribed VAN for clinical care. Coincident with VAN TDM in plasma (P), we collected 20 µL of capillary whole blood (C) and venous/arterial whole blood (V) using VAMS. Paired VAMS-P samples drawn >5 mins apart and VAMS samples with over- or under-loaded filter tip on visual inspection were excluded. Plasma concentrations were measured via chemiluminescent immunoassay in the Chemistry Laboratory. VAMS C and V concentrations were measured using LC/MS in the Bioanalytic Core Laboratory. Plasma concentrations were predicted from whole blood VAMS with Passing-Bablok regression using 3 methods: 1) uncorrected VAMS measures, 2) hematocrit-corrected VAMS, and 3) lab-corrected VAMS (Figure 1). We then assessed bias, imprecision, and accuracy of plasma predictions from VAMS (C and V) as compared to coincident P concentrations for each technique (Figure 1).Figure 1. Methods for relating whole blood vancomycin concentrations collected via VAMS to plasma concentrations and measure to evaluate predictive performance. ResultsPaired samples were collected from 31 enrolled subjects (Figure 2), with a median age of 3.3 years (range 0.1-17.9). Measured P concentrations ranged from 4.6 - 54.9 mg/L. 11 C samples (29%) and 3 V samples (10%) were excluded due to collection issues. Prediction results are shown in Figure 3. The 3 prediction techniques had similar performance characteristics, with each method displaying minimal bias (-0.4-2.0%) and reasonable imprecision (13.7-20.2%). The accuracy of prediction of P concentrations using VAMS was better for V than C samples.Figure 2. Flow diagram from sample collection to evaluation. Abbreviations: C-P, capillary VAMS-plasma; V-P, venous/arterial VAMS-plasma; VAMS, volumetric absorptive microsampling.Figure 3. Performance of 3 techniques to predict plasma vancomycin concentrations using whole blood collected via VAMS. ConclusionOur pilot highlights the challenges of using VAMS for TDM. Sample collection issues were common. When VAMS is used, education on collection techniques is imperative. The predictive performance of VAMS was modest and V sampling had higher accuracy than C, although our sample size was small. Larger studies will be needed to further evaluate the predictive performance of the regression equations derived by our study.Disclosures Kevin J. Downes, MD, Merck, Inc. (Grant/Research Support)

Exploration of Vancomycin Concentrations in Cerebrospinal Fluid and Plasma after Craniocerebral Surgery

Patients who underwent cranial hematoma removal, extra-ventricular drainage, intracranial arteriovenous malformation resection, and other craniotomy procedures and were administered vancomycin were selected. Cerebrospinal fluid (CSF) and plasma specimens were collected simultaneously from patients at different time points using the random number method, and vancomycin concentrations in CSF and plasma were determined by enzyme amplification immunoassay. The ratio of vancomycin in CSF to plasma concentration was calculated, and the medical records were analyzed to initially investigate the relevant factors that can affect the drug concentration or blood-brain barrier. The mean plasma concentration of vancomycin was 11.87±8.5μg/mL, the CSF concentration was 2.42±1.34μg/mL, and the cerebral blood ratio was 0.28±0.21. This study suggests that the transmission rate of vancomycin did not increase significantly after craniocerebral surgery; due to individual differences, CSF and plasma concentrations vary greatly, and drug concentration monitoring is recommended.

Are vancomycin dosing guidelines followed? A mixed methods study of vancomycin prescribing practices.

Despite the availability of international consensus guidelines, vancomycin dosing and therapeutic drug monitoring (TDM) remain suboptimal. This study aimed to assess concordance of vancomycin dosing and TDM with institutional guidelines and to identify factors taken into consideration by clinicians when prescribing vancomycin. A retrospective audit of 163 patients receiving vancomycin therapy (≥48 hours) was undertaken. Data collected included patient characteristics, dosing history and plasma vancomycin and creatinine concentrations. Concordance of dosing and TDM with institutional guidelines was evaluated. Semi-structured interviews, including simulated prescribing scenarios, were undertaken with prescribers (n = 17) and transcripts analysed. Plasma vancomycin concentrations (n = 1043) were collected during 179 courses of therapy. Only 24% of courses commenced with a loading dose with 72% lower than recommended. The initial maintenance dose was concordant in 42% of courses with 34% lower than recommended. Only 14% of TDM samples were trough vancomycin concentrations. Dose was not adjusted for 60% (21/35) of subtherapeutic and 43% (18/42) of supratherapeutic trough vancomycin concentrations, respectively. Interview participants reported that patient characteristics (including renal function), vancomycin concentrations, guidelines and expert advice influenced vancomycin prescribing decisions. Despite referring to guidelines when completing simulated prescribing scenarios, only 37% of prescribing decisions aligned with guideline recommendations. Poor compliance with institutional vancomycin guidelines was observed, despite prescriber awareness of available guidelines. Multifaceted strategies to support prescriber decision-making are required to improve vancomycin dosing and monitoring.

Vancomycin concentrations during cardiopulmonary bypass in pediatric cardiac surgery: a prospective study.

Few data are available regarding intraoperative plasma concentrations of vancomycin administered as prophylaxis in pediatric cardiac surgery. The aims of this study were to investigate during pediatric cardiac surgery with cardiopulmonary bypass(CPB) the attainment of the area-under-the-curve of the vancomycin serum concentrations versus time over surgery to minimum inhibitory concentration ratio(AUCintra/MIC) of 400 (mg × h)/l and/or a target concentration of 15-20 mg/l. In a prospective study, 40 patients divided into four subgroups (neonates, infants, children <10 years-old, ⩾10 years-old) undergoing cardiac surgery with cardiopulmonary bypass (CPB) were enrolled. A slow vancomycin bolus of 20 mg/kg, up to a maximum dose of 1000 mg was administered before skin incision and a further dose of 10 mg/kg (up to 500 mg) at CPB start. Vancomycin samples were collected intraoperatively at four time points. The median (interquartile range) age was 241.5 days (47-3898) and the median weight was 7.1 kg (3.1-37). The median AUCintra/MIC was 254.73 (165.89-508.06). In 11 patients the AUCintra/MIC target was not reached. Neonates displayed the lowest AUCintra/MIC values, and these were significantly lower than those of children ⩾10 years old (p = 0.02). Vancomycin concentrations were above the maximal target of 20 mg/l in 82.5% and 80% of patients at surgery and CPB start, respectively. At CPB and surgery end, 42.5% of patients showed vancomycin concentrations above 20 mg/l and 42.5% below 15 mg/l. Patients⩾10 years old showed the highest peak values whereas neonates were those with the lowest troughs. AUCintra/MIC correlated with age(r:0.36, p = 0.02), weight(r:0.35, p = 0.03), intraoperative protein value(r:0.40, p = 0.01), CPB priming volume/kg(r:-0.33, p = 0.04), CPB duration(r:0.36, p = 0.02) and vancomycin troughs(r:0.35, p = 0.04). An AUCintra/MIC ⩾400 target was not reached in one-quarter of children undergoing heart surgery. Vancomycin peaked before the start of surgery and neonates were those with the lowest troughs. Vancomycin concentrations are affected by CPB hemodilution and by patients' age and weight.

Predictive performance of Smart Dose, PharmVan and JPKD on Vancomycin plasma concentration

To evaluate the predictive performance of the individualized drug delivery decision-making system including Smart Dose, PharmVan and JPKD on predicting the Vancomycin plasma concentration and to analyze the related factors affecting the predictive performance. The clinical data of patients who were treated with Vancomycin and received therapeutic drug monitoring (TDM) admitted to the First Affiliated Hospital of Wenzhou Medical University from January 2018 to July 2020 were retrospectively collected. Smart Dose and PharmVan were used to predict the plasma concentration of Vancomycin of the initial regimen. Smart Dose, PharmVan and JPKD were used to predict the plasma concentration of Vancomycin of the adjustment regimen for patients whose initial steady-state trough concentration were not qualified. The relative predictive error (PE) between the measured plasma concentration and predicted plasma concentration was calculated and box plotted. Mann-Whitney U test was used to evaluate the difference of the absolute value of PE (APE) predicted by each software for Vancomycin plasma concentration. The TDM results were divided into accurate prediction group (APE < 30%) and the inaccurate prediction group (APE ≥ 30%) according to the APE value. Patients and disease characteristics including gender, age, body weight complication, Vancomycin medication and TDM results were collected from electronic medical records. Univariate analysis and multivariate Logistic regression analysis were used to screen the related factors that influence the predictive performance of Smart Dose, PharmVan and JPKD; and receiver operating characteristic curve (ROC curve) was drawn to evaluate its predictive value. A total of 185 patients were enrolled, and 258 plasma concentration of Vancomycin were collected, including 185 concentrations of initial regimen and 73 concentration of adjustment regimen. There was no significant difference in the APE of the initial regimen of plasma concentration between Smart Dose and PharmVan. No significant difference in the APE of the adjustment regimen of plasma concentration was found among Smart Dose, PharmVan and JPKD. The accuracy of Smart Dose in predicting the plasma concentration of the adjustment regimen was better than that of the initial regimen [22.94% (10.50%, 36.24%) vs. 29.33% (13.07%, 47.99%), P < 0.05]. The univariate analysis of factors affecting the performance of Smart Dose in predicting the concentration of initial regimen showed that the proportion of patients with hypertension in the accurate prediction group was significantly higher than that in the inaccurate prediction group [43.3% (42/97) vs. 27.3% (24/88), P < 0.05]. The univariate analysis of factors affecting the performance of Smart Dose in predicting the concentration of adjustment regimen showed that the proportion of patients with valvular heart disease in the accurate prediction group was significantly lower than that in the inaccurate prediction group [23.4% (11/47) vs. 46.2% (12/26), P < 0.05]. The univariate analysis of factors affecting the performance of JPKD in predicting the concentration of adjustment regimen showed that the body weight of patients in the accurate prediction group was significantly higher than that in the inaccurate prediction group (kg: 62.8±14.9 vs. 54.8±12.8, P < 0.05). Multivariate Logistic regression analysis indicated that hypertension was a beneficial factor for Smart Dose to predict the initial plasma concentration of Vancomycin [odds ratio (OR) = 0.526, 95% confidence interval (95%CI) was 0.281-0.983, P = 0.044], and low body weight was an independent risk factor for the inaccurate prediction of JPKD for adjustment regimen (OR = 1.042, 95%CI was1.001-1.085, P = 0.043). ROC curve analysis indicated that the area underROC curve (AUC) of the body weight for evaluating the accuracy of JPKD in predicting Vancomycin plasma concentration was 0.663, and 95%CI was 0.529-0.796 (P = 0.023). When the body weight was less than 55.95 kg, the risk of inaccurate prediction of JPKD in predicting Vancomycin plasma concentration was increased, and the predictive sensitivityand specificity were 75% and 60% respectively. There is no significant difference in the predictive performance of Smart Dose, PharmVan or JPKD on Vancomycin plasma concentration. Smart Dose had a better predictive performance for the Vancomycin plasma concentration of adjustment regimen than initial regimen. Smart Dose had a better predictive performance when the patient was concomitant with hypertension. JPKD had a poor predictive performance for low-body weight patients. The predictive performance of JPKD was decreased when the body weight was lower than 55.95 kg.

1308. Ex vivo Impact of Autologous Blood Transfusion (ABT) on Concentrations of Antibiotics used for Surgical Prophylaxis

BackgroundABT is widely employed during surgical procedures involving high blood loss, such as liver transplantation and open heart surgery. While ABT mitigates the need for allogeneic blood transfusions, an unintended consequence may be removal of drugs, including antimicrobials. Herein, we determined the ex vivo loss of antimicrobials utilized for surgical prophylaxis through an ABT system.MethodsExperiments were conducted in duplicate to simulate processing of ABT blood during surgery. Packed red blood cells and fresh frozen plasma (300ml) were acquired from banked blood and inoculated to achieve clinically-relevant plasma concentrations of vancomycin (VAN), the piperacillin (PIP) component of piperacillin/tazobactam, and the ampicillin (AMP) component of ampicillin/sulbactam. Inoculated blood was processed through a Cell Saver® Elite™ ABT system to fill a 125mL Latham bowl and washed with 500mL of normal saline. Processed fluid was directed to a reinfusion or waste bag; additional blood samples were collected from each. Drug concentrations were measured in all samples. The amount of VAN, PIP, and AMP infused through the Cell Saver (initial), and resulting in the reinfusion and waste bags was calculated.ResultsA range of 193-265mL of combined blood containing drug were processed in each experiment through the ABT system. Initial average plasma concentrations were 61, 107, and 172 mg/L for VAN, PIP, and AMP, respectively. When corrected for volume and hematocrit, plasma concentrations translated to a mean ± SD of 3 ± 1% of VAN in the reinfusion bag and 93 ± 2% in the waste bag. For PIP, plasma concentrations translated to 2 ± 1% of PIP in the reinfusion bag and 84 ± 13% in waste, while 2 ± 1% and 120 ± 5% of AMP was found in the reinfusion and waste bags, respectively. Unaccounted drug (0-14%) was considered sequestered in the device.ConclusionThese ex vivo assessments of antibiotic removal during ABT are the first to demonstrate significant loss of antibiotics (>95%) when processed through the ABT system. Further studies measuring impact of ABT on drug concentrations in patients undergoing surgery are warranted.Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)bioMérieux (Research Grant or Support, Other Financial or Material Support, Speaker Honorarium)Melinta (Research Grant or Support)Merck & Co., Inc. (Research Grant or Support)Paratek (Speaker’s Bureau)Summit (Other Financial or Material Support, Research funding (clinical trials))

604. Factors Associated with Adverse Drug Reactions Leading to Discontinuation of Vancomycin in Outpatient Parenteral Antimicrobial Therapy

BackgroundOver 250,000 patients receive outpatient parenteral antimicrobial therapy (OPAT) in the United States each year. Vancomycin is commonly used in OPAT but has a high rate of discontinuations due to adverse drug reactions (ADRs). Being able to predict the occurrence of these ADRs and assess their impact could improve the overall quality of OPAT services when utilizing vancomycin.MethodsThis was a retrospective chart review of all adult University of Utah Health (UUH) patients who received vancomycin OPAT and had planned follow-up with UUH infectious disease (ID) providers between October 25, 2018 and July 31, 2019. Patients were excluded if they were less than 18 years of age, pregnant, did not have planned follow up with UUH ID physicians, or were on any form of renal replacement therapy. The primary outcome assessed was discontinuation of vancomycin due to ADR, as documented by the ID provider. Type of ADR leading to discontinuation and 30-day unplanned readmission were also assessed.ResultsOne hundred fifty-eight patients met inclusion criteria (n=158). The mean age of patients was 55 years with a median Charlson comorbidity score of 3. Most patients utilized a non-UUH infusion service (116, 73% vs 42, 27%) and utilized vancomycin as their sole antibiotic (83, 53%). The majority of patients were being treated for orthopedic infections (78, 49%). Twenty-eight patients discontinued vancomycin OPAT due to an ADR (18%). The most common ADR leading to discontinuation was acute kidney injury (10, 36%). Variables associated with ADRs leading to discontinuation included utilization of UUH home infusion services (54% vs 21%, P < 0.001) and initial vancomycin plasma concentrations obtained less than 7 days after discharge (92% vs 71%, P < 0.001). The overall 30 day readmission rate was 10% and the rate among patients who experienced an ADR leading to discontinuation was higher than those who did not (25% vs 8%, P < 0.001).ConclusionThe overall rate of discontinuation of vancomycin OPAT due to ADR in the UUH population is similar to what has been described in previous literature. The higher rate of unplanned readmission in the population of patients who experienced ADRs warrants further study. The results of this study will be utilized for future quality improvement interventions at our institution.DisclosuresRussell J. Benefield, PharmD, Merck and Co (Grant/Research Support)Paratek Pharmaceuticals (Grant/Research Support)Rempex Pharmaceuticals (Grant/Research Support)