Vancomycin Serum Trough Research Articles

Predicting vancomycin trough serum concentration in augmented renal clearance patients through an artificial neural network model

PurposeArtificial neural network (ANN) model has been developed in prediction of serum drug concentration. The aim of this study was verifying the accuracy of ANN model in predicting vancomycin trough serum concentration in ARC adult patients. MethodsA total of 162 ARC patients (258 observations) who received vancomycin treatment (500–2000 ​mg) at the First Affiliated Hospital of China Medical University between Jan 2017 and Nov 2020 were included. The performance and accuracy of the ANN model was evaluated by mean absolute deviation (MAD), mean absolute percent error (MAPE), mean square error (MSE), and root mean squared error (RMSE). In addition, the vancomycin calculator and multivariable linear regressions were compared with the ANN model in predicting vancomycin concentration. ResultsFrom results of linear regression analyses, dosage, dosage interval, age, creatinine clearance, sex, weight, total bilirubin (T-Bil), haemoglobin (HGB) and total protein (TP) were used as input variables to develop an ANN model for predicting vancomycin concentration in ARC patients. The MAPE, MSE, RMSE, MAD and R2 were 14.81%, 2.47%, 0.44%, 1.40% and 0.88%, respectively.The ANN model might be an useful tool to predict vancomycin concentration and help modify the dosing regimen accurately and in a timely manner to improve the clinical efficacy in ARC patients. In the future, ANN model could be developed to predict serum concentration and modify dosing regimens for more types of therapeutic drugs and patients with more complex diseases.

Relationship between Vancomycin Trough Serum Concentrations and Clinical Outcomes in Children: a Systematic Review and Meta-Analysis.

ABSTRACTTo systematically evaluate the relationships between vancomycin trough serum concentrations and clinical outcomes in children using meta-analysis. Several databases, including PubMed, Elsevier, Web of Science, EMBASE, Medline, clinicaltrials.gov, the Cochrane Library, and three Chinese databases (Wanfang Data, China National Knowledge Infrastructure, and SINOMED), were comprehensively searched to obtain research articles on vancomycin use in children from inception through December 2021. All studies were screened and evaluated using the Cochrane systematic review method. Then, the feature information was extracted for meta-analysis. The evaluated results included clinical efficacy, vancomycin-associated nephrotoxicity, hepatotoxicity, ototoxicity, mortality, and microbial clearance. A total of 35 studies involving 4820 children were included in the analysis. The meta-analysis showed that compared with children with vancomycin trough concentrations <10 μg/mL, those with vancomycin trough concentrations ≥10 μg/mL had a higher clinical efficacy rate [OR: 2.23, 95% CI: 1.29 to 3.84, P = 0.004] and higher incidences of nephrotoxicity [OR: 2.76, 95% CI: 1.51 to 5.07, P = 0.001], ototoxicity [OR: 1.87, 95% CI: 1.08 to 3.23, P = 0.02] and microbial clearance [OR: 2.36, 95% CI: 1.53 to 3.64, P = 0.0001]. All-cause mortality [OR: 1.07, 95% CI: 0.45 to 2.53, P = 0.88] and hepatotoxicity [OR: 0.84, 95% CI: 0.46 to 1.53, P = 0.57] were similar between the two groups. Subgroup analysis showed that compared with children with vancomycin trough concentrations of 10 to 15 μg/mL, those with vancomycin trough concentrations >15 μg/mL had a higher incidence of nephrotoxicity [OR: 2.64, 95% CI: 1.28 to 5.43, P = 0.008], but there was no significant difference in clinical efficacy [OR: 0.85, 95% CI: 0.30 to 2.44, P = 0.76]. A vancomycin trough concentration of 10 to 15 μg/mL can improve clinical efficacy in children. Additionally, avoidance of trough concentrations >15 μg/mL can reduce the incidence of adverse reactions.

Factors influencing the vancomycin trough level in patients admitted at King Fahad Specialist Hospital, Qassim, KSA.

Although vancomycin is an effective antibiotic against methicillin-resistant Staphylococcus aureus, its usage is often associated with nephrotoxicity which necessitates optimization of the vancomycin dose to be both precise and appropriate. To achieve this, the importance of therapeutic drug monitoring arises, and serum trough vancomycin concentrations are the most accurate and practical method for monitoring vancomycin effectiveness and even risk of nephrotoxicity. This study evaluated the influences on the trough levels of vancomycin given to admitted patients at King Fahad Specialist Hospital (KFSH). This cross-sectional hospital-based study has been conducted at KFSH among 197 patients, of which 53.3% were male and 46.7% were female. They received intravenous vancomycin at intermittent dose of 30 mg/kg/day with no clinical or laboratory renal impairment. The serum was drawn trough concentrations within 15 to 45 minutes before the fourth vancomycin dose. One-way ANOVA test showed a significantly higher trough level of vancomycin among females, patients older than 50 years, and CCU and CSICU admitted patients (p-value < 0.05). Spearman correlation test also showed significant correlation with the serum vancomycin trough levels, site of infection (Rho=0.406, p=0.009), age (Rho=0.341, p=0.044) and patients' admission (Rho=0.321, p=0.041). Even at body adjusted dosing, vancomycin serum trough levels varied among patients with significant variations of age, gender, site of infection and type of admission, especially CCU and CSICU, which raises the concept of dose individualization, age and gender considerations especially among critically ill patients.

Risk Scoring System for Vancomycin-Associated Acute Kidney Injury.

Vancomycin-associated acute kidney injury (AKI) remains a major challenge for patients and clinicians. This study aimed to construct a risk scoring system for vancomycin-associated AKI. We retrospectively reviewed medical records of patients who underwent therapeutic drug monitoring for vancomycin from June 2018 to July 2019. We selected possible risk factors for AKI by univariate and multivariable logistic regression analyses and developed a scoring system for vancomycin-associated AKI. Machine learning methods were utilized to predict risk factors for the occurrence of AKI. The incidence of vancomycin-associated AKI was 31.7% among 104 patients included in this study. A bodyweight ≤60 kg (two points), a Charlson comorbidity index ≥3 (two points), a vancomycin trough serum level >15 μg/ml (one point), and concomitant use of ≥6 nephrotoxic agents (two points) were included to construct a risk scoring system based on the coefficient from the logistic regression model. The area under the receiver operating characteristic curve (AUROC) (mean, 95% confidence interval (CI)) across 10 random iterations using five-fold cross-validated multivariate logistic regression, elastic net, random forest, support vector machine (SVM)-linear kernel, and SVM-radial kernel models was 0.735 (0.638–0.833), 0.737 (0.638–0.835), 0.721 (0.610–0.833), 0.739 (0.648–0.829), and 0.733 (0.640–0.826), respectively. For total scores of 0–1, 2–3, 4–5, 6–7, the risk of vancomycin-associated AKI was 5, 25, 45, and 65%, respectively. Our scoring system can be applied to clinical settings in which several nephrotoxic agents are used along with vancomycin therapy.

Evaluation of association between parameters related to penetration into cerebrospinal fluid and the microbiological efficacy of vancomycin in patients with bacterial meningitis

Vancomycin (VM) is used as empirical therapy for bacterial meningitis (BM). We investigated the relationship of the microbiological efficacy of VM for BM with VM minimum inhibitory concentration (MICVM), serum VM trough concentration (VMser) and cerebrospinal fluid (CSF) protein (P)/serum albumin (SA) ratio, which may reflect the extent of blood–brain barrier (BBB) disruption. Twelve BM patients were enrolled and VM was microbiologically effective in seven (58.3%). VMser, MICVM, and CSF-P/SA ratio were not associated with the microbiological efficacy of VM. The microbiological efficacy of VM was significantly associated with CSF-P/SA ratio multiplied by VMser relative to the MICVM (η = 0.61, p = 0.04). These results indicate that the parameter combining VMser, MICVM, and the extent of BBB disruption could be associated with the microbiological efficacy of VM in BM patients.

#50: Vancomycin Doses and Trough Concentrations in Pediatric Patients

Abstract Background Vancomycin serum trough concentrations are monitored to reduce nephrotoxicity and optimize therapeutic efficacy. Vancomycin pharmacokinetics and trough levels used in pediatric patients are extrapolated from the adult population. The pediatric dosing strategies are empirical and there is limited evidence to suggest that these doses result in the recommended steady-state trough concentrations. The objective of the study was to determine the association between vancomycin dosing regimens and trough concentrations levels of 10 to 20 μg/mL in pediatric patients with complicated infections. Methods Retrospective cohort, 505 trough vancomycin serum concentrations of patients of 1 month to 18 years from hospital wards and the Intensive Care Unit of the Instituto Nacional de Salud del Niño San Borja during December 2015 to April 2019. It included only the first vancomycin trough level measured 30 minutes before the fourth doses and serum trough concentrations of 10 to 20 μg/mL were considered as therapeutic levels. A multinomial logistic regression model to estimate the relative risk ratio (RRR) with a 95% confidence interval was used, the comparator group was therapeutic vancomycin levels and it was adjusted by glomerular filtration rate, age group, hospital room, dose interval, and weight. Results Five hundred and five vancomycin dosages were analyzed. Infants and children were 43.12% and 39.22%, respectively, 45.17% were women. 56.77% had a high glomerular filtration rate and only 28.02% of the patients obtained therapeutic trough levels of vancomycin. The RRR of having sub-therapeutic levels in patients with low glomerular filtration rates compared with normal filtration rates was 0.31 (P = 0.049) and the RRR of having sub-therapeutic levels in patients from 2 to 12 years compared with patients under 2 years old was 2.38 (P = 0.007). There was no difference in having therapeutic levels using doses equal or greater than 60 mg/kg/day vs. less than 40 mg/kg/day comparing sub-therapeutic levels (P = 0.655) and supratherapeutic levels (P = 0.264). Conclusions The empirical vancomycin regimens used in pediatric patients did not reach the recommended therapeutic trough levels of 10 to 20 μg/mL. Patients of 2 to 12 years and low glomerular filtration rates were associated to have sub-therapeutic trough levels.

A higher dose of vancomycin is needed in critically ill patients with augmented renal clearance.

BackgroundUsing standard vancomycin dosage in critically ill patients might lead to therapy failure and worse patient outcomes, augmented renal clearance (ARC) may be the leading risk factor. In this study, we comprehensively investigated the pharmacokinetics-pharmacodynamics (PK-PD) of vancomycin in critically ill patients with ARC, hoping to explore the precise and accurate dose adjustment method for vancomycin.MethodsAll critically ill patients tested for steady-state trough vancomycin serum concentrations during the recent 6 years in a tertiary level hospital were collected retrospectively and divided into ARC and non-ARC groups, respectively, according to creatinine clearance (CLcr). Serum vancomycin concentrations were measured by the fluorescence polarization immunoassay method. PK-PD parameters of vancomycin were recorded or calculated. The desired daily dose successful in achieving the lower target trough levels (10 mg/L) of vancomycin were investigated correspondingly.ResultsA total of 280 vancomycin concentrations were eligible for analysis. The ARC group (n=139) contained more male patients (64.7%) with average age and CLcr of 40 years old (P<0.05) and 180.8 mL/min (P<0.001), respectively. Those patients exhibited higher clearance (CL) and lower trough serum concentrations than the non-ARC patients under comparable daily doses of vancomycin. All the ICU patients demonstrated lower AUC24h values than the target level of 400 µg·h/mL, and this value showed a lower trend in the ARC group than the non-ARC group (232.9 vs. 316.2 µg·h/mL). Subtherapeutic trough concentrations of vancomycin (<10.0 mg/L) were observed in 77.7% and 68.8% of the ARC and non-ARC patients (P<0.05). The proportion of patients with a trough concentration of 10–15 and 15–20 mg/L was 17.9% and 4.3%, respectively, in the ARC group and 24.8% and 2.8%, respectively, in the non-ARC group., a daily dose of 46.0 and 35.5 mg/kg of vancomycin is needed, respectively, in the ARC and non-ARC group to achieve a target trough concentration of 10 mg/L.ConclusionsA higher dose of vancomycin is needed in critically ill patients, especially those with ARC, and appropriate TDM-guided dose adjustment should be considered to achieve the targeted therapeutic range and to provide dosing guidance for this: patient population.

Should the Vancomycin Minimal Inhibitory Concentration be used as an Infant Critical Care Regular Criteria?

Vancomycin is the first-line antibiotic used for the treatment of staphylococcal infections. Because of its narrow therapeutic window and the pharmacokinetics variability, vancomycin trough serum concentration should be monitored. However, due to the increased cases of staphylococcus' commensal species infections and the case of vancomycin resistance, the minimal inhibitory concentration should be considered on antimicrobial therapy. This article aimed to show the importance of the minimal inhibitory concentration to infants on vancomycin therapy as regular criteria. Three infants in the use of vancomycin, hospitalized in the same maternity hospital, and that had at least one blood culture performed during the intensive-care-unit hospitalization were included in the study. Vancomycin serum concentrations were determined by particleenhanced- turbidimetric inhibition-immunoassay. The vancomycin minimal inhibitory concentration data were interpreted by following the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). The trough serum concentration range of 10 to 20 mg.L-1 was considered therapeutic. All three patients had at least one infection by S. epidermidis, being one patient exhibit vancomycin- resistant S. epidermidis infection. All patients had stoppages in the vancomycin treatment, and the minimal inhibitory concentration was performed for only one patient. The data obtained from these patients also showed the need to perform therapeutic monitoring by using minimal inhibitory concentration values, because, although the serum concentrations were within the reference range, they are insufficient to guarantee patient therapeutic success.

Vancomycin-associated acute kidney injury in Hong Kong in 2012\u20132016

BackgroundTo study the incidence of vancomycin-associated acute kidney injury (VA-AKI) in Hong Kong and identify risk factors for VA-AKI.MethodPatients with vancomycin prescription and blood level measurement in 2012–2016 were identified using the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System. Acute kidney injury was defined using KDIGO criteria. Patients without creatinine measurements, steady-state trough vancomycin level or who had vancomycin treatment < 3 days were excluded. Results were analyzed using SPSS version 22.0. Logistic regression was used to identify the predictors for VA-AKI. Odds ratio and 95% confidence interval were estimated.ResultsOne thousand four hundred fifty patients were identified as VA-AKI from 12,758 records in Hong Kong in 2012–2016. The incidence was respectively 10.6, 10.9, 11.3, 12.2, 11.2% from 2012 to 2016. The incidence of VA-AKI was 16.3, 12.2, 11.3 and 6.2% in patients aged 1–12, 12–60, elderly aged > 60 and newborn and infants, respectively. Baseline creatinine, serum trough vancomycin level, systematic disease history including respiratory failure, hypertension, congestive heart failure, chronic renal failure, anemia and type II diabetes, and concomitant diuretics, piperacillin-tazobactam (PTZ) and meropenem prescription were significantly higher in VA-AKI patients older than 12 years. Logistic regression showed that older age group, higher baseline creatinine, serum trough vancomycin level, respiratory failure, chronic renal failure and congestive heart failure, concomitant diuretics, PTZ and meropenem prescription, and longer hospital stay were all associated with increased risk of VA-AKI.ConclusionThe incidence of VA-AKI in Hong Kong is low but shows no decline. Patients with higher baseline creatinine, multi-organ diseases and multiple drugs administration should have their vancomycin level monitored to decrease the risk of VA-AKI.

Use of Body Surface Area for Dosing of Vancomycin.

Vancomycin weight-based dosing regimens often fail to achieve therapeutic trough serum concentration in children ≤12 years of age and rigorous studies evaluating efficacy and safety of body surface area (BSA)-based dosing regimens have not been performed. We compared vancomycin trough serum concentrations in pediatric patients receiving a weight- or BSA-based dosing regimen. This was a single-center, retrospective study evaluating pediatric patients, ages 1 to 12 years, who received vancomycin from September 2012 to October 2015. Patients received a minimum of 3 consecutive doses at the same scheduled interval within a dosing regimen prior to a measured vancomycin serum trough concentration. The primary outcome was percentage of initial vancomycin trough concentrations ≥10 mg/L. The secondary outcomes were percentage of supratherapeutic, therapeutic, and subtherapeutic vancomycin serum concentration for all patients, including a subset of overweight and obese patients, and number of nephrotoxic occurrences. BSA-based dosing regimens resulted in 50% of the initial vancomycin trough concentrations ≥ 10 mg/L compared with 17% for the weight-based dosing regimens (p < 0.0001). No statistically significant differences were noted between the 2 dosing regimens for supratherapeutic, therapeutic, or subtherapeutic trough concentrations for all patients, and for the subset of overweight and obese patients. Nephrotoxic occurrences were noted in 7% of the weight-based dosing regimens compared with none in the BSA-based dosing regimens. A BSA-based vancomycin dosing regimen resulted in significantly more initial vancomycin trough concentrations ≥10 mg/L and trended towards higher initial vancomycin trough concentrations without observable nephrotoxicity.

Implementation of a two-point pharmacokinetic AUC-based vancomycin therapeutic drug monitoring approach in patients with methicillin-resistant Staphylococcus aureus bacteraemia

Limited evidence exists evaluating pharmacokinetic thresholds for vancomycin efficacy and nephrotoxicity using non-Bayesian methods. The objective of this study was to evaluate the 24-h steady-state vancomycin area under the concentration-time curve (AUC24) thresholds for efficacy and nephrotoxicity in patients with methicillin-resistant Staphylococcus aureus bacteraemia (MRSA-B) after implementing two-point pharmacokinetic therapeutic drug monitoring. A single-centre, retrospective cohort study was performed including adult patients admitted between 1 June 2016 and 1 January 2018 with MRSA-B treated with vancomycin for ≥72 h. The AUC24 was calculated using peak and trough vancomycin serum concentrations. Clinical success was defined as defervescence and blood culture sterilisation by Day 7. Nephrotoxicity was defined as an increase in serum creatinine of >0.5 mg/dL (or ≥50%) from baseline. Classification and regression tree (CART) analyses were performed to identify AUC24 thresholds for efficacy and nephrotoxicity. Forty-six patients were included in the study. Clinical success and nephrotoxicity were observed in 81.8% and 13.0%, respectively. The CART-derived vancomycin AUC24 thresholds for clinical success and nephrotoxicity were ≥297 mg·h/L and ≥710 mg·h/L, respectively. Patients with an AUC24 ≥297 mg·h/L had a >2.7-fold increase in clinical success compared with those who did not (89.5% vs. 33.3%, respectively; P = 0.01), and patients with an AUC24 ≥710 mg·h/L had a >7-fold increase in nephrotoxicity compared with those with an AUC24 <710 mg·h/L (66.7% vs. 9.3%, respectively; P = 0.04). This study supports current recommendations to target vancomycin AUC24 values of 400-600 mg·h/L when calculated using two-point pharmacokinetics, although a wider range may exist.

Clinical study of vancomycin for appropriate dosing in severe infective patients with augmented renal clearance

To explore the impact of augmented renal clearance (ARC) on vancomycin pharmacokinetic target attainment in severe infective patients, and to analyze the initial dose of vancomycin based on the measured 12-hour urinary creatinine clearance (12 h-CLCR). A retrospective observational study was conducted. The patients with severe infection, who receiving vancomycin empiric or targeted therapy, admitted to intensive care unit (ICU) of the Affiliated Drum Tower Hospital of Nanjing University Medical School from February 2013 to December 2017 were enrolled. All patients were treated with vancomycin intravenously by intermittent bolus every 6-12 hours. After four or five doses, blood samples were drawn before the next dosage for serum trough vancomycin concentration (Cmin), and target concentration was defined between 15 mg/L and 20 mg/L. The urine creatinine (UCr) was measured, and CLCR was calculated. ARC was defined as 12 h-CLCR > 130 mL×min-1×1.73 m-2. According to 12 h-CLCR before treatment, the patients were divided into ARC group and non-ARC group. The basic renal function of the patients was monitored, and the dosage of vancomycin and the dosage of vancomycin when the blood concentration reached the target were recorded. The correlations between 12 h-CLCR and the dosage of vancomycin when the blood concentration reached the target as well as the blood concentration of vancomycin were analyzed by Spearman correlation analysis. Dosage stratification analysis was carried out according to different 12 h-CLCR. The predictive value of 12 h-CLCR for vancomycin dosage when the blood concentration reached the target was evaluated by using the receiver operator characteristic curve (ROC). Data was provided from a total of 135 patients with severe infection, in which 102 patients met the inclusion criteria. The patients with vancomycin treatment duration less than 72 hours, chronic kidney disease V phase, vancomycin treatment before entering ICU and those with incomplete data were excluded. The mean 12 h-CLCR was (114.31±73.38) mL×min-1×1.73 m-2. The 12 h-CLCR in ARC group (n = 44, 43.14%) was significantly higher than that in non-ARC group (n = 58, 56.86%) (mL×min-1×1.73 m-2: 179.37±59.04 vs. 65.95±35.71, P < 0.01). Target Cmin of vancomycin was achieved in 50.98% of patients (52/102), the target rate in ARC group was significantly lower than that in non-ARC group [29.55% (13/44) vs. 67.24% (39/58), P < 0.01], and the Cmin of vancomycin in ARC group was significantly lower than that in non-ARC group (mg/L: 10.98±6.09 vs. 14.67±6.20, P < 0.01). Spearman correlation analysis showed that there was a significantly negative correlation between 12 h-CLCR and initial Cmin of vancomycin (n = 102, r = -0.436, P < 0.001), but a positive correlation was found between 12 h-CLCR and vancomycin dosage when the blood concentration reached the target (n = 52, r = 0.275, P = 0.048). The patients with ARC need higher dosage for blood concentration reaching the target than those without ARC (mg×kg-1×d-1: 42.47±13.17 vs. 31.53±14.43, P < 0.01). According to 12 h-CLCR, the patients with initial treatment reaching the target were divided into five subgroups, < 40, 40-70, 71-100, 101-130 and > 130 mL×min-1×1.73 m-2. The results showed that as 12 h-CLCR increased, the attained dosage of vancomycin was also increased correspondingly. ROC curve analysis showed that when 12 h-CLCR≥69.83 mL×min-1×1.73 m-2, the attained dose of vancomycin when the blood concentration reached the target was greater than conventional dosage of 30 mg×kg-1×d-1. Patients with ARC have low concentrations of vancomycin and often fail to achieve therapeutic target. The initial dose of vancomycin can be selected according to 12 h-CLCR, the higher the 12 h-CLCR, the more the dosage of vancomycin is. When 12 h-CLCR is greater than or equal to 69.83 mL×min-1×1.73 m-2, the dosage of vancomycin should be higher than the conventional dosage.

The relationship between serum vancomycin trough and patient age: examining the performance of a high dose regimen.

The relationship between serum vancomycin trough and patient age: examining the performance of a high dose regimen.

The ratio of pre-dialysis vancomycin trough serum concentration to minimum inhibitory concentration is associated with treatment outcomes in methicillin-resistant Staphylococcus aureus bacteremia.

BackgroundVancomycin is a standard treatment for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, and its efficacy is closely linked to the recommended serum trough concentration of 15–20 mg/L. However, it is unknown how the pre-dialysis trough serum concentration (Cpre-HD) correlates with MRSA eradication in renal failure patients undergoing intermittent hemodialysis (HD).ObjectiveTo evaluate the relationship between Cpre-HD and the treatment outcomes in this population.Materials and methodsA retrospective study was conducted to enroll renal failure patients undergoing HD who had received vancomycin treatment for MRSA bacteremia during January 2013 to June 2016. Treatment failure was defined as persistent bacteremia after ≥ 7 days of vancomycin therapy or recurrent MRSA infection within 30 days. Patient characteristics, vancomycin dosing regimen, Cpre-HD, vancomycin minimum inhibitory concentration (MIC), and subsequent culture data were reviewed. The receiver operating characteristic (ROC) curve was used to find the optimal cut-off point of Cpre-HD.Results42 patients were enrolled and 64% had treatment failure. Although there were no significant differences in demographics or Cpre-HD between the two groups, Cpre-HD/MIC was significantly higher in the success group than that in the failure group (22.80±10.90 vs. 14.94±6.11, p = 0.019). The area under the ROC curve was 0.74, while the sensitivity, specificity, positive predictive value, and negative predictive value were 67%, 78%, 62.5%, and 81%, respectively, at the optimal Cpre-HD/MIC of ≧ 18.6.ConclusionsCpre-HD/MIC was associated with vancomycin treatment outcome in MRSA bacteremia, and targeting to achieve a Cpre-HD/MIC of ≧ 18.6 may improve treatment outcomes in renal failure patients who are on intermittent HD.

Creation and Validation of a Pediatric Vancomycin Nomogram for a Goal Trough of 10–15 mg/L at a Quaternary Care Children’s Hospital

Abstract Background Recent data suggest a serum vancomycin (vanc) trough (VT) of 11mg/L correlates with an AUC/MIC24 &amp;gt; 400 which has shown to be the optimal concentration to eradicate MRSA infection and improve mortality. There are currently limited published recommendations on how to achieve such a VT in children. This study validates a vancomycin nomogram used to achieve a VT of 10–15 mg/L in pediatric inpatients (pts) at a quaternary care children’s hospital. Methods This is an 18 month (mo) prospective analysis beginning in September 2015. Included pts were ≥2 mo of age and had ≥2 consecutive VT. Pts receiving renal replacement therapy or those with a serum creatinine (Scr) of ≥0.5 mg/dL from a prior admission or within 48 hours of vanc initiation were excluded. The starting dose (SD) of vanc was determined by age and creatinine clearance (CrCl) (Tables 1 and 2). CrCl was measured by Bedside Schwartz equation for patients ≤18 years old (yo) and Cockcroft-Gault equation for patients &amp;gt;18 yo. The maximum CrCl was set to 120 ml/minute. Patients who were on vanc and experienced a Scr increase of ≥0.5 mg/dL were considered to have acute kidney injury (AKI). The study had a 6 mo evaluation period which led to a revised version (RVN) on March 2016. The primary endpoint (PE) was achievement of 10–15 mg/L by the Second VT for patients with the First trough outside of this range, using our RVN (Table 3). Results Overall, a total of 276 patients received vanc, 17 and 29 patients were dosed according to the initial and RVN, respectively. For young children (Table 1), the SD for patients with a CrCL ≥90 ml/minute was therapeutic, sub-, and supra-therapeutic in 43.75%, 47.5% and 8.75%, respectively. For older children (Table 2), the SD for patients with a CrCl ≥100 ml/minute was therapeutic, sub-, and supra-therapeutic in 41.1%, 35.7% and 23.2%, respectively. The initial VN was successful 12/17 (70.6%) in achieving the PE. Success in achieving the PE after the RVN was 26/29 (89.7%). In the RVN group, the most common initial troughs were 5–7 mg/L (33.3%), followed by &amp;gt;18 mg/L (27.6%). The mean VT using the RVN was 13.7 mg/L. The overall AKI incidence throughout the study was 3.2% (9/276) and 0% using the RVN. Conclusion Our RVN led to a Second VT within a target range of 10–15 mg/L for 89.7% of patients, allowing for more accurate and safer use of vancomycin in our institution. Disclosures All authors: No reported disclosures.

The Whole Price of Vancomycin: Toxicities, Troughs, and Time.

Vancomycin is a glycopeptide antibiotic that is active against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. Nephrotoxicity, which is usually reversible, is the most serious common adverse effect of vancomycin. Vancomycin-associated nephrotoxicity prolongs hospital stays, imposes a need for additional antibiotics and, in rare circumstances, dialysis treatment, and increases medical costs and mortality. Risk factors for nephrotoxicity include the dose and duration of vancomycin treatment, serum trough concentration, patient characteristics, and concomitant receipt of nephrotoxins. Contemporary guidelines recommend targeting vancomycin trough concentrations of ≥10 mg/L to prevent resistance and trough concentrations of 15–20 mg/L to optimize outcomes. There is significant correlation between vancomycin trough serum concentrations and the incidence of vancomycin-associated nephrotoxicity; however, evidence of an association between trough concentrations and efficacy is less convincing. Routine monitoring of serum vancomycin concentrations consumes time and limited healthcare resources and may not be cost effective. The use of alternative antibacterial agents that do not require monitoring would free up pharmacy resources. This time could then be devoted to initiatives such as pharmacist-led antibiotic stewardship programs that are known to reduce antibiotic use and promote improved patient outcomes.

Vancomycin AUC/MIC and Corresponding Troughs in a Pediatric Population.

Adult guidelines suggest an area under the curve/minimum inhibitory concentration (AUC/MIC) > 400 corresponds to a vancomycin trough serum concentration of 15 to 20 mg/L for methicillin-resistant Staphylococcus aureus infections, but obtaining these troughs in children are difficult. The primary objective of this study was to assess the likelihood that 15 mg/kg of vancomycin every 6 hours in a child achieves an AUC/MIC > 400. This retrospective chart review included pediatric patients >2 months to <18 years with a positive S aureus blood culture and documented MIC who received at least two doses of vancomycin with corresponding trough. Patients were divided into two groups: group 1 initially receiving ≥15 mg/kg every 6 hours, and group 2 initially receiving any other dosing ranges or intervals. AUCs were calculated four times using three pharmacokinetic methods. A total of 36 patients with 99 vancomycin trough serum concentrations were assessed. Baseline characteristics were similar between groups. For troughs in group 1 (n = 55), the probability of achieving an AUC/MIC > 400 ranged from 16.4% to 90.9% with a median trough concentration of 11.4 mg/L, while in group 2 (n = 44) the probability of achieving AUC/MIC > 400 ranged from 15.9% to 54.5% with mean trough concentration of 9.2 mg/L. The AUC/MICs were not similar between the different pharmacokinetic methods used; however, a trapezoidal equation (Method A) yielded the highest correlation coefficient (r2 = 0.59). When dosing every 6 hours, an AUC/MIC of 400 correlated to a trough serum concentration of 11 mg/L. The probability of achieving an AUC/MIC > 400 using only a trough serum concentration and an MIC with patients receiving 15 mg/kg every 6 hours is variable based on the method used to calculate the AUC. An AUC/MIC of 400 in children correlated to a trough concentration of 11 mg/L using a trapezoidal Method to calculate AUC.

Relationship between vancomycin dosage and serum trough vancomycin concentrations in pediatric patients with cystic fibrosis.

The association between vancomycin dosage and serum trough vancomycin concentrations in pediatric patients with cystic fibrosis (CF) was examined. A retrospective chart review was conducted for pediatric patients with CF who received vancomycin between 2006 and 2012 at a children's hospital. Admission-level data, including vancomycin dosage regimens and corresponding serum trough vancomycin concentrations, were collected. Student's t tests, analysis of variance, and Pearson's correlation coefficients were used to test for associations between vancomycin dosage and trough concentrations. Data from 40 hospital admissions (31 patients) were analyzed. Initial vancomycin dosages ranged from 45 to 100 mg/kg/day (mean ± S.D. 62.9 ± 14.5 mg/kg/day), and the mean ± S.D. serum trough vancomycin concentration was 9.7 ± 5.1 mg/L. Patients received a mean ± S.D. of 1.5 ± 1.1 dosage adjustments. Final dosage regimens ranged from 50 to 120 mg/kg/day (mean ± S.D., 78.8 ± 16.0 mg/kg/day), and the mean ± S.D. trough vancomycin concentration was 13.6 ± 4.4 mg/L. There was no significant correlation between the initial (r = -0.272, p = 0.090) or final (r = 0.024, p = 0.882) vancomycin dosage and corresponding trough vancomycin concentration. A significant correlation was found between dosage and trough vancomycin concentration in patients age 12 years or older for the initial (r = 0.545, p = 0.003) and final (r = 0.425, p = 0.024) dosages, with no significant correlations found in patients younger than 12 years. A study of hospital admissions involving pediatric patients with CF revealed no significant correlation, when all admissions were considered, between the initial or final vancomycin dosage regimen and the corresponding serum trough vancomycin concentration. Both correlations were significant for the subgroup of admissions representing patients who were at least 12 years old.

Vancomycin Therapeutic Targets and Nephrotoxicity in Critically Ill Children With Cancer.

To obtain pharmacokinetic and pharmacodynamic data for vancomycin in a cohort of critically ill pediatric oncology patients, we analyzed 256 measurements of vancomycin concentrations in 94 patients. Variables were tested as possible risk factors for vancomycin-related nephrotoxicity or death for 28 days. We found the following: mean vancomycin trough serum concentration, 15.6 ± 12.4 μg/mL; mean vancomycin clearance, 0.16 ± 0.098 L/h/kg; and mean vancomycin distribution volume, 1.04 ± 0.11 L/kg. Only 13.6% of serum trough level measurements were between 15 and 20 μg/mL. The trough levels showed a strong correlation with the AUC (area under the curve of serum concentrations vs. time over 24 h to the minimum inhibitory concentration ratio), with a 94% positive predictive value for AUC/MIC ≥ 400, but only for MIC=1. The doses that are currently used (60 mg/kg/d) attained the therapeutic target (AUC/MIC ≥ 400) in only 56% of measurements, considering MIC=1. A serum trough level of ≥ 20 μg/mL was an independent risk for nephrotoxicity (P = 0.0008; odds ratio = 17.83). Vancomycin-related nephrotoxicity was a predictor of death for up to 28 days (P = 0.003, odds ratio = 7.68). Currently administered doses of vancomycin do not reach the therapeutic target for critical cancer patients, particularly if staphylococci isolates have a MIC>1.

Correlation of a Vancomycin Pharmacokinetic Model and Trough Serum Concentrations in Pediatric Patients

Vancomycin trough concentrations specific to pediatric patients have yet to be validated that achieve an area under the curve (AUC) over 24 hours to minimum inhibitory concentration (MIC) ratio ≥400. The primary objective of this study was to validate a pharmacokinetic model in a pediatric hospital and determine the correlation between a calculated AUC/MIC ratio and measured trough vancomycin concentration. A retrospective evaluation of patients aged 3 months to 18 years prescribed vancomycin at a pediatric hospital between January 2012 and June 2013. The correlation between patient-specific AUC/MIC and measured vancomycin trough concentration was assessed. Forty pediatric patients with 40 vancomycin trough concentrations and documented Staphylococcus aureus cultures were included in the study. Median age was 8.5 (interquartile range, 2-14.3) years, median weight 28.7 (range, 14-50.2) kg, and mean baseline serum creatinine 0.51 ± 0.3 mg/dL. The mean daily dose of vancomycin prescribed was 58 ± 13.8 mg/kg/d. The mean vancomycin trough concentration was 11 ± 5.5 mcg/mL, and the mean AUC/MIC was 534 ± 373. No correlation was found between trough concentration and AUC/MIC (r = 0.082, p = 0.07). This study validates the clinical applicability of a pharmacokinetic model for calculating vancomycin clearance to determine patient-specific AUC over 24 hours in pediatrics. Trough concentrations associated with proposed therapeutic AUC/MIC ratios were lower than reported in the adult population. Further research is needed to determine if AUC/MIC, trough concentration, or both is best for monitoring therapeutic efficacy of vancomycin in pediatrics.