Clinical application of voriconazole in pediatric patients: a systematic review.

The purpose of this study was to review the literature on the clinical use of voriconazole (VRC) in pediatric patients. MEDLINE, Embase, PubMed, Web of Science, and Cochrane Library were searched from January 1, 2000, to August 15, 2023 for relevant clinical studies on VRC use in pediatric patients. Data were collected based on inclusion and exclusion criteria, and a systematic review was performed on recent research related to the use of VRC in pediatric patients. This systematic review included a total of 35 observational studies among which there were 16 studies investigating factors influencing VRC plasma trough concentrations (Ctrough) in pediatric patients, 14 studies exploring VRC maintenance doses required to achieve target range of Ctrough, and 11 studies focusing on population pharmacokinetic (PPK) research of VRC in pediatric patients. Our study found that the Ctrough of VRC were influenced by both genetic and non-genetic factors. The optimal dosing of VRC was correlated with age in pediatric patients, and younger children usually required higher VRC doses to achieve target Ctrough compared to older children. Establishing a PPK model for VRC can assist in achieving more precise individualized dosing in children.

The dosing regimen for 17-hydroxyprogesterone caproate was suboptimal: lessons for future pharmacotherapy for pregnant women.

BACKGROUND: Makena (17-hydroxyprogesterone caproate) was approved by the United States Food and Drug Administration for the prevention of recurrent spontaneous preterm birth in 2011 under the accelerated approval pathway, but fundamental pharmacokinetic or pharmacodynamic (Phase 1 and Phase 2) studies were not performed. At the time, there were no dose-response or concentration-response data. The therapeutic concentration was not known. The lack of such data brings into question the dosing regimen for 17-hydroxyprogesterone caproate and if it was optimized. OBJECTIVE: The purpose of this study was to evaluate the dosing regimen for 17-hydroxyprogesterone by analyzing 3 data sets in which the 17-hydroxyprogesterone caproate pharmacology was evaluated, namely the Maternal-Fetal Medicine Omega 3 study, the Obstetric-Fetal Pharmacology Research Units study, and the Obstetrical-Fetal Pharmacology Research Centers study. If an inappropriate dosing regimen could be identified, such information could inform future studies of pharmacotherapy in pregnancy. STUDY DESIGN: Data from the Omega 3 study were used to determine if plasma concentration was related to spontaneous preterm birth risk and if a threshold concentration could be identified. Data from the Obstetric-Fetal Pharmacology Research Units study were used to determine the half-life of 17-hydroxyprogesterone caproate and to develop a model to simulate drug concentrations with various dosing regimens. Data from the Obstetrical-Fetal Pharmacology Research Centers study were used to determine the relationship between dose and safety outcomes. RESULTS: Analysis of the Omega 3 data set indicated that the risk for spontaneous preterm birth decreased as the log concentration of 17-hydroxyprogesterone caproate increased (odds ratio, 0.04; 95% confidence interval, 0.00-0.90). A steady state concentration of >9 ng/mL (equivalent to >8 ng/mL at 25-28 weeks) was associated with the lowest risk for spontaneous preterm birth (hazard ratio, 0.52; 95% confidence interval, 0.27-0.98; P=.04); this concentration was not achieved in 25% of subjects who received the 250 mg weekly dose. In the Obstetrical-Fetal Pharmacology Research Units study, the adjusted half-life (median and interquartile range) of 17-hydroxyprogesterone caproate was 14.0 (11.5-17.2) days. Simulations indicated that with the 250 mg weekly dose, >5 weekly injections were required to reach the 9 ng/mL target; however, those with the shortest half-life (corresponding to higher clearance), never reached the targeted 9 ng/mL concentration. In 75% of subjects, a loading dose of 500 mg weekly for 2 weeks followed by 250 mg weekly achieved and maintained the 9 ng/mL concentration within 2 weeks but in those 25% with the shortest half-life, concentrations exceeded the 9 ng/mL target for only 3 weeks. In the Obstetrical-Fetal Pharmacology Research Centers study, all 65 subjects who received a weekly dose of 500 mg exceeded the 9 ng/mL steady state. CONCLUSION: The dosing regimen for 17-hydroxyprogesterone caproate was inadequate. There is a significant inverse relationship between drug concentration and spontaneous preterm birth. The risk was lowest when the concentration exceeded 9 ng/mL, but 25% of women who received the 250 mg weekly dose never reached or maintained this concentration. The drug's long half-life necessitates a loading dose to achieve therapeutic concentrations rapidly. The omission of basic pharmacologic studies to determine the proper dosing may have compromised the effectiveness of 17-hydroxyprogesterone caproate. Future pharmacotherapy trials in pregnancy must first complete fundamental pharmacology studies.

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

BACKGROUND: 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. OBJECTIVE: Evaluate the initial itraconazole serum trough concentrations after the administration of oral capsule of itraconazole for the treatment of CPA. METHODS: The measurement was performed at least 7-days after initiation of therapy. The standard treatment at our institution was a 200 mg capsule every 12 h. We defined that an adequate serum trough concentration of itraconazole during treatment was 1-4 mg/L. RESULTS: This study recruited 28 patients. The median value was 0.30 mg/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 ≤ 0.8 mg/L. CONCLUSION: 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 ≤ 0.8 mg/L, and the patient presents with clinical deterioration. Larger studies are needed to evaluate the adequate concentrations recommended for CPA.

Voriconazole-Induced Hepatotoxicity in a Patient with Pulmonary Aspergillosis: A Case Report.

Voriconazole is the therapy of choice for aspergillosis. However, hepatotoxicity is the most common reason for the discontinuation of voriconazole. In contrast, posaconazole is well tolerated, with a low incidence of hepatotoxicity. In most cases, hepatotoxicity is associated with high voriconazole trough concentration influenced mainly by cytochrome P450 (CYP) 2C19 gene polymorphism. Compared with normal metabolizers, intermediate and poor metabolizers generally have higher voriconazole trough concentrations with an increased risk of hepatotoxicity. Here, we describe changes in hepatotoxicity throughout azole therapy in a patient with pulmonary aspergillosis (PA). Nevertheless, the patient with the normal metabolism genotype of CYP2C19 developed severe hepatotoxicity caused by voriconazole but tolerated posaconazole well, with a lack of direct cross-hepatotoxicity between the both. Interestingly, the patient had a high risk of hepatotoxicity at a low voriconazole trough concentration. Fortunately, elevated liver enzymes declined to the baselines with posaconazole treatment.

Ustekinumab Tissue and Serum Levels in Patients With Crohn's Disease Are Closely Correlated Though Not Consistently Associated With Objective Response After Induction.

BACKGROUND: Ustekinumab (UST), which targets p40/interleukin (IL)-23 and IL-12, is an effective treatment for Crohn's disease (CD). Therapeutic drug monitoring may optimize UST posology. The aim of this study was to investigate UST and IL-23 serum and tissue concentrations in relation to mucosal inflammation and treatment response at an early time point. METHODS: CD patients starting UST between December 2016 and November 2018 were prospectively enrolled. Endoscopies were performed at baseline and week 16. UST and IL-23 serum and tissue concentrations were measured at week 16. Clinical and biochemical response were defined as decline of ≥3 points in Harvey-Bradshaw Index and reduction of ≥50% in fecal calprotectin levels. Endoscopic response was defined as a ≥50% decline in Simple Endoscopic Score or a decline of ≥1 points in Rutgeerts score. Histological remission was defined as Global Histologic Disease Activity Score ≤4. RESULTS: Of 56 included patients, 17 (30%) of 56 showed clinical response, 16 (30%) of 53 showed biochemical response, and 20 (36%) of 56 showed endoscopic response. UST, but not IL-23, concentration in biopsies was correlated to levels in corresponding sera (P < .0001). No correlation was found between UST tissue levels and treatment response. Patients achieving biochemical response showed significantly higher UST serum levels (3.12 µg/mL vs 1.41 µg/mL; P = .01). Tissue IL-23-to-UST ratio correlated with mucosal inflammation (P = .01). CONCLUSIONS: This is the first study to demonstrate a correlation between serum and tissue UST levels. While tissue IL-23-to-UST ratio correlated with mucosal inflammation, UST serum levels were more indicative for biochemical response. The role of UST levels for therapeutic drug monitoring in inflammatory bowel disease needs further research.

Ustekinumab (UST) serum levels correlate with UST tissue levels in patients with Crohn's disease. Tissue interleukin-23-to-UST ratio correlates with histological inflammation (Global Histologic Disease Activity Score). Serum UST levels correlate with biochemical response (reduction of ≥50% in fecal calprotectin levels).

Safety of linezolid in patients with decreased renal function and trough monitoring: a systematic review and meta-analysis.

BACKGROUND: Linezolid causes hematological toxicity, mostly thrombocytopenia, which leads to treatment discontinuation and failure. Recent studies revealed that during linezolid therapy, the incidence of treatment-related hematological toxicity is significantly higher in patients with decreased renal function (DRF) than in those with normal renal function. Linezolid monitoring is necessary due to the high frequency of hematological toxicity in patients with DRF and the relationship between blood concentration and safety. We performed a systematic review and meta-analysis to evaluate the safety correlation between DRF and trough monitoring. METHODS: Articles published before June 24, 2022, on MEDLINE, Web of Sciences, Cochrane Register of Controlled Trials, and ClinicalTrials.gov were systematically analyzed. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel method and the variable effects model. RESULTS: The incidence of hematological toxicity was significantly higher in patients with DRF than in those without DRF (OR = 2.37; p < 0.001). Subgroup analysis, performed according to hematotoxicity classification, including thrombocytopenia, anemia, and pancytopenia, revealed a significantly higher incidence of thrombocytopenia (OR = 2.45; p < 0.001) and anemia (OR = 2.31; p = 0.006) in patients with DRF than in those without; pancytopenia (OR = 1.41; p = 0.80) incidences were not significantly higher. Based on a systematic review, linezolid trough concentrations > 6-7 µg/mL may be associated with an increased incidence of thrombocytopenia. However, no confidential threshold values for the development of thrombocytopenia were found in the area under the concentration curve values for children or adults. CONCLUSION: We observed a high frequency of hematological toxicity during linezolid therapy in patients with DRF. To ensure safety, linezolid trough concentrations should be ≤6-7 µg/mL.

Voriconazole therapeutic drug monitoring and hepatotoxicity in critically ill patients: A nationwide multi-centre retrospective study.

OBJECTIVES: To characterize trough concentrations (Cmin) of voriconazole and associated hepatotoxicity, and to determine predictors of hepatotoxicity and identify high-risk groups in critically ill patients. METHODS: This was a nationwide, multi-centre, retrospective study. Cmin and hepatotoxicity were studied from 2015 to 2020 in 363 critically ill patients who received voriconazole treatment. Logistic regression and classification and regression tree (CART) models were used to identify high-risk patients. RESULTS: Large interindividual variability was observed in initial voriconazole Cmin and concentrations ranged from 0.1 mg/L to 18.72 mg/L. Voriconazole-related grade ≥2 hepatotoxicity developed in 101 patients, including 48 patients with grade ≥3 hepatotoxicity. The median time to hepatotoxicity was 3 days (range 1-24 days), and 83.2% of cases of hepatotoxicity occurred within 7 days of voriconazole initiation. Voriconazole Cmin was significantly associated with hepatotoxicity. The CART model showed that significant predictors of grade ≥2 hepatotoxicity were Cmin >3.42 mg/L, concomitant use of trimethoprim-sulfamethoxazole or tigecycline, and septic shock. The model predicted that the incidence of grade ≥2 hepatotoxicity among these high-risk patients was 48.3-63.4%. Significant predictors of grade ≥3 hepatotoxicity were Cmin >6.87 mg/L, concomitant use of at least three hepatotoxic drugs, and septic shock; the predictive incidence among these high-risk patients was 22.7-36.8%. CONCLUSION: Higher voriconazole Cmin, septic shock and concomitant use of hepatotoxic drugs were the strongest predictors of hepatotoxicity. Plasma concentrations of voriconazole should be monitored early (as soon as steady state is achieved) to avoid hepatotoxicity.

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

To 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.

Predictors of Voriconazole Trough Concentrations in Patients with Child-Pugh Class C Cirrhosis: A Prospective Study.

This prospective observational study aimed to clinically describe voriconazole administrations and trough concentrations in patients with Child-Pugh class C and to investigate the variability of trough concentration. A total of 144 voriconazole trough concentrations from 43 Child-Pugh class C patients were analyzed. The majority of patients (62.8%) received adjustments. The repeated measured trough concentration was higher than the first and final ones generally (median, 4.33 vs. 2.99, 3.90 mg/L). Eight patients with ideal initial concentrations later got supratherapeutic with no adjusted daily dose, implying accumulation. There was a significant difference in concentrations among the six groups by daily dose (p = 0.006). The bivariate correlation analysis showed that sex, CYP2C19 genotyping, daily dose, prothrombin time activity, international normalized ratio, platelet, and Model for end-stage liver disease score were significant factors for concentration. Subsequently, the first four factors mentioned above entered into a stepwise multiple linear regression model (variance inflation factor <5), implying that CYP2C19 testing makes sense for precision medicine of Child-Pugh class C cirrhosis patients. The equation fits well and explains the 34.8% variety of concentrations (R2 = 0.348). In conclusion, it needs more cautious administration clinically due to no recommendation for Child-Pugh class C patients in the medication label. The adjustment of the administration regimen should be mainly based on the results of repeated therapeutic drug monitoring.

High infliximab trough concentrations are associated with sustained histologic remission in inflammatory bowel disease: a prospective cohort study.

BACKGROUND: The threshold concentration of infliximab during maintenance therapy has not been well-defined in relation to histologic remission. The aim of the study is to dentify the maintenance-phase infliximab concentration associated with histologic remission in inflammatory bowel disease patients (IBD). METHODS: A prospective cohort study was carried out in 104 IBD patients seen at a tertiary care centre in London, Canada. Infliximab trough concentrations were collected during the maintenance phase of treatment and compared between participants with and without evidence of histologic remission. Participants were additionally evaluated for sustained histologic remission, and relapse to active disease. RESULTS: Participants in histologic remission attained higher mean concentrations of infliximab during the maintenance phase (10.34 ± 0.69 µg/ml) compared to those with persistent disease activity (6.23 ± 0.67 µg/ml, p-value < 0.0001). Additionally, during the maintenance phase, sustained histologic remission was also associated with a higher mean concentration of infliximab (10.81 ± 5.46 µg/ml) compared to those who relapsed to active disease (5.68 ± 3.70, p < 0.001). Overall, participants with a mean infliximab trough concentration greater than 8ug/ml were more likely to have histologic remission (area under the receiver operating characteristic curve, AUROC = 0.72, 95%CI = 0.65-0.84, p < 0.0001) and sustained histologic remission (AUC = 0.77, 95%CI = 0.63-0.91, p = 0.002). CONCLUSION: Maintenance-phase infliximab trough concentrations greater than 8 µg/ml, which is higher than the currently recommended target concentration, are highly associated with histologic remission and sustained histologic remission.

Influence of donor and recipient CYP3A5 genotype on tacrolimus trough concentrations in the early stage after liver transplantation and its clinical significance / 中国临床药理学与治疗学

AIM: To analyze the influence of donor and recipient CYP3A5 genotype on tacrolimus trough concentrations in the early stage after liver transplantation and its clinical significance under therapeutic drug monitoring (TDM) strategy retrospectively. METHODS: A total of 125 patients undergoing liver transplantation in Shanghai General Hospital from January 2015 to March 2019 were involved in this study. Clinical pharmacology parameters and liver function indexes from 1 to 28 days after operation, the occurrence of new onset diabetes mellitus (NODM) was collected. Donor and recipient cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5) gene rs776746 locus were genotyped by RT-PCR technology.RESULTS: Median trough concentration (Ct

Meropenem serum concentrations in intensive care patients: a retrospective analysis.

OBJECTIVES: To determine whether currently used meropenem dosages in our hospital provide adequate serum concentrations. METHODS: Trough blood samples taken during the first meropenem concentration monitoring were included. For the evaluation of achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target, MIC of the pathogens defined by the European Committee on Antimicrobial Susceptibility testing was selected. RESULTS: Eighty three patients were enrolled. A large variability in meropenem trough serum concentrations was observed (median 34.3 mg/L, range < 1.0-146.1 mg/L). The lowest PK/PD target for susceptible pathogens (100% T > MIC) was achieved in 100% of patients on dialysis and continuous renal replacement therapy (CRRT) and in 91% non-RRT patients. For pathogens with intermediate susceptibility, 100% T > MIC was attained in all patients on CRRT and 96% on dialysis, only 74% non-RRT patients achieved this PK/PD target. Patients on RRT were more likely to achieve the highest PK/PD target 100% T > 5 × MIC, P < 0.05. Higher proportion of patients on RRT would also require meropenem dose reduction if upper limit 100% T > 10 × MIC was chosen, P < 0.05. CONCLUSIONS: Administration of a standard meropenem dose to critically ill patients leads to a large concentration variability. Thus, a personalised dosing regimen is crucial for the achievement of adequate meropenem exposure.

Cytotoxicity Evaluation of Chloroquine and Hydroxychloroquine in Multiple Cell Lines and Tissues by Dynamic Imaging System and Physiologically Based Pharmacokinetic Model.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been challenged in treating COVID-19 patients and still under debate due to the uncertainty regarding the effectiveness and safety, and there is still lack of the systematic study on the toxicity of these two drugs. To further uncover the toxicity profile of CQ and HCQ in different tissues, we evaluated the cytotoxicity of them in eight cell lines and further adopted the physiologically based pharmacokinetic models to predict the tissue risk, respectively. Retina, myocardium, lung, liver, kidney, vascular endothelium, and intestinal epithelium originated cells were included in the toxicity evaluation of CQ and HCQ, respectively. The proliferation pattern was monitored in 0-72 h by IncuCyte S3. CC50 and the ratio of tissue trough concentrations to CC50 (RTTCC) were brought into predicted toxicity profiles. Compared to CQ, HCQ was found to be less toxic in six cell types except Hep3B and Vero cells. In addition, RTTCC was significantly higher in CQ treatment group compared to HCQ group, which indicates relative safety of HCQ. To further simulate the situation of the COVID-19 patients who suffered the dyspnea and hypoxemia, we also tested the cytotoxicity upon hypoxia and normoxia (1, 5 vs. 21% O2). It was found that the cytotoxicity of CQ was more sensitive to hypoxia compared with that of HCQ, particularly in liver originated cells. Both CQ and HCQ showed cytotoxicity in time-dependent manner which indicates the necessity of short period administration clinically.

The impact of vancomycin trough concentrations on outcomes in non-deep seated infections: a retrospective cohort study.

BACKGROUND: Guidelines recommending vancomycin trough concentrations > 10 mg/L in non-deep seated infections are based on expert opinion. The objective of this study was to evaluate patients with non-deep seated infections treated with short-course vancomycin to determine whether there were differences in outcomes with trough concentrations of ≤10 mg/L (low) versus > 10 mg/L (high). METHODS: A retrospective cohort study of patients hospitalized between March 10, 2010 and December 31, 2015 who received ≤14 days of vancomycin to treat a non-deep seated infection and had at least one steady state trough concentration was completed. Patient data for the low versus high trough cohorts were compared using appropriate statistical tests and binary logistic regression was used to identify factors associated with clinical outcome. RESULTS: Of 2098 patients screened, 103 (5%) met inclusion criteria. Baseline characteristics between cohorts were not different. Clinical cure was not different between the low (42/48 [88%]) and high trough (48/55 [87%]) cohorts (p > 0.99) and vancomycin trough concentration was not associated with clinical outcome (p = 0.973). More patients in the high trough group had dosing changes (7/48 [15%] vs. 22/55 [40%], p = 0.0046), with approximately three times more dose adjustments per patient (0.17 vs. 0.55, p = 0.0193). No signal for increased vancomycin resistance associated with vancomycin troughs was identified. CONCLUSIONS: No difference in clinical or microbiological outcomes based on vancomycin trough concentrations were observed in patients with non-deep seated infections treated with vancomycin for ≤14 days. Targeting higher vancomycin trough concentrations of > 10 mg/L may be associated with increased workload with no corresponding benefit in clinical or microbiological outcomes in these patients.

Efficacy of Vancomycin on Gram-Positive Bacterial Infection in Elderly Critical Patients and Risk Factors Associated With Nephrotoxicity.

BACKGROUND: Vancomycin is widely used for infections caused by gram-positive bacteria, but little attention has been paid to vancomycin in the treatment of critically ill patients aged ≥80 years. The aim of the current study was to investigate the efficacy of vancomycin and risk factors associated with nephrotoxicity of vancomycin in elderly critically ill patients. METHODS: A retrospective study was performed in a 14-bed medical-surgical geriatric ICU between January 2007 and June 2014. The patients (aged ≥80 years) were included if they received ≥4 doses of vancomycin and the therapy duration was ≥ 2 hours. RESULTS: The clinical efficacy was 74.0% (37/50). The 28-day mortality was 26.0% (13/50). Of the patients, 24% (12/50) had nephrotoxicity during vancomycin treatment period. The clinical efficacy was 60%, 86.7%, 58.3%, and 33.3%, and the 28-day mortality rate was 20%, 23.3%, 33.3%, and 33.3%, respectively, when the trough concentrations were ≤10 µg/mL, 10-15 µg/mL, 15-20 µg/mL, and ≥20 µg/mL. The multivariate logistic regression analysis showed that an Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥25 points, vancomycin trough concentrations ≥15 µg/mL, and the combined use of diuretics (furosemide ≥40 mg/d) were independent risk factors leading to nephrotoxicity. CONCLUSION: We did not find that higher vancomycin trough concentrations lead to better clinical outcomes in elderly critically ill patients. Increased vancomycin trough concentrations, high APACHE II scores, and the combined use of diuretics may increase the risks of nephrotoxicity in elderly critically ill patients.

Establishment of an AUC0-24 Threshold for Nephrotoxicity Is a Step towards Individualized Vancomycin Dosing for Methicillin-Resistant Staphylococcus aureus Bacteremia.

Unlike vancomycin trough concentrations, data on the utility of vancomycin pharmacokinetic (PK) parameters, namely, the area under the concentration-time curve from 0 to 24 h (AUC0-24), in predicting acute kidney injury (AKI) are limited. Our aim was to investigate this relationship in patients receiving vancomycin therapy for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B). A single-center retrospective observational cohort study involving 127 consecutive MRSA-B patients was conducted to examine the incidence of AKI (defined as serum creatinine of ≥0.5 mg/liter and a 50% increase from baseline) and vancomycin exposure parameters associated with nephrotoxicity. Bayesian estimation was used to predict individual vancomycin AUC0-24 All patients received vancomycin monotherapy for a minimum of 14 days following the diagnosis of MRSA-B. AKI was observed in 15.7% of patients (20/127). Clinical characteristics were similar between patients with and without AKI. At steady state, higher vancomycin trough concentrations were associated with AKI (17.2 mg/liter versus 13.1 mg/liter; P = 0.003). A vancomycin AUC0-24 threshold for AKI of >563 mg · h/liter was detected by classification and regression tree (CART) analysis; patients with exposures above this threshold were significantly more likely to experience AKI than patients with lower vancomycin exposures (40% [8/20] versus 11.2% [12/107]; P = 0.002). This parameter remained an independent predictor of AKI on multivariate logistic regression (odds ratio [OR], 5.07; 95% confidence interval [CI], 1.57 to 16.29; P = 0.006) and was a better predictor of nephrotoxicity than vancomycin trough concentrations. Overall, AKI is associated with higher vancomycin exposure as measured by AUC0-24 These results suggest that individualized patient dosing may be possible with dose modifications directed toward established pharmacodynamic targets while balancing AKI risks.

Pharmacokinetic Dashboard-Recommended Dosing Is Different than Standard of Care Dosing in Infliximab-Treated Pediatric IBD Patients.

Standard of care (SOC; combination of 5-10 mg/kg and an interval every 6-8 weeks) dosing of infliximab (IFX) is associated with significant loss of response. Dashboards using covariates that influence IFX pharmacokinetics (PK) may be a more precise way of optimizing anti-TNF dosing. We tested a prototype dashboard to compare forecasted dosing regimens with actual administered regimens and SOC. Fifty IBD patients completing IFX induction were monitored during maintenance (weeks 14-54). Clinical and laboratory data were collected at each infusion; serum was analyzed for IFX concentrations and anti-drug antibodies (ADA) at weeks 14 and 54 (Prometheus Labs, San Diego). Dosing was blinded to PK data. Dashboard-based assessments were conducted on de-identified clinical, laboratory, and PK data. Bayesian algorithms were used to forecast individualized troughs and determine optimal dosing to maintain target trough concentrations (3 µg/mL). Dashboard forecasted dosing post-week 14 was compared to actual administered dose and frequency and SOC. Using week 14 clinical data only, the dashboard recommended either a dose or an interval change (<0.5 mg/kg or <1 week difference) in 43/50 patients; only 44% recommended to have SOC dosing. When IFX14 concentration and ADA status were added to clinical data, dose and/or interval changes based on actual dosing were recommended in 48/50 (96%) patients; SOC dosing was recommended in only 11/50 (22%). Dashboard recommended SOC IFX dosing in a minority of patients. Dashboards will be an important tool to individualize IFX dosing to improve treatment durability.

Cost-effectiveness of drug monitoring of anti-TNF therapy in inflammatory bowel disease and rheumatoid arthritis: a systematic review.

BACKGROUND: Therapeutic drug monitoring (TDM) of anti-TNF is increasingly used to manage inflammatory bowel diseases (IBD) and rheumatoid arthritis (RA). The cost-effectiveness of this strategy is debated. METHODS: All studies comparing the cost-effectiveness of a TDM-based strategy and an empirical dose management of anti-TNF in IBD or RA were screened. Studies were identified through the MEDLINE electronic database (up to July 2016), and annual international meeting abstracts were also manually reviewed. RESULTS: Seven studies were included: two randomized controlled trials (RCTs) enrolling 332 patients [247 Crohn's disease (CD) and 85 ulcerative colitis (UC)] and five modeling approaches. Four studies included only CD patients, one included both CD and UC patients, and two included only RA patients. Three studies compared the cost-effectiveness of the two strategies in patients with secondary infliximab (IFX) failure (dose-escalation strategy), one in patients in remission on optimized IFX (de-escalation strategy), one in patients starting adalimumab, and two in patients with clinical response to maintenance anti-TNF therapy. The two RCTs demonstrated that a TDM strategy led to major cost savings, ranging from 28 to 34 %. The three modeling approaches with regard to CD patients demonstrated cost savings ranging from $5396 over a 1-year period to €13,130 per patient at 5 years of follow-up. A TDM strategy also led to major cost savings in the two modeling approaches in RA patients. CONCLUSIONS: Available evidence indicates that a TDM strategy leads to major cost savings related to anti-TNF therapy in both IBD and RA patients, with no negative impact on efficacy.

The relationship between trough concentrations of vancomycin and its clinical effect / 中华急诊医学杂志

Objective To compare the clinical efficacy of different trough concentrations of vancomycin in patients.Methods A retrospective study in patients having at least one trough concentration of vancomycin for enrollment between January 2009 and December 2013 was carried out.The eligibility patients were divided into 3 groups according to the level of trough concentrations namely group A (＜ 10 mg/L),Group B (10 ～ 15 mg/L),and Group C (＞ 15 mg/L).The clinical efficacy,clearance of pathogens and in-hospital mortality were analyzed with the help of SPSS Statistics 17.0.The comparison of dosing days,length of hospital stay and time consumed from initial dosing to the appearance of recovery signs of survivors among the 3 groups.Results There were no significant difference among 3 groups in terms of clinical efficacy (55.6％ vs.33.3％ vs.51.7％),clearance of pathogens (38.9％ vs.25％ vs.24.1％) and in-hospital mortality (44.4％ vs.25％ vs.27.6％).After adjusting by age,the in-hospital mortality decreased along with the trough concentrations vancomycin.Along with increase in the trough concentrations vancomycin,the dosing day (14.90 ± 6.44 vs.18.75 ± 7.23 vs.17.93 ± 9.42) and length of hospitalization [(33.70 ± 18.17) vs.(79 ±45.53) vs.(66.20 ±52.48)] increased,and time required from dosageinitial dosing to the appearance of recovery signs of survivors among the 3 groups [(4.82 ± 2.62) vs.(3.75 ± 0.50) vs.(4.07 ± 3.20)] shortened.Conclusions Improving the trough concentrations of vancomycin could not increase clinical efficacy rate or bacterial clearance rate,but could lower in-hospital mortality.However,it might enhance the financial burden on patients as well.