Initial Trough Concentrations Research Articles

Enhancing voriconazole therapy in liver dysfunction: exploring administration schemes and predictive factors for trough concentration and efficacy.

Introduction: The application of voriconazole in patients with liver dysfunction lacks pharmacokinetic data. In previous study, we proposed to develop voriconazole dosing regimens for these patients according to their total bilirubin, but the regimens are based on Monte Carlo simulation and has not been further verified in clinical practice. Besides, there are few reported factors that significantly affect the efficacy of voriconazole. Methods: We collected the information of patients with liver dysfunction hospitalized in our hospital from January 2018 to May 2022 retrospectively, including their baseline information and laboratory data. We mainly evaluated the efficacy of voriconazole and the target attainment of voriconazole trough concentration. Results: A total of 157 patients with liver dysfunction were included, from whom 145 initial and 139 final voriconazole trough concentrations were measured. 60.5% (95/157) of patients experienced the adjustment of dose or frequency. The initial voriconazole trough concentrations were significantly higher than the final (mean, 4.47 versus 3.90μg/mL, p = 0.0297). Furthermore, daily dose, direct bilirubin, lymphocyte counts and percentage, platelet, blood urea nitrogen and creatinine seven covariates were identified as the factors significantly affect the voriconazole trough concentration. Binary logistic regression analysis revealed that the lymphocyte percentage significantly affected the efficacy of voriconazole (OR 1.138, 95% CI 1.016-1.273), which was further validated by the receiver operating characteristic curve. Conclusion: The significant variation in voriconazole trough concentrations observed in patients with liver dysfunction necessitates caution when prescribing this drug. Clinicians should consider the identified factors, particularly lymphocyte percentage, when dosing voriconazole in this population.

Itraconazole Serum Trough Concentrations Using Oral Capsules for the Treatment of Chronic Pulmonary Aspergillosis: What is the Target?

In regions where there is only itraconazole capsule as a therapeutic option for treatment of chronic pulmonary aspergillosis (CPA), measuring the serum concentrations becomes even more important for therapeutic success. Evaluate the initial itraconazole serum trough concentrations after the administration of oral capsule of itraconazole for the treatment of CPA. The measurement was performed at least 7-days after initiation of therapy. The standard treatment at our institution was a 200mg capsule every 12h. We defined that an adequate serum trough concentration of itraconazole during treatment was 1-4mg/L. This study recruited 28 patients. The median value was 0.30mg/L (IQR 0.01-0.70). Only 11% (n = 3) had adequate serum concentrations based on guideline recommendation. All patients with clinical deterioration had itraconazole serum levels ≤ 0.8mg/L. The initial serum concentrations of itraconazole after capsule formulation administration were low. Increasing the dose should be considered when the itraconazole concentration is low, especially if it is ≤ 0.8mg/L, and the patient presents with clinical deterioration. Larger studies are needed to evaluate the adequate concentrations recommended for CPA.

Optimization of the vancomycin administration regimen by clinical pharmacists based on a population pharmacokinetics model: a prospective interventional study

In vancomycin treatment, the rates of correct blood sampling and initial trough concentrations within the target range are very low. Studies of interventions by clinical pharmacists based on population pharmacokinetics (PPK) models are limited. This study aimed to evaluate the intervention effect of clinical pharmacist-mediated optimization of the vancomycin administration regimen based on a PPK model. Retrospectively enrolled patients constituted the control group, and prospectively enrolled patients constituted the intervention group. The vancomycin administration regimen, trough concentration, pharmacokinetic parameters, and clinical outcomes of the two groups were compared. The control and intervention groups comprised 236 and 138 patients, respectively. Compared with those in the control group, the therapeutic drug monitoring (TDM) and correct TDM sampling time rates in the intervention group were significantly higher (76.92% vs. 43.59%; 63.9% vs. 39.0%, both p < 0.001). The rates of an initial trough concentration within 10–20 mg/L and an adjusted regimen were also significantly higher in the intervention group (55.80% vs. 30.51%, 71.95% vs. 39.18%, both p < 0.001). The rate of an area under the curve (AUC) within 400–650 mg·h/L was higher in the intervention group than in the control group (52.7% vs. 36.6%, p < 0.001). The eradication rates of Gram-positive bacteria were 91.4% in the intervention group and 81.3% in the control group (p = 0.049). Eight patients developed acute kidney injury (AKI) in the control group; however, no AKI occurred in the intervention group (p = 0.029). Intervention by clinical pharmacists can increase the rate of correct sampling time. Using the PPK model combined with Bayesian estimation, clinical pharmacists can greatly increase the trough concentration and AUCs within the target range, especially for adjusted regimens. Higher PK/PD target rates resulted in better Gram-positive bacterial eradication and reduced renal toxicity of vancomycin.

Initial trough concentration may be beneficial in preventing linezolid-induced thrombocytopenia

We assessed whether prospective therapeutic drug monitoring to optimise the therapeutic range could prevent linezolid-induced thrombocytopenia. This prospective interventional study was conducted from September 2017 to October 2020 among 37 adult patients receiving linezolid. Patients were administered one of the following two initial dosages: 600 mg twice or once daily for patients with a creatinine clearance rate of ≥50 or <50 mL/min, respectively. Linezolid dosage adjustment was performed on days 3–5 based on the trough concentration. The serum linezolid levels in 22 and 15 patients were within and above the therapeutic range (2–7 µg/mL), respectively. The incidence of thrombocytopenia was significantly lower among patients whose linezolid levels were within the therapeutic range (4.5%;1/22) than in those whose levels were above the therapeutic range (80%; 12/15). It is important to maintain the linezolid level within the therapeutic range at the first therapeutic drug monitoring to prevent thrombocytopenia.

Association between CYP3A4, CYP3A5, and ABCB1 Genotype, Tacrolimus Concentrations, and Outcomes Among Allogeneic Hematopoietic Stem Cell Transplantation Patients

Association between CYP3A4, CYP3A5, and ABCB1 Genotype, Tacrolimus Concentrations, and Outcomes Among Allogeneic Hematopoietic Stem Cell Transplantation Patients

A Regression Model to Predict Augmented Renal Clearance in Critically Ill Obstetric Patients and Effects on Vancomycin Treatment.

Background: Augmented renal clearance (ARC) risk factors and effects on vancomycin (VCM) of obstetric patients were possibly different from other populations based on pathophysiological characteristics. Our study was to establish a regression model for prediction of ARC and analyze the effects of ARC on VCM treatment in critically ill obstetric patients. Methods: We retrospectively included 427 patients, grouped into ARC and non-ARC patients. Logistic regression analysis was used to analyze the factors related to ARC. Receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of the model for ARC. Patients who received VCM therapy were collected. The published VCM population pharmacokinetic (PPK) model was used to calculate pharmacokinetic parameters. A linear regression analysis was made between the predicted and measured concentrations. Results: Of the 427 patients, ARC was present in 201 patients (47.1%). The independent risk factors of ARC were heavier, greater gestational age, higher albumin level, fewer caesarean section, severe preeclampsia and vasoactive drug; more infection, hypertriglyceridemia and acute pancreatitis. We established the above nine-variable prediction regression model and calculated the predicted probability. ROC curve showed that the predicted probability of combined weight, albumin and gestational age had better sensitivity (70.0%) and specificity (89.8%) as well as the maximal area under the curve (AUC, AUC = 0.863). 41 cases received VCM; 21 cases (51.2%) had ARC. The initial trough concentration in ARC patients was lower than in non-ARC patients (7.9 ± 3.2 mg/L vs 9.5 ± 3.3 mg/L; p = 0.033). Comparing the predicted trough concentration of two published VCM PPK models with the measured trough concentration, correlation coefficients (r) were all more than 0.8 in the ARC group and non-ARC group. AUC was significantly decreased in the ARC group (p = 0.003; p = 0.013), and clearance (CL) increased in the ARC group (p < 0.001; p = 0.008) when compared with the non-ARC group. Conclusion: ARC is a common state in critically ill obstetric patients. The regression model of nine variables had high predictive value for predicting ARC. The published VCM PPK models had good predictive performance for predicting trough concentrations of obstetric patients. Pharmacokinetic parameters of VCM are different in ARC obstetric patients, which results in enhanced VCM clearance and decreased trough concentration.

#28: Serum Posaconazole Concentrations Among Children, Adolescents, and Young Adults Receiving Delayed-Release Tablet And Intravenous Posaconazole

Abstract Background Posaconazole is a broad-spectrum antifungal used for prophylaxis and treatment of invasive fungal infections. There are limited data on the optimal dosing, safety, and effectiveness of the delayed-released tablets (DRT) and intravenous (IV) formulations in immunocompromised pediatric and adolescent patients. Methods A retrospective chart review was performed to study all immunocompromised patients who received DRT or IV formulations of posaconazole at our institution from January 1, 2014, to July 31, 2019, and had at least one plasma trough concentration. Plasma concentrations ≥0.7 µg /mL were considered therapeutic for prophylaxis, and ≥1.0 µg/mL for treatment. We describe our experience including dosing, plasma trough concentrations, safety, and tolerability. Results We identified 54 patients (28 males/26 females) who received DRT or IV formulations of posaconazole. The median age was 14 years (range 2–21 years). Thirty-one (57%) patients received posaconazole for treatment and 23 (43%) for prophylaxis. The most common underlying condition was hematological malignancies (66%) and 19 patients (35%) had received an allogeneic HSCT and were receiving immunosuppressive therapy. Overall, 36 (67%) patients achieved targeted initial plasma trough concentrations (median 1.3 µg/mL, IQR 0.758–1.760 µg/mL) (Figure). The median daily dose among patients &amp;lt;13 years of age who achieved the targeted initial plasma trough concentrations was 7.3 mg/kg/day (IQR 6.8–11.0) for the DRT formulation and 9.8 mg/kg/day (IQR 7.4–11.7) for the IV formulation. The median daily dose among patients ≥ 13 years of age who achieved the targeted initial plasma trough concentrations was 4.9 mg/kg/day (IQR 4.1–6.5) for the DRT formulation and 5.6 mg/kg/day (IQR 3.9–5.8) for the IV formulation. Concomitant use of H2-receptor blockers (H2RA) and/or proton pump inhibitors (PPI) medications were not associated with failure to achieve target trough levels (P = 0.96). Thirty-six patients (67%) developed transaminitis, mostly grade 1. Conclusions Our results show that DRT and IV formulations are safe and effective in immunocompromised children, adolescents, and young adults. Higher dosing per body weight of DRT and IV posaconazole may be required in patients &amp;lt;13 years of age compared with patients 13 years of age and older to achieve therapeutic plasma concentrations. It appears that neither a PPI nor an H2RA has an effect on the plasma exposure of the DRT.

Low vancomycin trough concentration in neonates and young infants.

Vancomycin (VCM) is useful for treating methicillin-resistant Staphylococcus aureus. In infants, calibrating the initial VCM dose is difficult, and many regimens have been proposed. For instance, our center uses the VCM regimen recommended for infants in the 2012-13 Nelson's Pediatric Antimicrobial Therapy. Nonetheless, our experience has shown that the initial VCM trough concentrations were frequently off target. We therefore analyzed the data on the initial VCM trough concentration in infant patients at our center. The study subjects were inborn infants born between July 2014 and June 2019 who were given VCM at earlier than day 60 in the neonatal intensive care unit. The primary outcome was the initial VCM trough concentration. The patients were divided into three groups by VCM trough concentration: <10, 10-15, and >15mg/L. We also estimated VCM trough concentration by one method using Monte Carlo simulation, based on Nelson regimen dosage. Thirty-three patients were analyzed. The number of patients with <10, 10-15, and >15mg/L was 24, 4, and 5, respectively. There was no significant difference in clinical characteristics between <10 versus 10-15 and 10-15 versus >15mg/L. The numbers of patients with <10, 10-15, and >15mg/L in the simulation were 26, 6, and 1, respectively. Most initial VCM trough concentrations were below the target. We could not find any significant clinical characteristics, which affected VCM trough concentration. Increasing the VCM dosage of the Nelson regimen with simulation should therefore be considered.

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.

Factors Associated With Voriconazole Concentration in Pediatric Patients.

Serum concentrations of voriconazole are difficult to predict, especially in pediatric patients, because of its complex pharmacokinetic characteristics. This study aimed to identify the factors associated with the concentration of voriconazole in pediatric patients. This cohort study was based on retrospective data collection and involved the administration of voriconazole to pediatric patients younger than 18 years, between January 2010 and August 2017. Electronic medical records of the patients were reviewed to collect demographic characteristics, voriconazole treatment regimen, and factors that could potentially influence voriconazole trough concentrations. A voriconazole trough serum concentration of less than 1.0 mcg/mL or greater than 5.5 mcg/mL was defined as outside the therapeutic range and was set as the outcome of this study. Among the 114 patients enrolled, 61 patients were included in the analysis. Oral administration of a maintenance dose of voriconazole and C-reactive protein (CRP) level were significantly and independently associated with a low initial trough concentration of voriconazole (<1.0 mcg/mL). Alanine aminotransferase levels were a significant factor associated with a high initial trough concentration of voriconazole (>5.5 mcg/mL) after adjusting for sex, age, weight, and serum creatinine (odds ratio 5.42; 95% confidence interval 1.34-21.97). Considering the variability of voriconazole concentrations in pediatric patients, monitoring certain parameters and considering the route of administration could help determine the therapeutic range of voriconazole and subsequently avoid unwanted effects.

Comparison of trough concentration and area under the curve of vancomycin associated with the incidence of nephrotoxicity and predictors of a high trough level

PurposeA high vancomycin trough concentration during therapy is associated with increased nephrotoxicity, and the recent guidelines for therapeutic monitoring of vancomycin recommend target of the ratio of area under the curve (AUC) to minimum inhibitory concentration. We aimed to determine vancomycin trough concentration and AUC that induce nephrotoxicity and evaluate predictive factors associated with a high serum vancomycin trough level according to the initial dosing strategy. MethodsWe conducted a retrospective cohort study in patients administered intravenous vancomycin from June 2013 to February 2017. Totally, 346 patients were included. Results38 experienced nephrotoxicity during therapy. The both trough level and AUC were significant risk factors for the occurrence of vancomycin induced-nephrotoxicity (p < 0.001, p = 0.001). The exposure–response analysis revealed that the trough level of 15 μg/mL was associated with 12.0% nephrotoxicity incidence and AUC of 600 was associated with 12.9% nephrotoxicity incidence. During the treatment, 90 patients had an initial trough concentration of ≥15 μg/mL, and 124 patients had AUC of ≥600 μg h/mL. The multiple logistic regression analysis revealed body weight (p = 0.001), serum creatinine level (p = 0.028), daily vancomycin dose (p = 0.001), and ICU (p = 0.015) were independent predictive factors for a high trough concentration. And same factors were selected for the high AUC. ConclusionThe risk factors for vancomycin induced nephrotoxicity were comparable in both trough concentration and AUC. The incidence of nephrotoxicity can be reduced by controlling vancomycin trough concentration similarly AUC and promoting antimicrobial stewardship.

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

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

A Prospective Study on the Usefulness of Initial Voriconazole Dose Adjustment Based on CYP2C19 Gene Polymorphism Analysis

Genetic polymorphism exists for CYP2C19, a dominant metabolic enzyme of voriconazole (VRCZ), and VRCZ pharmacokinetics has been shown to fluctuate according to the CYP2C19 phenotype. Although dosages for different phenotypes have been recommended in various retrospective studies, few reports have adjusted the initial VRCZ dose based on CYP2C19 phenotype determined prior to administration. In this study, we prospectively evaluated the usefulness of CYP2C19 polymorphism analysis in adjusting the initial VRCZ maintenance dose. The study enrolled 19 patients who underwent analysis of CYP2C19 polymorphism prior to VRCZ administration. Subjects were classified into 3 phenotype subgroups: extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM). The initial VRCZ maintenance doses given twice daily were proposed as follows: approximately 8, 6, and 4 mg/kg/day for EM, IM and PM, respectively, according to previous reports. In EM, the initial maintenance dose was 8.0 ± 0.5 mg/kg/day, and trough level was 6.6 ± 2.4 μg/mL. By contrast, the initial maintenance doses in IM and PM were 5.5 ± 0.7 and 4.1 ± 0.3 mg/kg/day, and the initial trough concentrations were 2.9 ± 1.2 and 2.6 ± 0.4 μg/mL, respectively. The attainment rate of target trough concentration of 1–6 μg/mL was 50% in EM, and was 100% in IM and PM. Determining the initial dose of VRCZ only by phenotype based on CYP2C19 gene polymorphism was found to be challenging. However, decreasing the initial maintenance dose in IM and PM may be important for adjusting the initial trough level to target range.

Low initial trough concentration of rituximab is associated with unsatisfactory response of first-line R-CHOP treatment in patients with follicular lymphoma with grade 1/2.

For follicular lymphoma (FL) with grade 1/2, the complete response (CR) rate of the first-line R-CHOP treatment was significantly low. In this study, we assessed the rationality of the administration of rituximab for FL patients with grade 1/2 based on concentration-response relationship analyses. Thus, we conducted a prospective pharmacokinetic (PK) study in 68 FL patients with grades 1-3 treated with R-CHOP at 21-day intervals. Plasma rituximab concentrations were quantified using ELISA and the population PK modeling was established with Phoenix® NLMETM. The first cycle trough concentration (C1-trough) of rituximab was a significant independent risk factor for achieving CR in matched-pair logistic regression analysis, rather than the concentrations in later cycles; the recommendatory minimum optimal C1-trough was 13.60 μg/mL. Patients with grade 1/2 had significantly lower C1-trough compared with grade 3 (12.21 μg/mL vs. 23.45 μg/mL, P < 0.001), only 30% patients with grade 1/2 could reach 13.60 μg/mL, compared with 91.67% in patients with grade 3, which was in accord with its unsatisfactory CR rates (43.33% vs. 76.32%). The stage indicating the tumor burden (the target) was a crucial influence factor for C1-trough, accounting for 40.70% of its variability, 70% patients with grade 1/2 were stage IV in this study, since the systemic therapy only started at the disseminated disease stage. The initial dose of 1800 mg was recommended by Monte Carlo simulation for patients with grade 1/2. In summary, low C1-trough accounted for low-grade FL's unsatisfactory CR rate, designing the first dosage of rituximab should be a very important component of individualized therapy for FL.

Initial posaconazole dosing to achieve therapeutic serum posaconazole concentrations among children, adolescents, and young adults receiving delayed-release tablet and intravenous posaconazole.

Posaconazole is a broad-spectrum antifungal used for prophylaxis and treatment of invasive fungal diseases. There are limited data on the optimal dosing, safety, and efficacy of the DRT and IV formulations in immunocompromised pediatric and adolescent patients. We describe our experience including dosing, plasma trough concentrations, safety, and tolerability. Plasma concentrations ≥.7µg/mL were considered therapeutic for prophylaxis and ≥1.0µg/mL for treatment. Fifty-four patients (median age of 16years) received DRT or IV formulations of posaconazole. Thirty-one (57%) patients received posaconazole for treatment and 23 (43%) for prophylaxis. Overall, 36 (67%) patients achieved targeted initial plasma trough concentrations (median 1.3µg/mL) (Figure1). The median daily dose among patients <13years of age who achieved the targeted initial concentrations was 7.3mg/kg/day for the DRT formulation and 9.8mg/kg/day for the IV formulation. The median daily dose among patients ≥13years of age who achieved the targeted initial concentrations was 4.9mg/kg/day for the DRT formulation and 5.6mg/kg/day for the IV formulation. Thirty-six patients (67%) developed transaminitis, mostly grade 1. Our observations show that DRT and IV formulations are safe and effective in immunocompromised children, adolescents, and young adults. Higher dosing per body weight of DRT and IV posaconazole may be required in patients <13years of age compared with patients 13years of age and older to achieve therapeutic plasma concentrations. [Figure: see text].

Vancomycin loading dose is associated with increased early clinical response without attainment of initial target trough concentration at a steady state in patients with methicillin-resistant Staphylococcus aureus infections.

Vancomycin therapeutic guidelines suggest a loading dose of 25-30mg/kg for seriously ill patients. However, high-quality data to guide the use of loading doses are lacking. We aimed to evaluate whether a loading dose (a) achieved a target trough concentration at steady state and (b) improved early clinical response. Patients with an estimated glomerular filtration rate ≥90mL/min/1.73m2 were included. A loading dose of 25mg/kg vancomycin followed by 15mg/kg twice daily was compared with traditional dosing. A Cmin sample was obtained before the fifth dose. An early clinical response 48-72hours after the start of therapy and clinical success at end of therapy (EOT) was evaluated in patients with methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative Staphylococci or Enterococcus faecium. There was no significant difference in Cmin between the regimen with and without a loading dose (median: 10.4 and 10.2µg/mL, P=.54). Proportions of patients achieving 10-20 and 15-20µg/mL were 56.9% and 5.6%, respectively, in patients with a loading dose. Although there was no significant difference in success rate at EOT between groups, a loading dose was associated with increased early clinical response for all infections (adjusted odds ratio [OR]: 4.588, 95% confidence interval [CI]: 1.373-15.330) and MRSA infections (OR: 12.065, 95% CI: 1.821-79.959). Study limitations included no Cmin measurements within 24hours and the inclusion of less critically ill patients. A loading dose of 25mg/kg followed by 15mg/kg twice daily did not achieve the optimal Cmin at steady state in patients with normal renal function. However, more early clinical responses were obtained with a loading dose compared with traditional dosing, possibly because of a prompt albeit temporary achievement of a more effective concentration.

The characteristics and impact indicator of vancomycin pharmacokinetics in cancer patients complicated with severe pneumonia

ObjectiveThis study was designed to investigate the characteristics and impact indicator of vancomycin pharmacokinetics in cancer patients complicated with severe pneumonia. MethodsFifty-seven cancer patients complicated with severe pneumonia were included in this research. Vancomycin serum trough concentrations were measured using the fluorescence polarization immunoassay (FPIA) method. The Bayesian estimator was used to calculate the pharmacokinetic parameters. ResultsThe average initial therapeutic dose of vancomycin was 15.18 ± 3.29 mg/kg (q12 h). Our study shows that vancomycin initial trough concentrations measured in cancer patients are significantly reduced (6.54 ± 3.11 mg/L; p < 0.0001) compared with the recommended standard vancomycin trough concentration (10–15 or 15–20 mg/L). Meanwhile, the clearance (CL) and volume of distribution (Vd) of vancomycin was increased significantly in cancer patients. Multivariate linear regression analysis revealed that Cys-C was the most important variable for vancomycin trough concentration (r2 = 0.439). The relationships between vancomycin trough concentrations and Cys-C were further evaluated after the 57 patients were grouped by cut-off point (1.44 mg/L) of the serum Cys- C levels before vancomycin was administered. Compared with group Early group (Cys-C>1.44 mg/L), Delayed group (Cys-C≤1.44 mg/L) had much lower trough concentrations. Meanwhile, CL and CLcr were significantly increased in Delayed group (Cys-C≤1.44 mg/L). Although the clinical outcomes were similar between two groups, the duration of vasoactive agent in Early group was considerably shorter compared with Delayed group (χ2 = 4.213; p < 0.05). ConclusionsThe serum trough concentration of vancomycin was significantly reduced in cancer patients complicated with severe pneumonia. Higher dosage regimen is needed to ensure clinical effectiveness. The Cys-C level measured prior to administration of vancomycin is suggested to be the most suitable parameter to predict whether vancomycin trough concentration is up to standard dosage. Especially for patients with baseline Cys-c less than 1.44 mg/L, it is more likely to need higher dosage algorithm.

Effect of serum concentration and concomitant drugs on vancomycin-induced acute kidney injury in haematologic patients: a single-centre retrospective study.

Appropriate use of vancomycin (VCM) is important in preventing acute kidney injury (AKI). Because of the high frequency of VCM use for febrile neutropenia and concomitant use of other nephrotoxic drugs, haematologic patients have a different nephrotoxic background compared with patients with other diseases. Therefore, it is unclear whether the risk factors of VCM-induced AKI identified in other patient groups are also applicable to haematologic patients. Herein, we performed a single-centre retrospective analysis to identify the factors associated with VCM-induced AKI in haematologic patients. We retrospectively analysed 150 haematologic patients to whom VCM was administered between April 2010 and March 2018 at Tokushima University Hospital. VCM-induced AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. Multivariate logistic regression analyses were performed to identify risk factors for VCM-induced AKI. Seventeen patients had VCM-induced AKI. Multivariate analysis revealed that the risk factors of VCM-induced AKI were an initial VCM trough concentration of > 15mg/L and concomitant use of tazobactam/piperacillin (TAZ/PIPC) and liposomal amphotericin B (L-AMB). Patients with an initial VCM trough concentration of < 10mg/L showed significantly lower efficacy in febrile neutropenia. Interestingly, concomitant L-AMB use increased the incidence of VCM-induced AKI in a VCM concentration-dependent manner, whereas concomitant TAZ/PIPC increased the incidence in a VCM concentration-independent manner. The optimal initial VCM trough concentration was 10-15mg/L in haematologic patients, considering safety and effectiveness. There were differences in the effect of VCM-induced AKI between nephrotoxic drugs.

Effect of augmented renal clearance on plasma concentration of vancomycin and treatment outcome in children with methicillin-resistant Staphylococcus aureus infection

To investigate the effect of augmented renal clearance (ARC) on plasma concentration of vancomycin, bacteriological outcome, and clinical outcome in children with methicillin-resistant Staphylococcus aureus (MRSA) infection treated by vancomycin. A retrospective analysis was performed for the clinical data of 60 critically ill children who were treated with vancomycin due to MRSA infection from January 2013 to July 2017 and underwent plasma concentration monitoring. According to estimated glomerular filtration rate, these children were divided into an ARC group with 19 children and a normal renal function group with 41 children. The two groups were compared in terms of the use of vancomycin, plasma concentration of vancomycin, and treatment outcome. The children in the ARC group had an age of 1-12 years, and the ARC group had significantly higher body weight and body surface area than the normal renal function group (P<0.05). Compared with the normal renal function group, the ARC group had a significantly lower initial trough concentration of vancomycin and a significantly lower proportion of children who achieved the effective trough concentration of vancomycin (10-20 mg/L) (P<0.05). There were no significant differences in bacteriological outcome and clinical outcome between the two groups (P>0.05), but the ARC group had significantly longer length of stay in the pediatric intensive care unit (PICU) and length of hospital stay than the normal renal function group (P<0.05). ARC can significantly reduce the trough concentration of vancomycin and prolong the length of PICU stay and the length of hospital stay in children with MRSA infection. Idividualized medication should be administered to children with ARC.

Vancomycin is commonly under-dosed in critically ill children and neonates.

AimsVancomycin is frequently used in critically ill children in whom the drug pharmacokinetics are significantly altered as a result of changes in renal clearance and volume of distribution. Therapeutic drug monitoring (TDM) is recommended to achieve vancomycin trough concentrations between 10 and 20 mg/L. In this study we reviewed vancomycin dosing, TDM and treatment outcomes in paediatric and neonatal intensive care unit patients.MethodsWe reviewed the medical records of all patients receiving intravenous vancomycin in a tertiary paediatric and neonatal intensive care unit over a 10‐month period. Demographic, vancomycin dosing, TDM and drug‐related adverse effects data were collected.ResultsIn total, 115 children received 126 courses of vancomycin and had at least 1 TDM blood sample taken at steady state. In only 38/126 (30%) courses was the target concentration (10–20 mg/L) achieved at the initial steady state trough sample. Of the 88 courses that had initial trough concentrations outside the target range, the dose was adjusted in only 49 (56%). Overall, minimum doses of 30 mg/kg/day in neonates with a corrected gestational age of <35 weeks, and 50 mg/kg/day in older children, were required to achieve target vancomycin concentrations. Vancomycin‐attributable nephrotoxicity occurred in 10/126 (8%) courses and there were no episodes of red man syndrome.ConclusionIn critically ill children, individualised dosing is needed. In the absence of Bayesian model‐based dosing, in children with normal renal function, empiric vancomycin doses of at least 30 mg/kg/day in neonates of <35 weeks corrected gestational age, and 50 mg/kg/day in older children, should be considered. Optimisation of TDM practices through the development of protocols, ideally built into electronic medical records, should be considered.